Non‐invasive measurement of retinal permeability in a diabetic rat model

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordObjective The gold standard for measuring blood‐retinal barrier permeability is the Evans blue assay. However, this technique has limitations in vivo, including non‐specific tissue binding and toxicity. This study describes a non‐toxic, high throughput and cost effective alternative technique that minimizes animal usage. Methods Sodium fluorescein fundus angiography was performed in non‐ and diabetic Brown Norway rats on days 0, 7, 14, 21 and 28. Sodium fluorescein intensity in the retinal interstitium and a main retinal vessel were measured over time. The intensity gradients were used to quantify retinal vascular permeability. Post study eyes were fixed, dissected and stained (isolectin B4) to measure required parameters for permeability quantification including: Total vessel length per retinal volume, radius and thickness. Results In the non‐diabetic cohort retinal permeability remained constant over the 28‐day study period. However, in the diabetic cohort there was a significant and progressive increase in retinal permeability from day 14 to 28 (p<0.01, p<0.001, p<0.0001). Conclusions This novel imaging methodology in combination with mathematical quantification allows retinal permeability to be non‐invasively and accurately measured at multiple time points in the same animal. In addition, this technique is a non‐toxic, rapid, sensitive and cost‐effective alternative to the Evans blue assay.Medical Research Council (MRC)National Eye Research CentreMasonic Charitable Foundatio

Impacts of household sources on air pollution at village and regional scales in India

Approximately 3 billion people worldwide cook with solid fuels, such as wood, charcoal, and agricultural residues. These fuels, also used for residential heating, are often combusted in inefficient devices, producing carbonaceous emissions. Between 2.6 and 3.8 million premature deaths occur as a result of exposure to fine particulate matter from the resulting household air pollution (Health Effects Institute, 2018a; World Health Organization, 2018). Household air pollution also contributes to ambient air pollution; the magnitude of this contribution is uncertain. Here, we simulate the distribution of the two major health-damaging outdoor air pollutants (PM2:5 and O3) using state-of-thescience emissions databases and atmospheric chemical transport models to estimate the impact of household combustion on ambient air quality in India. The present study focuses on New Delhi and the SOMAARTH Demographic, Development, and Environmental Surveillance Site (DDESS) in the Palwal District of Haryana, located about 80 km south of New Delhi. The DDESS covers an approximate population of 200 000 within 52 villages. The emissions inventory used in the present study was prepared based on a national inventory in India (Sharma et al., 2015, 2016), an updated residential sector inventory prepared at the University of Illinois, updated cookstove emissions factors from Fleming et al. (2018b), and PM2:5 speciation from cooking fires from Jayarathne et al. (2018). Simulation of regional air quality was carried out using the US Environmental Protection Agency Community Multiscale Air Quality modeling system (CMAQ) in conjunction with the Weather Research and Forecasting modeling system (WRF) to simulate the meteorological inputs for CMAQ, and the global chemical transport model GEOS-Chem to generate concentrations on the boundary of the computational domain. Comparisons between observed and simulated O3 and PM2:5 levels are carried out to assess overall airborne levels and to estimate the contribution of household cooking emissions

Negative Effect of Smoking on the Performance of the QuantiFERON TB Gold in Tube Test.

False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively. Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results. Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02). Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status

Hydrogen Sulfide Is a Novel Protector of the Retinal Glycocalyx and Endothelial Permeability Barrier

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData Availability Statement: The original contributions presented in the study are included in the article/supplementary material. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Significantly reduced levels of the anti-inflammatory gaseous transmitter hydrogen sulfide (H2S) are observed in diabetic patients and correlate with microvascular dysfunction. H2S may protect the microvasculature by preventing loss of the endothelial glycocalyx. We tested the hypothesis that H2S could prevent or treat retinal microvascular endothelial dysfunction in diabetes. Bovine retinal endothelial cells (BRECs) were exposed to normal (NG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) ± the slow-release H2S donor NaGYY4137 in vitro. Glycocalyx coverage (stained with WGA-FITC) and calcein-labeled monocyte adherence were measured. In vivo, fundus fluorescein angiography (FFA) was performed in normal and streptozotocin-induced (STZ) diabetic rats. Animals received intraocular injection of NaGYY4137 (1 μM) or the mitochondrial-targeted H2S donor AP39 (100 nM) simultaneously with STZ (prevention) or on day 6 after STZ (treatment), and the ratio of interstitial to vascular fluorescence was used to estimate apparent permeability. NaGYY4137 prevented HG-induced loss of BREC glycocalyx, increased monocyte binding to BRECs (p ≤ 0.001), and increased overall glycocalyx coverage (p ≤ 0.001). In rats, the STZ-induced increase in apparent retinal vascular permeability (p ≤ 0.01) was significantly prevented by pre-treatment with NaGYY4137 and AP39 (p < 0.05) and stabilized by their post-STZ administration. NaGYY4137 also reduced the number of acellular capillaries (collagen IV + /IB4-) in the diabetic retina in both groups (p ≤ 0.05). We conclude that NaGYY4137 and AP39 protected the retinal glycocalyx and endothelial permeability barrier from diabetes-associated loss of integrity and reduced the progression of diabetic retinopathy (DR). Hydrogen sulfide donors that target the glycocalyx may therefore be a therapeutic candidate for DR.Medical Research Council (MRC)British Heart FoundationRoyal SocietyBrian Ridge ScholarshipNational Eye Research CentreMasonic Charitable Foundatio

Building Online Platforms for Peer Support Groups as a Persuasive Behavioural Change Technique

Online peer group approach is inherently a persuasive technique as it is centered on peer pressure and surveillance. They are persuasive social net- works equipped with tools and facilities that enable behaviour change. This paper presents the case for domain-specific persuasive social networks and provides insights on problematic and addictive behaviour change. A 4-month study was conducted in an addiction rehab centre in the UK, followed by 2-month study in an online peer group system. The study adopted qualitative methods to under- stand the broad parameters of peer groups including the sessions' environment, norms, interaction styles occurring between groups' members and how such in- teractions are governed. The qualitative techniques used were (1) observations, (2) form and document analysis, and (3) semi-structured interviews. The findings concern governing such groups in addition to the roles to be enabled and tasks to be performed. The Honeycomb framework was revisited to comment on its build- ing blocks with the purpose of highlighting points to consider when building do- main-specific social networks for such domain, i.e. online peer groups to combat addictive behaviour

Review of cigarette smoking and tuberculosis in China: intervention is needed for smoking cessation among tuberculosis patients

<p>Abstract</p> <p>Background</p> <p>As a risk factor of tuberculosis (TB), tobacco smoking has increased substantially over the past three decades, especially in developing countries. However, the association between smoking and TB, which has been shown to exist in different studies with different ethnic background, has not yet received sufficient attention in terms of TB care standards and research in China.</p> <p>Methods</p> <p>An observational study was conducted in two rural areas of China. A total of 613 TB patients frequency matched with 1226 controls were interviewed by using a structured questionnaire. The associations between cigarette smoking and risk of TB were estimated by computing odds ratios (ORs) and 95% confidence intervals (95% CIs) from logistic regression model. Patients' smoking behavior and patterns of smoking cessation were followed after TB diagnosis. Multivariate Cox proportional hazards model was applied to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) in analyzing the risk factors for smoking relapse. The Kaplan-Meier estimate was computed to plot the ability of smoking-free after cessation among different groups, with the Log-rank test being used to compare the difference.</p> <p>Results</p> <p>The proportion of cigarette smoking was 54.6% in TB cases, which was significantly higher than that in controls (45.1%) with adjusted OR of 1.93(95% CI: 1.51–2.48). Though 54.9% smokers stopped smoking after being diagnosed with TB, more than 18% relapsed during the follow-up period. The proportion of relapse was higher within 6–9 months (6%) and 12–15 months (11%) after cessation. In the Cox regression estimates adjusted for age and gender, compared with those highly educated and previously treated patients, the hazard ratios of smoking relapse were 3.48(95% CI: 1.28–9.47) for less educated (< 6 years) and 4.30(95% CI: 1.01–18.30) for newly treated patients, respectively.</p> <p>Conclusion</p> <p>Cigarette smoking is associated with TB in the Chinese. Interventions of smoking cessation are recommended to be included in the current TB control practice.</p

The Effects of Previous Error and Success in Alzheimer’s Disease and Mild Cognitive Impairment

This work investigated in Alzheimer’s disease dementia (AD), whether the probability of making an error on a task (or a correct response) was influenced by the outcome of the previous trials. We used the antisaccade task (AST) as a model task given the emerging consensus that it provides a promising sensitive and early biological test of cognitive impairment in AD. It can be employed equally well in healthy young and old adults, and in clinical populations. This study examined eye-movements in a sample of 202 participants (42 with dementia due to AD; 65 with mild cognitive impairment (MCI); 95 control participants). The findings revealed an overall increase in the frequency of AST errors in AD and MCI compared to the control group, as predicted. The errors on the current trial increased in proportion to the number of consecutive errors on the previous trials. Interestingly, the probability of errors was reduced on the trials that followed a previously corrected error, compared to the trials where the error remained uncorrected, revealing a level of adaptive control in participants with MCI or AD dementia. There was an earlier peak in the AST distribution of the saccadic reaction times for the inhibitory errors in comparison to the correct saccades. These findings revealed that the inhibitory errors of the past have a negative effect on the future performance of healthy adults as well as people with a neurodegenerative cognitive impairment

Combination of p53AIP1 and survivin expression is a powerful prognostic marker in non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>p53AIP1 is a potential mediator of apoptosis depending on p53, which is mutated in many kinds of carcinoma. High survivin expression in non-small cell lung cancer is related with poor prognosis. To investigate the role of these genes in non-small cell lung cancer, we compared the relationship between p53AIP1 or survivin gene expression and the clinicopathological status of lung cancer.</p> <p>Materials and methods</p> <p>Forty-seven samples from non-small cell lung cancer patients were obtained between 1997 and 2003. For quantitative evaluation of RNA expression by PCR, we used Taqman PCR methods.</p> <p>Results</p> <p>Although no correlation between p53AIP1 or survivin gene expression and clinicopathological factors was found, the relationship between survivin gene expression and nodal status was significant (p = 0.03). Overall survival in the p53AIP1-negative group was significantly worse than in the positive group (p = 0.04); however, although survivin expression was not a prognostic factor, the combination of p53AIP1 and survivin was a significant prognostic predictor (p = 0.04). In the multivariate cox proportional hazard model, the combination was an independent predictor of overall survival (p53AIP1 (+) survivin (+), HR 0.21, 95%CI = [0.01–1.66]; p53AIP1 (+) survivin (-), HR 0.01, 95%CI = [0.002–0.28]; p53AIP1 (-) survivin (-), HR 0.01, 95%CI = [0.002–3.1], against p53AIP1 (-) survivin (+), p = 0.03).</p> <p>Conclusion</p> <p>These data suggest that the combination of p53AIP1 and survivin gene expression may be a powerful tool to stratify subgroups with better or worse prognosis from the variable non-small cell lung cancer population.</p

Genome Sequence of E. coli O104:H4 Leads to Rapid Development of a Targeted Antimicrobial Agent against This Emerging Pathogen

A recent widespread outbreak of Escherichia coli O104:H4 in Germany demonstrates the dynamic nature of emerging and re-emerging food-borne pathogens, particularly STECs and related pathogenic E. coli. Rapid genome sequencing and public availability of these data from the German outbreak strain allowed us to identify an O-antigen-specific bacteriophage tail spike protein encoded in the genome. We synthesized this gene and fused it to the tail fiber gene of an R-type pyocin, a phage tail-like bacteriocin, and expressed the novel bacteriocin such that the tail fiber fusion was incorporated into the bacteriocin structure. The resulting particles have bactericidal activity specifically against E. coli strains that produce the O104 lipopolysaccharide antigen, including the outbreak strain. This O-antigen tailspike-R-type pyocin strategy provides a platform to respond rapidly to emerging pathogens upon the availability of the pathogen's genome sequence

Analysing key influences over actors' use of evidence in developing policies and strategies in Nigeria: a retrospective study of the Integrated Maternal Newborn and Child Health strategy

Background Evidence-informed policymaking has been promoted as a means of ensuring better outcomes. However, what counts as evidence in policymaking lies within a spectrum of expert knowledge and scientifically generated information. Since not all forms of evidence share an equal validity or weighting for policymakers, it is important to understand the key factors that influence their preferences for different types of evidence in policy and strategy development. Method A retrospective study was carried out at the national level in Nigeria using a case-study approach to examine the Nigerian Integrated Maternal Newborn and Child Health (IMNCH) strategy. Two frameworks were used for conceptualization and data analysis, namely (1) to analyse the role of evidence in policymaking and (2) the policy triangle. They were used to explore the key contextual and participatory influences on choice of evidence in developing the IMNCH strategy. Data was collected through review of relevant national documents and in-depth interviews of purposively selected key policy and strategic decision makers. Thematic analysis was applied to generate information from collected data. Results The breadth of evidence used was wide, ranging from expert opinions to systematic reviews. The choice of different types of evidence was found to overlap across actor categories. Key influences over actors’ choice of evidence were: (1) perceived robustness of evidence – comprehensive, representative, recent, scientifically sound; (2) roles in evidence process, i.e. their degree and level of participation in evidence generation and dissemination, with regards to their role in the policy process; and (3) contextual factors such as global agenda and influence, timeline for strategy development, availability of resources for evidence generation, and lessons learnt from previous unsuccessful policies/plans. Conclusion Actors’ preferences for different types of evidence for policy are influenced not only by the characteristics of evidence itself, but on actors’ roles in the evidence process, their power to influence the policy, and the context in which evidence is used