Epithelial senescence in idiopathic pulmonary fibrosis is propagated by small extracellular vesicles

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects 3 million people worldwide. Senescence and small extracellular vesicles (sEVs) have been implicated in the pathogenesis of IPF, although how sEVs promote disease remains unclear. Here, we profile sEVs from bronchial epithelial cells and determine small RNA (smRNA) content. METHODS: Conditioned media was collected and sEVs were isolated from normal human bronchial epithelial cells (NHBEs) and IPF-diseased human bronchial epithelial cells (DHBEs). RESULTS: Increased sEV release from DHBEs compared to NHBEs (n = 4; p < 0.05) was detected by nanoparticle tracking analysis. NHBEs co-cultured with DHBE-derived sEVs for 72 h expressed higher levels of SA-β-Gal and γH2AX protein, p16 and p21 RNA and increased secretion of IL6 and IL8 proteins (all n = 6-8; p < 0.05). sEVs were also co-cultured with healthy air-liquid interface (ALI) cultures and similar results were observed, with increases in p21 and p16 gene expression and IL6 and IL8 (basal and apical) secretion (n = 6; p < 0.05). Transepithelial electrical resistance (TEER) measurements, a reflection of epithelial barrier integrity, were decreased upon the addition of DHBE-derived sEVs (n = 6; p < 0.05). smRNA-sequencing identified nineteen significantly differentially expressed miRNA in DHBE-derived sEVs compared to NHBE-derived sEVs, with candidate miRNAs validated by qPCR (all n = 5; p < 0.05). Four of these miRNAs were upregulated in NHBEs co-cultured with DHBE-derived sEVs and three in healthy ALI cultures co-cultured with DHBE-derived sEVs (n = 3-4; p < 0.05). CONCLUSIONS: This data demonstrates that DHBE-derived sEVs transfer senescence to neighbouring healthy cells, promoting the disease state in IPF

Community health workers improve contact tracing among immigrants with tuberculosis in Barcelona

Background: The important increase in immigration during recent years has changed the epidemiology and control strategies for tuberculosis (TB) in many places. This study evaluates the effectiveness of intervention with community health workers (CHW) to improve contact tracing among immigrants. Methods: The study included all TB cases detected by the Barcelona TB Program from 2000 to 2005 and compared a period without CHW intervention (2000-2002) to a period with CHW intervention (2003-2005). The influence on contact tracing of sex, age, hospital of diagnosis, district of residence, birthplace, HIV, homeless and CHW intervention was analysed by logistic regression. Odds ratio (OR) and 95 % confidence intervals (CI) were calculated. Results: 960 foreign born TB cases were detected, 388 in the intervention period. Contact tracing was performed on 65,7 % of 201 smear-positive cases during the pre-intervention period compared to 81.6 % of 152 smear-positive TB cases during the intervention period (p &lt; 0.001). Risk factors associated with incomplete contact tracing of smear-positive index cases included being diagnosed in two hospitals without contact tracing TB unit (OR = 3.5; CI:1.4-8.9) and (OR = 4.6; CI:1.6-13.5) respectively, birth place in India-Pakistan (OR = 4.4; CI:1.9-10.3) or North Africa (OR = 4.3; CI:1.8-10.5), having an unknown residence (OR = 5.4; CI:1.6-18.0), being HIV-infected (OR = 6.1; CI:2.5-14.8

Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease:Systematic review and meta-analysis

Complete search strategy. The complete search strategy for the systematic review for both Medline and Embase. (DOCX 22 kb

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Women-focused development intervention reduces delays in accessing emergency obstetric care in urban slums in Bangladesh: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Recognizing the burden of maternal mortality in urban slums, in 2007 BRAC (formally known as Bangladesh Rural Advancement Committee) has established a woman-focused development intervention, Manoshi (the Bangla abbreviation of mother, neonate and child), in urban slums of Bangladesh. The intervention emphasizes strengthening the continuum of maternal, newborn and child care through community, delivery centre (DC) and timely referral of the obstetric complications to the emergency obstetric care (EmOC) facilities. This study aimed to assess whether Manoshi DCs reduces delays in accessing EmOC.</p> <p>Methods</p> <p>This cross-sectional study was conducted during October 2008 to January 2009 in the slums of Dhaka city among 450 obstetric complicated cases referred either from DCs of Manoshi or from their home to the EmOC facilities. Trained female interviewers interviewed at their homestead with structured questionnaire. <it>Pearson's </it>chi-square test, <it>t</it>-test and Mann-Whitney test were performed.</p> <p>Results</p> <p>The median time for making the decision to seek care was significantly longer among women who were referred from home than referred from DCs (9.7 hours vs. 5.0 hours, p < 0.001). The median time to reach a facility and to receive treatment was found to be similar in both groups. Time taken to decide to seek care was significantly shorter in the case of life-threatening complications among those who were referred from DC than home (0.9 hours vs.2.3 hours, p = 0.002). Financial assistance from Manoshi significantly reduced the first delay in accessing EmOC services for life-threatening complications referred from DC (p = 0.006). Reasons for first delay include fear of medical intervention, inability to judge maternal condition, traditional beliefs and financial constraints. Role of gender was found to be an important issue in decision making. First delay was significantly higher among elderly women, multiparity, non life-threatening complications and who were not involved in income-generating activities.</p> <p>Conclusions</p> <p>Manoshi program reduces the first delay for life-threatening conditions but not non-life-threatening complications even though providing financial assistance. Programme should give more emphasis on raising awareness through couple/family-based education about maternal complications and dispel fear of clinical care to accelerate seeking EmOC.</p

Post-Transcriptional Regulation of BCL2 mRNA by the RNA-Binding Protein ZFP36L1 in Malignant B Cells

The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3′ untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the ‘maximum information coefficient’ (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3′ untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3′ untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells

In situ formation of 1D nanostructures from ceria nanoparticle dispersions by liquid cell TEM irradiation

Deliberate electron irradiation of cerium oxide nanoparticles in water is used to trigger chemical reactions in a liquid cell transmission electron microscope. Formation of nanorods and nanoneedles is observed starting from predominantly octahedral shape nanoparticles. Detailed morphologies found include free-standing needles, needles connected to specific octahedral ceria facets and star-shaped multi-needle patterns. It is found that rod-axis orientations and crystallographic directions are aligned. It is suggested that high ion and radical concentration of radiolysed water dissolves layers of the original CeO2 particles which re-arrange as needles in the direction of energetically preferred facets