142 research outputs found

    Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells

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    NO2 and O3 are ubiquitous air toxicants capable of inducing lung damage to the respiratory epithelium. Due to their oxidizing capabilities, these pollutants have been proposed to target specific biological pathways, but few publications have compared the pathways activated

    Seasonal Variations in Air Pollution Particle-Induced Inflammatory Mediator Release and Oxidative Stress

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    Health effects associated with particulate matter (PM) show seasonal variations. We hypothesized that these heterogeneous effects may be attributed partly to the differences in the elemental composition of PM. Normal human bronchial epithelial (NHBE) cells and alveolar macrophages (AMs) were exposed to equal mass of coarse [PM with aerodynamic diameter of 2.5ā€“10 Ī¼m (PM(2.5ā€“10))], fine (PM(2.5)), and ultrafine (PM (< 0.1)) ambient PM from Chapel Hill, North Carolina, during October 2001 (fall) and January (winter), April (spring), and July (summer) 2002. Production of interleukin (IL)-8, IL-6, and reactive oxygen species (ROS) was measured. Coarse PM was more potent in inducing cytokines, but not ROSs, than was fine or ultrafine PM. In AMs, the October coarse PM was the most potent stimulator for IL-6 release, whereas the July PM consistently stimulated the highest ROS production measured by dichlorofluorescein acetate and dihydrorhodamine 123 (DHR). In NHBE cells, the January and the October PM were consistently the strongest stimulators for IL-8 and ROS, respectively. The July PM increased only ROS measured by DHR. PM had minimal effects on chemiluminescence. Principal-component analysis on elemental constituents of PM of all size fractions identified two factors, Cr/Al/Si/Ti/Fe/Cu and Zn/As/V/Ni/Pb/Se, with only the first factor correlating with IL-6/IL-8 release. Among the elements in the first factor, Fe and Si correlated with IL-6 release, whereas Cr correlated with IL-8 release. These positive correlations were confirmed in additional experiments with PM from all 12 months. These results indicate that elemental constituents of PM may in part account for the seasonal variations in PM-induced adverse health effects related to lung inflammation

    Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression

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    Traditional toxicological paradigms have relied on factors such as age, genotype, and disease status to explain variability in responsiveness to toxicant exposure; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modifiable factors that can be leveraged to mitigate the exposure effects. Unlike these factors, the epigenome is dynamic and shaped by an individualā€™s environment. We sought to determine whether baseline levels of specific chromatin modifications correlated with the interindividual variability in their ozone (O3)-mediated induction in an airā€“liquid interface model using primary human bronchial epithelial cells from a panel of 11 donors. We characterized the relationship between the baseline abundance of 6 epigenetic markers with established roles as key regulators of gene expressionā€”histone H3 lysine 4 trimethylation (H3K4me3), H3K27 acetylation (H3K27ac), pan-acetyl H4 (H4ac), histone H3K27 di/trimethylation (H3K27me2/3), unmodified H3, and 5-hydroxymethylcytosine (5-hmC)ā€”and the variability in the O3-induced expression of IL-8, IL-6, COX2, and HMOX1. Baseline levels of H3K4me3, H3K27me2/3, and 5-hmC, but not H3K27ac, H4ac, and total H3, correlated with the interindividual variability in O3-mediated induction of HMOX1 and COX2. In contrast, none of the chromatin modifications that we examined correlated with the induction of IL-8 and IL-6. From these findings, we propose an ā€œepigenetic seed and soilā€ model in which chromatin modification states between individuals differ in the relative abundance of specific modifications (the ā€œsoilā€) that govern how receptive the gene is to toxicant-mediated cellular signals (the ā€œseedā€) and thus regulate the magnitude of exposure-related gene induction

    Inborn Errors of Immunity on the Island of Ireland - a Cross-Jurisdictional UKPID/ESID Registry Report

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    The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patientsā€‰ā‰„ā€‰18Ā years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population

    Inborn Errors of Immunity on the Island of Ireland - a Cross-Jurisdictional UKPID/ESID Registry Report

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    Correction; Early Access:The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients >= 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population.Peer reviewe

    Delirium prediction in the intensive care unit: comparison of two delirium prediction models

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    Background: Accurate prediction of delirium in the intensive care unit (ICU) may facilitate efficient use of early preventive strategies and stratification of ICU patients by delirium risk in clinical research, but the optimal delirium prediction model to use is unclear. We compared the predictive performance and user convenience of the prediction model for delirium (PRE-DELIRIC) and early prediction model for delirium (E-PRE-DELIRIC) in ICU patients and determined the value of a two-stage calculation. Methods: This 7-country, 11-hospital, prospective cohort study evaluated consecutive adults admitted to the ICU who could be reliably assessed for delirium using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. The predictive performance of the models was measured using the area under the receiver operating characteristic curve. Calibration was assessed graphically. A physician questionnaire evaluated user convenience. For the two-stage calculation we used E-PRE-DELIRIC immediately after ICU admission and updated the prediction using PRE-DELIRIC after 24 h. Results: In total 2178 patients were included. The area under the receiver operating characteristic curve was significantly greater for PRE-DELIRIC (0.74 (95% confidence interval 0.71-0.76)) compared to E-PRE-DELIRIC (0.68 (95% confidence interval 0.66-0.71)) (z score of -2.73 (p < 0.01)). Both models were well-calibrated. The sensitivity improved when using the two-stage calculation in low-risk patients. Compared to PRE-DELIRIC, ICU physicians (n = 68) rated the E-PRE-DELIRIC model more feasible. Conclusions: While both ICU delirium prediction models have moderate-to-good performance, the PRE-DELIRIC model predicts delirium better. However, ICU physicians rated the user convenience of E-PRE-DELIRIC superior to PRE-DELIRIC. In low-risk patients the delirium prediction further improves after an update with the PRE-DELIRIC model after 24 h

    The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families

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    Isolated complex I deficiency is the most frequently observed oxidative phosphorylation defect in children with mitochondrial disease, leading to a diverse range of clinical presentations, including Leigh syndrome. For most patients the genetic cause of the biochemical defect remains unknown due to incomplete understanding of the complex I assembly process. Nonetheless, a plethora of pathogenic mutations have been described to date in the seven mitochondrial-encoded subunits of complex I as well as in 12 of the nuclear-encoded subunits and in six assembly factors. Whilst several mitochondrial DNA mutations are recurrent, the majority of these mutations are reported in single families. We have sequenced core structural and functional nuclear-encoded subunits of complex I in a cohort of 34 paediatric patients with isolated complex I deficiency, identifying pathogenic mutations in 6 patients. These included a novel homozygous NDUFS1 mutation in an Asian child with Leigh syndrome, a previously identified NDUFS8 mutation (c.236C>T, p.P79L) in a second Asian child with Leigh-like syndrome and six novel, compound heterozygous NDUFS2 mutations in four white Caucasian patients with Leigh or Leigh-like syndrome. Three of these children harboured an identical NDUFS2 mutation (c.875T>C, p.M292T), which was also identified in conjunction with a novel NDUFS2 splice site mutation (c.866+4A>G) in a fourth Caucasian child who presented to a different diagnostic centre, with microsatellite and single nucleotide polymorphism analyses indicating that this was due to an ancient common founder event. Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes

    Determination of quantitative trait loci (QTL) for early maturation in rainbow trout (Oncorhynchus mykiss)

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    To identify quantitative trait loci (QTL) influencing early maturation (EM) in rainbow trout (Oncorhynchus mykiss), a genome scan was performed using 100 microsatellite loci across 29 linkage groups. Six inter-strain paternal half-sib families using three inter-strain F(1) brothers (approximately 50 progeny in each family) derived from two strains that differ in the propensity for EM were used in the study. Alleles derived from both parental sources were observed to contribute to the expression of EM in the progeny of the brothers. Four genome-wide significant QTL regions (i.e., RT-8, -17, -24, and -30) were observed. EM QTL detected on RT-8 and -24 demonstrated significant and suggestive QTL effects in both male and female progeny. Furthermore, within both male and female full-sib groupings, QTL on RT-8 and -24 were detected in two or more of the five parents used. Significant genome-wide and several strong chromosome-wide QTL for EM localized to different regions in males and females, suggesting some sex-specific control. Namely, QTL detected on RT-13, -15, -21, and -30 were associated with EM only in females, and those on RT-3, -17, and -19 were associated with EM only in males. Within the QTL regions identified, a comparison of syntenic EST markers from the rainbow trout linkage map with the zebrafish (Danio rerio) genome identified several putative candidate genes that may influence EM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10126-008-9098-5) contains supplementary material, which is available to authorized users
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