One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis

Objective: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Design: Retrospective study conducted between 1997 and 2004. Setting: University-affiliated paediatric intensive care unit (PICU). Patients and participants: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Interventions: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12h and 24h. To assess disease severity, PRISM score and selected laboratory parameters were determined. Measurements and main results: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24h after admission. Conclusions: Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24h. It might therefore increase risk of death

Purinergic receptors are part of a signalling system for proliferation and differentiation in distinct cell lineages in human anagen hair follicles

We investigated the expression of P2X5, P2X7, P2Y1 and P2Y2 receptor subtypes in adult human anagen hair follicles and in relation to markers of proliferation [proliferating cell nuclear antigen (PCNA) and Ki-67], keratinocyte differentiation (involucrin) and apoptosis (anticaspase-3). Using immunohistochemistry, we showed that P2X5, P2Y1 and P2Y2 receptors were expressed in spatially distinct zones of the anagen hair follicle: P2Y1 receptors in the outer root sheath and bulb, P2X5 receptors in the inner and outer root sheaths and medulla and P2Y2 receptors in living cells at the edge of the cortex/medulla. P2X7 receptors were not expressed. Colocalisation experiments suggested different functional roles for these receptors: P2Y1 receptors were associated with bulb and outer root sheath keratinocyte proliferation, P2X5 receptors were associated with differentiation of cells of the medulla and inner root sheaths and P2Y2 receptors were associated with early differentiated cells in the cortex/medulla that contribute to the formation of the hair shaft. The therapeutic potential of purinergic agonists and antagonists for controlling hair growth is discussed

A comparison of self reported air pollution problems and GIS-modeled levels of air pollution in people with and without chronic diseases

<p>Abstract</p> <p>Objective</p> <p>To explore various contributors to people's reporting of self reported air pollution problems in area of living, including GIS-modeled air pollution, and to investigate whether those with respiratory or other chronic diseases tend to over-report air pollution problems, compared to healthy people.</p> <p>Methods</p> <p>Cross-sectional data from the Oslo Health Study (2000–2001) were linked with GIS-modeled air pollution data from the Norwegian Institute of Air Research. Multivariate regression analyses were performed. 14 294 persons aged 30, 40, 45, 60 or 75 years old with complete information on modeled and self reported air pollution were included.</p> <p>Results</p> <p>People who reported air pollution problems were exposed to significantly higher GIS-modeled air pollution levels than those who did not report such problems. People with chronic disease, reported significantly more air pollution problems after adjustment for modeled levels of nitrogen dioxides, socio-demographic variables, smoking, depression, dwelling conditions and an area deprivation index, even if they had a non-respiratory disease. No diseases, however, were significantly associated with levels of nitrogen dioxides.</p> <p>Conclusion</p> <p>Self reported air pollution problems in area of living are strongly associated with increased levels of GIS-modeled air pollution. Over and above this, those who report to have a chronic disease tend to report more air pollution problems in area of living, despite no significant difference in air pollution exposure compared to healthy people, and no associations between these diseases and NO₂. Studies on the association between self reported air pollution problems and health should be aware of the possibility that disease itself may influence the reporting of air pollution.</p

Residential exposure to motor vehicle emissions and the risk of wheezing among 7-8 year-old schoolchildren: a city-wide cross-sectional study in Nicosia, Cyprus

<p>Abstract</p> <p>Background</p> <p>Several studies have reported associations between respiratory outcomes in children and a range of self-reported, administrative or geographical indicators of traffic pollution. First-time investigation into the frequency of asthmatic symptoms among 7-8 year-old Cypriot children in 1999-2000 showed increased prevalence in the capital Nicosia compared to other areas. Geographical differences on an island the size of Cyprus may reflect environmental and/or lifestyle factors. This study investigates the relationship between self-reported symptoms and residential exposure to motor vehicle emissions among Nicosia schoolchildren.</p> <p>Methods</p> <p>The addresses of children in the metropolitan area of Nicosia who participated in the original survey (N = 1,735) were geo-coded and the level of exposure of each child was assessed using distance- and emission-based indicators (i.e. estimated levels of particulate matter and nitrogen oxides emissions due to motor vehicles on main roads around the residence). Odds ratios of wheezing and asthma diagnosis in relation to levels of exposure were estimated in logistic regression models adjusting for person-based factors, co-morbidity and intra-school clustering.</p> <p>Results</p> <p>We found an increased risk of wheezing at distances less than 50 m from a main road and/or only among those experiencing the highest levels of exposure. The strongest effect estimates were observed when exposure was defined in terms of the cumulative burden at all roads around the residence. Adjusted odds ratios for current wheezing were 2.33 (95% CI 1.27, 4.30) amongst the quartile of participants exposed to the highest levels of PM at all roads 50 m of their residence and 2.14 (95% CI 1.05, 4.35) for NOx, with no effect at intermediate levels of exposure. While the direction of effect was apparent at longer distances, differences were generally not statistically significant.</p> <p>Conclusions</p> <p>Children experiencing the highest burden of emissions in Nicosia seem to be at a higher risk of reporting asthmatic symptoms. Due to the small number of children residing at close proximity to main roads and lack of evidence of risk at intermediate levels of exposure or longer distances, the observed pattern alone does not explain the generally higher prevalence observed in urban Nicosia compared to other areas.</p

Impacts of highway traffic exhaust in alpine valleys on the respiratory health in adults: a cross-sectional study

BACKGROUND: Most studies having shown respiratory health effects from traffic exhaust were conducted in urban areas with a complex mixture of air pollution sources. This study has investigated the potential impact of traffic exhaust on respiratory symptoms among adults living along a Swiss alpine highway corridor, where traffic exhaust from the respective trans-Alpine highway is the predominant source of air pollution. METHODS: In summer 2005, we recruited 1839 adults aged 15 to 70 from a random sample of 10 communities along the Swiss alpine highway corridors. Subjects answered a questionnaire on respiratory health (asthmatic and bronchitic symptoms), risk factors, and potential confounding variables. We used logistic regression models to assess associations between respiratory symptoms and traffic exposure being defined a) as living within 200 m of the highway, and b) as a bell-shaped function simulating the decrease of pollution levels with increasing distance to the highway. RESULTS: Positive associations were found between living close to a highway and wheezing without cold (OR = 3.10, 95%-CI: 1.27-7.55) and chronic cough (OR = 2.88, 95%-CI: 1.17-7.05). The models using a bell-shaped function suggested that symptoms reached background levels after 400-500 m from the highway. The association with chronic cough was driven by a subgroup reporting hay fever or allergic rhinitis. CONCLUSIONS: Highway traffic exhaust in alpine highway corridors, in the absence of other industrial sources, showed negative associations with the respiratory health of adults, higher than those previously found in urban areas

Patient-reported outcomes in a trial of exenatide and insulin glargine for the treatment of type 2 diabetes

BACKGROUND: Patient-reported measures can be used to examine whether drug differences other than clinical efficacy have an impact on outcomes that may be important to patients. Although exenatide and insulin glargine appear to have similar efficacy for treatment of type 2 diabetes, there are several differences between the two treatments that could influence outcomes from the patient's perspective. The purpose of the current study was to examine whether the two drugs were comparable as assessed by patient-reported outcomes using data from a clinical trial in which these injectable medications were added to pre-existing oral treatment regimens. METHODS: Patients were randomized to either twice daily exenatide or once daily insulin glargine during a 26-week international trial. At baseline and endpoint, five patient-reported outcome measures were administered: the Vitality Scale of the SF-36, The Diabetes Symptom Checklist – Revised (DSC-R), the EuroQol EQ-5D, the Treatment Flexibility Scale (TFS), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Change from baseline to endpoint was analyzed within each treatment group. Group differences were examined with General linear models (GLMs), controlling for country and baseline scores. RESULTS: A total of 549 patients with type 2 diabetes were enrolled in the trial, and current analyses were conducted with data from the 455 per protocol patients (228 exenatide and 227 insulin glargine). The sample was primarily Caucasian (79.6%), with slightly more men (55.2%) than women, and with a mean age of 58.5 years. Paired t-tests found that both treatment groups demonstrated statistically significant baseline to endpoint change on several of the health outcomes instruments including the DSC-R, DTSQ, and the SF-36 Vitality subscale. GLMs found no statistically significant differences between groups in change on the health outcomes instruments. CONCLUSION: This analysis found that both exenatide and insulin glargine were associated with significant improvements in patient-reported outcomes when added to oral medications among patients with type 2 diabetes. Despite an additional daily injection and a higher rate of gastrointestinal adverse events, treatment satisfaction in the exenatide group was comparable to that of the glargine group, possibly because of weight reduction observed in patients treated with exenatide

Geographical information system and environmental epidemiology: a cross-sectional spatial analysis of the effects of traffic-related air pollution on population respiratory health

<p>Abstract</p> <p>Background</p> <p>Traffic-related air pollution is a potential risk factor for human respiratory health. A Geographical Information System (GIS) approach was used to examine whether distance from a main road (the Tosco-Romagnola road) affected respiratory health status.</p> <p>Methods</p> <p>We used data collected during an epidemiological survey performed in the Pisa-Cascina area (central Italy) in the period 1991-93. A total of 2841 subjects participated in the survey and filled out a standardized questionnaire on health status, socio-demographic information, and personal habits. A variable proportion of subjects performed lung function and allergy tests. Highly exposed subjects were defined as those living within 100 m of the main road, moderately exposed as those living between 100 and 250 m from the road, and unexposed as those living between 250 and 800 m from the road. Statistical analyses were conducted to compare the risks for respiratory symptoms and diseases between exposed and unexposed. All analyses were stratified by gender.</p> <p>Results</p> <p>The study comprised 2062 subjects: mean age was 45.9 years for men and 48.9 years for women. Compared to subjects living between 250 m and 800 m from the main road, subjects living within 100 m of the main road had increased adjusted risks for persistent wheeze (OR = 1.76, 95% CI = 1.08-2.87), COPD diagnosis (OR = 1.80, 95% CI = 1.03-3.08), and reduced FEV₁/FVC ratio (OR = 2.07, 95% CI = 1.11-3.87) among males, and for dyspnea (OR = 1.61, 95% CI = 1.13-2.27), positivity to skin prick test (OR = 1.83, 95% CI = 1.11-3.00), asthma diagnosis (OR = 1.68, 95% CI = 0.97-2.88) and attacks of shortness of breath with wheeze (OR = 1.67, 95% CI = 0.98-2.84) among females.</p> <p>Conclusion</p> <p>This study points out the potential effects of traffic-related air pollution on respiratory health status, including lung function impairment. It also highlights the added value of GIS in environmental health research.</p

A Quorum Sensing Regulated Small Volatile Molecule Reduces Acute Virulence and Promotes Chronic Infection Phenotypes

A significant number of environmental microorganisms can cause serious, even fatal, acute and chronic infections in humans. The severity and outcome of each type of infection depends on the expression of specific bacterial phenotypes controlled by complex regulatory networks that sense and respond to the host environment. Although bacterial signals that contribute to a successful acute infection have been identified in a number of pathogens, the signals that mediate the onset and establishment of chronic infections have yet to be discovered. We identified a volatile, low molecular weight molecule, 2-amino acetophenone (2-AA), produced by the opportunistic human pathogen Pseudomonas aeruginosa that reduces bacterial virulence in vivo in flies and in an acute mouse infection model. 2-AA modulates the activity of the virulence regulator MvfR (multiple virulence factor regulator) via a negative feedback loop and it promotes the emergence of P. aeruginosa phenotypes that likely promote chronic lung infections, including accumulation of lasR mutants, long-term survival at stationary phase, and persistence in a Drosophila infection model. We report for the first time the existence of a quorum sensing (QS) regulated volatile molecule that induces bistability phenotype by stochastically silencing acute virulence functions in P. aeruginosa. We propose that 2-AA mediates changes in a subpopulation of cells that facilitate the exploitation of dynamic host environments and promote gene expression changes that favor chronic infections

A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing

Involvement of microRNAs in physiological and pathological processes in the lung

To date, at least 900 different microRNA (miRNA) genes have been discovered in the human genome. These short, single-stranded RNA molecules originate from larger precursor molecules that fold to produce hairpin structures, which are subsequently processed by ribonucleases Drosha/Pasha and Dicer to form mature miRNAs. MiRNAs play role in the posttranscriptional regulation of about one third of human genes, mainly via degradation of target mRNAs. Whereas the target mRNAs are often involved in the regulation of diverse physiological processes ranging from developmental timing to apoptosis, miRNAs have a strong potential to regulate fundamental biological processes also in the lung compartment. However, the knowledge of the role of miRNAs in physiological and pathological conditions in the lung is still limited. This review, therefore, summarizes current knowledge of the mechanism, function of miRNAs and their contribution to lung development and homeostasis. Besides the involvement of miRNAs in pulmonary physiological conditions, there is evidence that abnormal miRNA expression may lead to pathological processes and development of various pulmonary diseases. Next, the review describes current state-of-art on the miRNA expression profiles in smoking-related diseases including lung cancerogenesis, in immune system mediated pulmonary diseases and fibrotic processes in the lung. From the current research it is evident that miRNAs may play role in the posttranscriptional regulation of key genes in human pulmonary diseases. Further studies are, therefore, necessary to explore miRNA expression profiles and their association with target mRNAs in human pulmonary diseases