Background: Severe asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which the mechanisms are not fully understood. A disintegrin and metalloproteinase domain 8 (ADAM8) is an enzyme expressed on most leucocytes and may be important for facilitating leucocyte migration in respiratory disease. Objective: To investigate ADAM8 mRNA and protein expression in asthma and COPD and its relationship between asthma severity and inflammatory phenotypes. Methods: Induced sputum was collected from 113 subjects with asthma (severe n = 31, uncontrolled n = 39 and controlled n = 35), 20 subjects with COPD and 21 healthy controls. Sputum ADAM8 mRNA expression was measured by qPCR, and soluble ADAM8 (sADAM8) protein was measured in the sputum supernatant by validated ELISA. Results: ADAM8 mRNA correlated with ADAM8 protein levels (r = 0.27, P < 0.01). ADAM8 mRNA (P = 0.004) and sADAM8 protein (P = 0.014) levels were significantly higher in both asthma and COPD compared with healthy controls. ADAM8 mRNA (P = 0.035) and sADAM8 protein (P = 0.002) levels were significantly higher in severe asthma compared with controlled asthma. Total inflammatory cell count (P < 0.01) and neutrophils (P < 0.01) were also elevated in severe asthmatic sputum. Although ADAM8 mRNA was significantly higher in eosinophilic and neutrophilic asthma (P < 0.001), sADAM8 did not differ between asthma inflammatory phenotypes. ADAM8 expression positively correlated with sputum total cell count and sputum neutrophils. Conclusions and Clinical Relevance: ADAM8 expression is increased in both severe asthma and COPD and associated with sputum total cell count and neutrophils. ADAM8 may facilitate neutrophil migration to the airways in severe asthma and COPD. © 2013 John Wiley & Sons Ltd.

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© 2017 by the American Thoracic Society. Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1ß responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1ß in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

The relevance of increased methacholine airway responsiveness detected in children with no current or past symptoms of asthma is not known. We wished for determine whether the presence of airway hyperresponsiveness in asymptomatic children is also associated with abnormal variability of peak expiratory flow (PEF). In 12 asymptomatic children with methacholine hyperresponsiveness, we examined the diurnal variation of peak expiratory flow (PEF) and response to inhaled bronchodilator. Twelve asthmatic children with a comparable range of methacholine hyperresponsiveness, and 12 normal children without methacholine responsiveness, were used as positive and negative controls. The children were aged 11 (range 9-14) yrs. The mean diurnal variation of PEF in those children with asymptomatic hyperresponsiveness was increased at 9.3%, to a degree comparable to the symptomatic asthmatic children (10.7%), and greater than the normal children (5.7%). Methacholine stimulated airway constriction was associated with symptoms in subjects from each group, indicating that the children were capable of perceiving airway constriction. We conclude that asymptomatic children with methacholine airway hyperresponsiveness have other evidence of mild variable airflow obstruction with increased diurnal PEF variability, and can perceive airflow limitation. The lack of symptoms in the children with airway hyperresponsiveness could be due to an insufficient stimulus to cause symptomatic obstruction, or the absence of eosinophilic airway inflammation, which may be a requirement for the development of symptomatic airway hyperresponsiveness.

Chứng nhận bản quyền tác giả số 280/2009/QTG ngày 16/02/2009, cấp bởi Bộ Văn hoá – Thể thao – Du lịch

But in tandem with this the team is refining and building the considerably more advanced AC-class race boat that it hopes will eventually win the America’s Cup in Bermuda in 2017. And while the AC45 is capable of an impressive turn of speed, the AC-class vessel currently under development is estimated to be almost 2.5 times as powerful: capable of flying at around 85kph, and at up to three times the speed of the wind.

In smokers with chronic airflow limitation (CAL), airway hyperresponsiveness (AHR) to stimuli like methacholine, which act directly on airway smooth muscle, are not specific for the pathogenesis which is responsible for AHR to methacholine in subjects with normal spirometry, nor predictive for a beneficial effect of glucocorticosteroid (GCS) treatment. In contrast, AHR to stimuli like hyperventilation, which act indirectly through mediator release, may be specific for the pathogenesis of asthma and predictive for a beneficial effect of GCS. The validation of this possibility requires the demonstration that patients with CAL and AHR to hyper-ventilation demonstrate improvement after treatment with GCS (and have an increase in eosinophils and metachromatic cells in the sputum or bronchoalveolar lavage (BAL), like that seen in asthmatics uncomplicated by CAL).

Although the results of this study suggest screening is not worthwhile, several guidelines advocate offering screening in some cases. The study was much larger than previous studies, and existing trials had published more extended follow-up results, and the BMJ Rapid Recommendations team felt these merited a new appraisal of the body of evidence. This guideline aims to promptly and transparently translate potentially practice-changing evidence to usable recommendations for clinicians and patients, based on the GRADE framework and following standards for trustworthy guidelines.

|| … This country is the homeland of both Jews and Palestinians and both are indigenous and should enjoy equal rights. ||

Given our previous findings were in accordance with the other studies on the beneficial role of Tregs in protecting against adverse inflammation during CVB3-induced myocarditis32,33,34, we considered the possibility that the expansion or induction of Tregs may be involved in VM of miR-155−/− mice. Surprisingly, we did not observe a difference in the proportion of Tregs in the spleens and hearts of miR-155−/− and WT mice, which suggests that Tregs may not contribute to the protective effect of miR-155 silencing in VM.

Myocardial mitochondrial absorbance was recorded at 5 discrete time points (0, 0.5, 1, 2 and 3 min) following 3 min and 30 min of reperfusion. As shown in Fig. 4a, after 3 min of reperfusion, the absorbance of all groups decreased following the initial measurement. The absorbance in the R/I group was the lowest, followed by Hyd, Lac, Lac + Hyd, and M-Post groups. The mitochondrial absorbance in Lac and Lac + Hyd groups were both significantly higher than for those in the R/I group (P < 0.05), and similar to the M-Post group (P > 0.05). In contrast, mitochondrial absorbance in the Hyd group was lower than in the M-Post group (P < 0.05), and similar to the R/I group (P > 0.05).

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