Expression of eicosanoid receptors subtypes and eosinophilic inflammation: implication on chronic rhinosinusitis

BACKGROUND: Eicosanoid receptors are G-protein-coupled receptors playing an important immunomodulatory role in airway diseases. However, there is little information on the expression of these receptors and their link with eosinophilic inflammation in paranasal sinus diseases. We aimed with this study to investigate the tissue expression of leukotrienes and prostaglandin E2 receptors in chronic rhinosinusitis patients and the link of this regulation with eosinophilic inflammation. METHODS: Samples were prepared from nasal tissue of patients with chronic rhinosinusitis without nasal polyps (CRS, n = 11), with nasal polyps (CRS-NP, n = 13) and healthy subjects (Controls, n = 6). mRNA expression of CysLT(1), CysLT(2), BLT(1), BLT(2), E-prostanoid receptors (EP(1), EP(2), EP(3), EP(4)) and sol-IL-5Rα was determined by real-time PCR. Concentrations of PGE2, LTC4/D4/E4, LTB4 and sol-IL-5Rα were determined by ELISA and of ECP by ImmunoCap. Protein expression and tissue localization of eicosanoid receptors and activated eosinophils were evaluated by immunohistochemistry. RESULTS: CysLT(1 )mRNA expression was significantly increased in CRS-NP compared to CRS and controls, and CRS compared to controls, whereas CysLT(2 )mRNA was enhanced in both CRS groups without differences between them. Levels of both receptors correlated to the number of activated eosinophils, sol-IL-5Rα, ECP and LTC(4)/D(4)/E(4 )concentrations in the disease groups. PGE(2 )protein concentrations and prostanoid receptors EP(1 )and EP(3 )were down-regulated in the CRS-NP tissue vs. CRS and controls, whereas EP(2 )and EP(4 )expression was enhanced in CRS and CRS-NP patients vs. controls. No differences in BLT receptors were observed between patients and controls. CONCLUSION: CyLTs receptors are up-regulated in nasal polyp tissue and their expression correlate with eosinophilic inflammation supporting previous results. Eicosanoid receptors mRNA pattern observed suggests that down-regulation of EP(1 )and EP(3 )in CRS-NP and up-regulation EP(2 )and EP(4 )in CRS and CRS-NP groups may have some role in the development of the diseases and their regulation may not be directly linked to eosinophil activation but involve post-transcriptional events mainly related to other inflammatory cell sources

Demanding business travel:the evolution of the timespaces of business practice

To date, virtual ways of working have yet to substantially reduce demand for business travel. Emerging research claims that virtual and physical work compliment rather than substitute for one another. This suggests travel demand stems from business strategies and achieving business outcomes. In building on these ideas, this chapter draws upon Schatzki’s conception of timespace to capture changes in how two UK-based global construction and engineering consulting firms organise work and the implications in terms of demand for business travel. Overtime, particular forms of spatially stretched organisation which have developed are found to require the interweaving of timespaces through travel. As such, how each firm has evolved has in turn created the contemporary situation of significant and hard to reduce demand for travel

From West Indies to East Indies: Archipelagic Interchanges

In this paper, I work to rethink notions of comparison and area studies by viewing my ethnographic work in Indonesia through the lens of theories developed by anthropologists working in the Caribbean region. In bringing 'East Indies' and 'West Indies' together in this way, I explore the possibility of reconfigured networks of citation, collaboration and interchange that might help anthropology respond in new ways to contemporary dynamics of globalisation. © 2006 Copyright Discipline of Anthropology and Sociology, The University of Western Australia

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Induced sputum eicosanoid concentrations in asthma.

Further definition of the role of leukotrienes (LT) and prostaglandins (PG) in asthma would be helped by a noninvasive method for assessing airway production. The supernatant from sputum induced with hypertonic saline and dispersed using dithiotrietol has been successfully used to measure other molecular markers of airway inflammation and might be a useful method. We have measured induced sputum supernatant LTC(4)/D(4)/E(4) concentrations using enzyme immunoassay and PGE(2), PGD(2), TXB(2), and PGF(2alpha) using gas chromatography-negative ion chemical ionization-mass spectroscopy in 10 normal subjects and in 26 subjects with asthma of variable severity. Sputum cysteinyl-leukotrienes concentrations were significantly greater in subjects with asthma (median, 9.5 ng/ml) than in normal control subjects (6.4 ng/ml; p &lt; 0.02) and greater in subjects with persistent asthma requiring inhaled corticosteroids (median, 11.4 ng/ml) or studied within 48 h of an acute severe exacerbation of asthma (13 ng/ml) than in subjects with episodic asthma treated with inhaled beta(2)-agonists only (7.2 ng/ml). There were no significant differences in the concentrations of other eicosanoids between groups, although there was a negative correlation between the percentage sputum eosinophil count and sputum PGE(2) concentration (r = -0.48; p &lt; 0.01) in subjects with asthma. We conclude that induced sputum contains high concentrations of eicosanoids and that sputum LTC(4)/D(4)/E(4) concentrations are significantly greater in subjects with asthma than in normal subjects. The inverse relationship between eosinophilic airway inflammation and sputum PGE(2) concentration would be consistent, with the latter having an anti-inflammatory role

Sputum cysteinyl leukotrienes increase 24 hours after allergen inhalation in atopic asthmatics.

We have used the relatively noninvasive technique of induced sputum to measure allergen-induced changes in the concentration of eicosanoid mediators in bronchial secretions from atopic asthmatics. Sputum induction was performed before and 24 h after inhalational allergen challenge in 14 atopic asthmatics who developed a late asthmatic reaction (LAR). Differential cell counts were made on sputum cytospins and eicosanoid (cysteinyl leukotrienes [cys LTs], prostaglandin D(2) [PGD(2)], and PGE(2)) concentrations were measured in the sputum supernatants. The percentage of eosinophils at baseline correlated with the concentration of cys LTs (r = 0.84, p &lt; 0.001) but not prostanoid mediators. Allergen challenge produced a significant increase in the concentration of sputum cys LTs from 3. 45 ng/ml sputum to 11.95 ng/ml (p = 0.002), which correlated with the increase in sputum eosinophils (r = 0.55, p &lt; 0.05). There were no significant changes in PGD(2) or PGE(2) concentrations in sputum supernatants in response to challenge. Thus, the noninvasive technique of induced sputum has been used to demonstrate increased cys LTs, but not prostanoids associated with LAR after allergen challenge. The correlation between eosinophil numbers and cys LT concentrations at baseline values and 24 h after allergen challenge is consistent with these cells being a principal source of cys LTs within the airways at these time points

Induced sputum inflammatory mediator concentrations in eosinophilic bronchitis and asthma

Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but in contrast to asthma there is no variable airflow obstruction or airway hyperresponsiveness. Our hypothesis was that the differences in airway pathophysiology maybe due to less active airway inflammation in eosinophilic bronchitis, with reduced release of important effector mediators. We measured the concentration of various proinflammatory mediators in induced sputum cell-free supernatant in eight patients with eosinophilic bronchitis, 17 patients with asthma matched for sputum eosinophil count, and 10 normal subjects. Cysteinyl-leukotrienes (cys-LT) were measured by enzyme immunoassay, eosinophilic cationic protein (ECP) by fluoroimmunoassay, prostanoids (PGE2, PGD2, TXB2, and PGF(2α)) by gas chromatography-negative ion chemical ionization-mass spectroscopy, and histamine by radioenzymic assay. The geometric mean sputum eosinophil count was similar in asthma (13.4%) and eosinophilic bronchitis (12.5%). Sputum cys-LT and ECP were a mean (95% CI) 1.6-fold (1.1, 2.5) and 6.4-fold (1.4, 28) higher in eosinophilic bronchitis and 1.9-fold (1.3, 2.9) and 7.7-fold (1.2, 46) higher in asthma compared with that in control subjects (geometric mean, 5.9 and 95 ng/ml, respectively). In eosinophilic bronchitis the mean concentration of sputum PGD2 (0.79 ng/ml) and histamine (168 ng/ml) were significantly higher than in asthma (mean absolute difference in PGD2 concentration, 0.47 ng/ml [95% CI, 0.19 to 0.74] and mean-fold difference in histamine concentration, 6.7 [95% CI 1.7 to 26]) and normal subjects (0.64 ng/ml [0.36 to 0.90] and 11-fold [3.3 to 36]), respectively. In conclusion, eosinophilic bronchitis is associated with active airway inflammation with increased release of vasoactive and bronchoconstrictor mediators