No abstract

Background A comparison of the effects of regular v as needed inhaled p agonist treatment on the control of asthma in the last 16 weeks of each of two 24 week treatment periods has been reported. This paper presents additional information on exacerbations of asthma and trends in lung function, airways hyperresponsiveness to methacholine, and bronchodilator responsiveness during the entire 24 week periods of regular or as needed fp agonist treatment.Methods Subjects undertook a year long randomised, double blind crossover study of regular v as needed inhaled p1 agonist treatment. Fenoterol (400 4ug) or matching placebo was inhaled as a dry powder four times daily for 24 weeks, then subjects crossed over to the alternative regimen. Treatment with inhaled corticosteroids was used by 50 of the 64 subjects in constant doses throughout the study. Symptoms, peak expiratory flow rates, and drug use were recorded daily, spirometry was performed every four weeks, and methacholine and bronchodilator responsiveness were measured every eight weeks. Results Exacerbations of asthma symptoms occurred earlier and more often during regular treatment with fenoterol and four of five severe exacerbations requiring admission to hospital occurred during the period of regular treatment. Prebronchodilator forced expiratory volume in one second (FEV1) was on average 0.15 litres lower (95% confidence interval (95% CI) 0-11-0-19) and vital capacity (VC) 0-12 litres lower (95% CI 0-08-0-16) than during the placebo period. Morning peak flow rates were significantly lower and evening peak flow rates significantly higher, with an increase in diurnal variation from 9'8% (95% CI 6-9-12-8) to 17-5% (95% CI 13.8-21-3) during regular treatment. Geometric mean concentration of methacholine causing a 20% fall in FEV, from the value after saline (PC20) decreased significantly from 1*63 to 1 15 mg/ml, indicating increased bronchial hyperresponsiveness during regular treatment. Response to bronchodilator, as measured by the % increase in postbronchodilator FEV, related to prebronchodilator FEV,, was maintained with no evidence for tachyphylaxis. Conclusion Chronic use of inhaled fenoterol resulted in more exacerbations, a significant decline in baseline lung function, and an increase in airway responsiveness to methacholine in asthmatic subjects, but did not alter bronchodilator responsiveness. These findings support the previous report that regular inhaled fa agonist treatment is deleterious in the long term control of asthma.

∆122p53 mice (a model of ∆133p53 isoform) are tumour-prone, have extensive inflammation and elevated serum IL-6. To investigate the role of IL-6 we crossed ∆122p53 mice with IL-6 null mice. Here we show that loss of IL-6 reduced JAK-STAT signalling, tumour incidence and metastasis. We also show that ∆122p53 activates RhoA-ROCK signalling leading to tumour cell invasion, which is IL-6-dependent and can be reduced by inhibition of JAK-STAT and RhoA-ROCK pathways. Similarly, we show that Δ133p53 activates these pathways, resulting in invasive and migratory phenotypes in colorectal cancer cells. Gene expression analysis of colorectal tumours showed enrichment of GPCR signalling associated with ∆133TP53 mRNA. Patients with elevated ∆133TP53 mRNA levels had a shorter disease-free survival. Our results suggest that ∆133p53 promotes tumour invasion by activation of the JAK-STAT and RhoA-ROCK pathways, and that patients whose tumours have high ∆133TP53 may benefit from therapies targeting these pathways.