Continuous-time random walks on networks with vertex- and time-dependent forcing.

We have investigated the transport of particles moving as random walks on the vertices of a network, subject to vertex- and time-dependent forcing. We have derived the generalized master equations for this transport using continuous time random walks, characterized by jump and waiting time densities, as the underlying stochastic process. The forcing is incorporated through a vertex- and time-dependent bias in the jump densities governing the random walking particles. As a particular case, we consider particle forcing proportional to the concentration of particles on adjacent vertices, analogous to self-chemotactic attraction in a spatial continuum. Our algebraic and numerical studies of this system reveal an interesting pair-aggregation pattern formation in which the steady state is composed of a high concentration of particles on a small number of isolated pairs of adjacent vertices. The steady states do not exhibit this pair aggregation if the transport is random on the vertices, i.e., without forcing. The manifestation of pair aggregation on a transport network may thus be a signature of self-chemotactic-like forcing.

Peripheral blood dendritic cell subtypes are significantly elevated in subjects with asthma.

BACKGROUND: Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non-smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. OBJECTIVE: Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. METHODS: Forty-three asthmatics (17 smokers, nine ex-smokers and 17 never-smokers) and 16 healthy volunteers (nine smokers and seven never-smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA-2, CD303), type 1 conventional (cDC) (BDCA-1, CD1c), and type 2 cDC (BDCA-3, CD141)]. RESULTS: Subjects with asthma displayed increases in all DC subtypes compared with normal never-smokers: [type 1 cDCs - asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never-smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs - asthma: 0.04% (0.02, 0.06), normal never-smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs - asthma: 0.32% (0.27, 0.46), normal never-smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never-smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non-asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical trials.gov identifier: NCT00411320)

Effect of improved home ventilation on asthma control and house dust mite allergen levels.

BACKGROUND: The warm, humid environment in modern homes favours the dust mite population, but the effect of improved home ventilation on asthma control has not been established. We tested the hypothesis that a domestic mechanical heat recovery ventilation system (MHRV), in addition to allergen avoidance measures, can improve asthma control by attenuating re-colonization rates. METHODS: We conducted a randomized double-blind placebo-controlled parallel group trial of the installation of MHRV activated in half the homes of 120 adults with asthma, allergic to Dermatophagoides pteronyssinus. All homes had carpets steam cleaned and new bedding and mattress covers at baseline. The primary outcome was morning peak expiratory flow (PEF) at 12 months. RESULTS: At 12 months, the primary end-point; change in mean morning PEF as compared with baseline, did not differ between the MHRV group and the control group (mean difference 13.5 l/min, 95% CI: -2.6 to 29.8, P = 0.10). However, a secondary end-point; evening mean PEF, was significantly improved in the MHRV group (mean difference 24.5 l/min, 95% CI: 8.9-40.1, P = 0.002). Indoor relative humidity was reduced in MHRV homes, but there was no difference between the groups in Der p 1 levels, compared with baseline. CONCLUSIONS: The addition of MHRV to house dust mite eradication strategies did not achieve a reduction in mite allergen levels, but did improve evening PEF.

Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma.

Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 microg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV(1)) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75)) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-gamma agonists in steroid-resistant airway disease are indicated.

Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study.

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.

Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma.

BACKGROUND: Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function and airway inflammation in atopic adults with asthma. METHODS: 54 adults with atopic asthma were recruited to a double-blind randomised controlled crossover trial comparing the effect of oral atorvastatin 40 mg daily with that of a matched placebo on asthma control and airway inflammation. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included forced expiratory volume in 1 s, asthma control questionnaire score, airway hyper-responsiveness to methacholine, induced sputum cytology and inflammatory biomarkers. RESULTS: At 8 weeks the change in mean morning PEF compared with baseline did not differ substantially between the atorvastatin and placebo treatment periods (mean difference -0.5 l/min, 95% CI -10.6 to 9.6, p = 0.921). Values for other clinical outcomes were similar between the atorvastatin and placebo treatment periods. The absolute sputum macrophage count was reduced after atorvastatin compared with placebo (mean difference -45.0 x 10(4) cells, 95% CI -80.1 to -9.7, p = 0.029), as was the sputum fluid leucotriene B4 (mean difference -88.1 pg/ml, 95% CI -156.4 to -19.9, p = 0.014). CONCLUSION: The addition of atorvastatin to inhaled corticosteroids results in no short-term improvement in asthma control but reduces sputum macrophage counts in mild to moderate atopic asthma. The change in sputum macrophage count suggests potential areas for investigation of statins in other chronic lung diseases.