Budesonide/formoterol maintenance and reliever therapy in moderate-to-severe asthma: effects on eosinophilic airway inflammation.

Although the budesonide and formoterol in a single inhaler for maintenance and reliever therapy has been evaluated in recent studies, the effects on eosinophilic airway inflammation remain uncertain. The purpose of this study was to compare the efficacy, including anti-inflammatory effects, of as-needed budesonide/formoterol with salbutamol in Japanese patients with moderate-to-severe asthma. Patients with asthma using an inhaled corticosteroid plus a long-acting beta2-agonist as a controller and at least one asthma exacerbation in the previous 12 months were randomized to budesonide/formoterol maintenance therapy (160/4.5 micrograms, 2 inhalations twice daily) plus either as-needed budesonide/formoterol (160/4.5 micrograms; n = 32) or salbutamol (100 micrograms; n = 31) up to 4 inhalation daily for 48 weeks. The time to first asthma exacerbation was significantly prolonged with as-needed budesonide/formoterol compared with salbutamol (log-rank test; p = 0.0342). There was a 66% reduction in the hazard ratio for a first exacerbation with as-needed budesonide/formoterol (p = 0.0334). The frequencies of both mild and severe exacerbations and reliever use were consistently less with budesonide/formoterol than salbutamol. As-needed budesonide/formoterol significantly improved in lung function and symptom scores compared with salbutamol. In addition, the contents of eosinophil cationic protein and B12 tryptase, as well as number of eosinophils and mast cells in induced sputum, decreased to a greater extent with budesonide/formoterol compared with salbutamol. In conclusion, the budesonide and formoterol for maintenance and reliever therapy seems more effective in controlling persistent asthma with a significant reduction of airway inflammation. Clinical trial 121104, www.clinicaltrials.gov.

[The efficacy of indisetron hydrochloride for the management of chemotherapy-induced nausea and vomiting for lung cancer].

We set out to determine the efficacy of indisetron hydrochloride for the management of chemotherapy-induced nausea and vomiting including carboplatin for lung cancer. Indisetron hydrochloride was given orally to 32 patients (indisetron group), and intravenous 5-HT3 receptor antagonists were given to 24 patients (control group). The number of patients with nausea or vomiting occurring within 24 hours and 24 to 72 hours after chemotherapy was measured. The complete inhibition of the vomiting within 24 hours after chemotherapy was 100% in the indisetron group and 95.8% in the control group. Twenty-four to 72 hours after chemotherapy, the complete inhibition of vomiting rate was 97.1% and 95.8%, respectively. In addition, the complete inhibition of nausea rate within 24 hours after chemotherapy was 87.5% in the indisetron group and that was 95.8% in the control group. The complete inhibition of nausea rate 24 to 72 hours after chemotherapy was 56.3% and 70.8%, respectively. No serious adverse events were observed. The comparison of the efficacy between the indisetron group and control groups did not reach statistical significance (p> 0.05). These findings suggest that prophylactic administration of indisetron hydrochloride is useful for the inhibition of acute and delayed nausea and vomiting caused by chemotherapy in lung cancer patients.

Satellite imagery technology in public health: analysis of site catchment areas for assessment of poliovirus circulation in Nigeria and Niger.

Environmental surveillance supplements the surveillance of acute flaccid paralysis by monitoring wastewater for poliovirus circulation. Building on previous work, we analysed wastewater flow to optimise selection and placement of sampling sites with higher digital surface model (DSM) resolution. The newly developed 5-m mesh DSM from the panchromatic, remote-sensing instruments for stereo mapping on-board the Japanese advanced land observing satellite was used to estimate catchment areas and flow of sewage water based on terrain topography. Optimal sampling sites for environmental surveillance were identified to maximise sensitivity to poliovirus circulation. Population data were overlaid to prioritise selection of catchment areas with dense populations. The results for Kano City, Nigeria were compared with an analysis based on existing 30- and 90-m mesh digital elevation model (DEM). Analysis based on 5-m mesh DSM was also conducted for three cities in Niger to prioritise the selection of new sites. The analysis demonstrated the feasibility of using DSMs to estimate catchment areas and population size for programme planning and outbreak response with respect to polio. Alternative sampling points in Kano City that would cover a greater population size have been identified and potential sampling sites in Niger are proposed. Comparison with lower-resolution DEMs suggests that the use of a 5-m mesh DSMs would be useful where the terrain is flat or includes small-scale topographic changes not captured by 30-m data searches.

Hypotonicity-induced ATP release is potentiated by intracellular Ca2+ and cyclic AMP in cultured human bronchial cells.

We have examined the cultured human bronchial epithelial cells (16HBE) to learn if changes in Cl(-) concentration or osmolality stimulate the cells to release ATP and to determine whether its release is cyclic AMP (cAMP)- and/or Ca(2+)-dependent by using the luciferin-luciferase luminometric assay. In a control solution (290 mosmol kg H(2)O(-1)), the external ATP concentration and the rate of ATP release were 0.52 +/- 0.20 nM and 0.036 +/- 0.034 pmol min(-1), respectively. Upon hypotonicity (205 mosmol kg H(2)O(-1)), they increased to 7.0 +/- 1.3 nM and 3.1 +/- 0.6 pmol min(-1), respectively, at 6 min, then decreased. At the peak, the rate of ATP release is estimated to be 6.2x10(4) ATP molecules s(-1) per cell. An accumulation of the released ATP for the initial 10 min increased significantly (p < 0.005) by 71.5% in the presence of forskolin (10 microM), adenylyl cyclase activator, however, it was abolished (p < 0.001) by pretreatment with BAPTA-AM (25 microM), a membrane permeable Ca(2+) chelator. On the other hand, neither low Cl(2-) (75 mM, isotonic) nor hypertonicity (+NaCl or +mannitol, 500 mosmol kg H(2)O(-1)) could significantly increase the ATP release. Further, forskolin or ionomycin (a Ca(2+) ionophore) or, both, failed to stimulate ATP release under the isotonic condition. In conclusion, first, hypertonicity and changes in Cl(-) concentrations are not effective signals for the ATP release; second, hypotonicity-induced ATP release is potentiated by the level of intracellular Ca(2+) and cAMP; and third, a biphasic increase in ATP release and its low rate at the peak support the hypothesis that ATP is released through a non-conducting pathway model, such as exocytosis, or through a volume-dependent, ATP-conductive anion channel.

Role of regular treatment with inhaled corticosteroid or leukotriene receptor antagonist in mild intermittent asthma.

Current guidelines for asthma treatment do not recommend daily maintenance therapy in patients with mild intermittent (step 1) asthma. However, because there is increasing evidence that airway inflammation is present even in this patient group, maintenance anti-inflammatory therapy may be considered. We investigated the clinical impact of regular treatment with the inhaled corticosteroid beclomethasone dipropionate and the leukotriene receptor antagonist pranlukast in the patients concerned. The study was a randomized, controlled, parallel-group, multicenter trial. Eighty-five symptomatic patients with newly diagnosed mild intermittent asthma having normal pulmonary function were assigned beclomethasone or pranlukast for 8 weeks. Then, these medications were stopped for the next 16 weeks. Main outcome measures were asthma symptoms, pulmonary function, and airway inflammation. Treatment with beclomethasone and pranlukast significantly increased forced expiratory volume in 1 second and peak expiratory flow from baseline and decreased asthma symptom scores and sputum eosinophil counts and eosinophil cationic protein contents. After discontinuation of the treatment, symptom scores remained unchanged, but pulmonary function and airway inflammation were aggravated and then returned to the baseline levels. Therefore, maintenance therapy with inhaled corticosteroid or leukotriene receptor antagonist can provide further improvements in asthma symptoms, pulmonary function, and airway inflammation, and discontinuation of the therapy causes worsening of asthma, indicating that stopping or interrupting anti-inflammatory therapy may not be advisable in patients with symptomatic mild intermittent asthma.

Elimination of IL-13 reverses established goblet cell metaplasia into ciliated epithelia in airway epithelial cell culture.

BACKGROUND: Interleukin (IL)-13 induces goblet cell metaplasia and plays an important role in mucus hypersecretion in asthma. We previously reported that IL-13 induced goblet cell differentiation along with less ciliated cell differentiation in guinea pig tracheal epithelial cells in vitro. In this study, we asked whether elimination of IL-13 could reverse the established goblet cell metaplasia into ciliated epithelia. METHODS: Primary epithelial cells from guinea pig tracheas were cultured at an air-liquid interface with the medium containing human recombinant IL-13 for 14 days, and continuously cultured with IL-13-eliminated medium, or cultured under the condition of neutralization of IL-13 with anti IL-13 antibody. RESULTS: 2 days after elimination of IL-13, the periodic acid-Schiff-positive area as well as MUC5AC protein level rapidly decreased. After 4 days, the number of goblet cells dramatically decreased, while that of ciliated cells inversely increased. The total number of epithelial cells did not change, and 5-bromo-2'-deoxyuridine uptake decreased after IL-13 elimination. Transitional cells with cilia and secretory granules increased after IL-13 elimination. Similarly, the neutralization of IL-13 with anti-IL-13 antibody for 5 days reversed the goblet cell metaplasia into ciliated epithelia, and transitional cells also increased. CONCLUSIONS: Elimination of IL-13 reverses goblet cell metaplasia into ciliated epithelia in vitro, and transition of goblet cells to other phenotypes, especially ciliated cells, may be involved in this phenomenon. IL-13 inhibition may be a therapeutic strategy of established goblet cell metaplasia in asthma.

Peripheral blood Th1 and Th2 profile in patients with moderate asthma: effect of inhaled corticosteroid.

The peripheral blood from healthy subjects and asthma patients was stimulated with phorbol 12-myristate 13-acetate and ionomycin, and the cells were stained with anti-CD4 antibody, permeabilized, stained with anti-IFN-gamma and anti-IL-4 antibodies, and analyzed by flow cytometry. Compared with healthy subjects, asthma patients showed a greater percentage of both IL-4(+) IFN-gamma(-) CD4 cells (Th2 cells) and IFN-gamma(+) IL-4(-) CD4 cells (Th1 cells). The percentage of Th2 cells was correlated with serum IgE level. After treatment with inhaled corticosteroid, Th2 cells decreased at week 24, but not week 4. Long-term therapy with inhaled steroid may thus be required for improvement in lymphocytic inflammation.

Ultrafine carbon black particles stimulate proliferation of human airway epithelium via EGF receptor-mediated signaling pathway.

Exposure to ambient ultrafine particles induces airway inflammatory reactions and tissue remodeling. In this experiment, to determine whether ultrafine carbon black (ufCB) affects proliferation of airway epithelium and, if so, what the mechanism of action is, we studied human primary bronchial epithelial cell cultures. Incubation of cells in the serum-free medium with ufCB increased incorporations of [(3)H]thymidine and [(3)H]leucine into cells in a time- and dose-dependent manner. This effect was attenuated by Cu- and Zn-containing superoxide dismutase (Cu/Zn SOD) and apocynin, an inhibitor of NADPH oxidase, and completely inhibited by pretreatment with the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitors AG-1478 and BIBX-1382, and the mitogen-activated protein kinase kinase inhibitor PD-98059. Transfection of a dominant-negative mutant of H-Ras likewise abolished the effect ufCB. Stimulation with ufCB also induced processing of membrane-anchored proheparin-binding (HB)-EGF, release of soluble HB-EGF into the medium, association of phosphorylated EGF-R and Shc with glutathione-S-transferase-Grb2 fusion protein, and phosphorylation of extracellular signal-regulated kinase (ERK). Pretreatment with AG-1478, [Glu(52)]Diphtheria toxin, a specific inhibitor of HB-EGF, neutralizing HB-EGF antibody, Cu/Zn SOD, and apocynin each inhibited ufCB-induced ERK activation. These results suggest that ufCB causes oxidative stress-mediated proliferation of airway epithelium, involving processing of HB-EGF and the concomitant activation of EGF-R and ERK cascade.