Polysomnographic features of low arousal threshold in overlap syndrome involving obstructive sleep apnea and chronic obstructive pulmonary disease.

PURPOSE: In patients with overlap syndrome (OVS), the pathophysiologies of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease can interact with one another. Focusing on low arousal threshold, the authors evaluated polysomnographic features of OVS patients. METHODS: This retrospective, multicenter study was conducted at three hospitals in Japan. Patients aged ≥ 60 years who underwent polysomnography and pulmonary function testing were reviewed. Severity of airflow limitation (AFL) was classified according to the Global Initiative for Chronic Obstructive Lung Disease criteria. Low arousal threshold was predicted based on the following polysomnography features: lower apnea-hypopnea index (AHI); higher nadir oxygen saturation, and larger hypopnea fraction of total respiratory events. These features were compared among patients with only OSA (n = 126), OVS with mild AFL (n = 16), and OVS with moderate/severe AFL (n = 22). RESULTS: A low arousal threshold was more frequently exhibited by OVS patients with moderate/severe AFL than by those with OSA only (p = 0.016) and OVS with mild AFL (p = 0.026). As forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) decreased in OVS patients, the mean length of apnea decreased (r = 0.388, p = 0.016), hypopnea fractions increased (r = - 0.337, p = 0.039), and AHI decreased (r = 0.424, p = 0.008). FEV1/FVC contributed to low arousal threshold independent of age, sex, smoking history, hospital, or body mass index in all subjects (OR 0.946 [95% CI 0.909-0.984]) and in OVS patients (OR 0.799 [95% CI 0.679-0.940]). CONCLUSIONS: This study first described peculiar polysomnographic features in OVS patients with moderate/severe AFL, suggesting a high prevalence of low arousal threshold.

Pharmacological effects of lysozyme on COPD and bronchial asthma with sputum: A randomized, placebo-controlled, small cohort, cross-over study.

BACKGROUND: Mucolytic agents are often used in Japan to ease excessive mucus production in patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma (BA); the treatment ameliorates dyspnea and improves quality of life (QOL). AIM: Efficacy and safety of lysozyme hydrochloride (LYS), an oral mucolytic enzyme preparation, for patients with COPD or BA were investigated. PATIENTS AND METHODS: This study was a placebo-controlled, double-blind, randomized, cross-over design. Twenty-four patients with COPD and twenty-four patients with BA were enrolled. LYS or placebo was administered for 28 days in each treatment period, with a 28-day washout between the first and second treatment periods. The results of spirometry, impulse oscillometry system (IOS) examination, fractional exhaled nitric oxide (FeNO) measurement, as well as the changes in the subjective symptoms, were evaluated after the treatment period. RESULTS: On spirometry, airway function (FEV1) improved in patients with COPD after administration of LYS (LYS vs placebo: 0.08 L vs 0.029 L, p = 0.030). Similar trends were also found in %FEV1 in COPD patients. On IOS examination, resistance of the respiratory system at 5 Hz levels was significantly improved only in patients with COPD (LYS vs placebo: -0.455 cm H2O/L/s vs 0.095 cmH2O/L/s, p = 0.012). Similar trends were found in terms of the resistance of the respiratory system at 20 Hz, and of the reactance area. In the COPD assessment test, subjective symptoms also significantly improved in patients with COPD during the LYS treatment period (improvement rates-LYS vs. placebo: 69.6% vs. 39.1%; p = 0.022). A similar effect of LYS was not seen in BA patients. CONCLUSION: LYS, a mucolytic agent, has capability to improve the function of peripheral airways in patients with COPD, which leads to improvements of the patients' symptoms and QOL.

Practical surrogate marker of pulmonary dysanapsis by simple spirometry: an observational case-control study in primary care.

BACKGROUND: We see patients who present with spirometry airflow limitation despite their forced expiratory volume in one second (FEV1) as well as forced vital capacity (FVC) to be supernormal (FEV1/FVC < 70%, both the %FEV1 and the %FVC ≧ 100%) in asymptomatic healthy non-smokers. Based on previous studies, we hypothesized these spirometry conditions (results measured with spirometry) could be suitably used as a practical surrogate marker of pulmonary dysanapsis: the condition of disproportionate but physiologically normal growth between airways and lung parenchyma. METHODS: We compared the conventional surrogate marker of dysanapsis, maximum mid-expiratory flow to FVC (MMF/FVC), in SUBJECTS (FEV1/FVC < 70%, both the %FEV1 and the %FVC ≧ 100% in healthy non-smokers) (n = 25), in EMPHYSEMA (CT confirmed pulmonary emphysema, same spirometry results with SUBJECTS) (n = 55), and in CONTROLS (age- and height- matched, normal spirometry results) (n = 25). Next we added imaging analysis to evaluate the relationship between the cross sectional airway luminal area (X-Ai) and the lung volume results among the three groups. RESULTS: The MMF/FVC was significantly lower in SUBJECTS and in EMPHYSEMA compared to CONTROLS. However, percent predicted peak expiratory flow (%PEFR) was significantly lower only in SUBJECTS and not in EMPHYSEMA compared to CONTROLS. The ratio of the X-Ai of the trachea and right apical bronchus to lung volume was significantly lower in SUBJECTS compared to CONTROLS. CONCLUSION: The simple spirometry conditions in SUBJECTS are highly suggestive of practical surrogate marker of pulmonary dysanapsis. Awareness of this concept would help to attenuate the risk of overdiagnosis of obstructive pulmonary disease.

Vitamin C prevents cigarette smoke-induced pulmonary emphysema in mice and provides pulmonary restoration.

Vitamin C (VC) is a potent antioxidant and is essential for collagen synthesis. We investigated whether VC treatment prevents and cures smoke-induced emphysema in senescence marker protein-30 knockout (SMP30-KO) mice, which cannot synthesize VC. Two smoke-exposure experiments using SMP30-KO mice were conducted. In the first one (a preventive study), 4-month-old mice received minimal VC (0.0375 g/l) [VC(L)] or physiologically sufficient VC (1.5 g/l) [VC(S)] and exposed to cigarette smoke or smoke-free air for 2 months. Pulmonary evaluations followed when the mice were 6 months of age. The second study began after the establishment of smoke-induced emphysema (a treatment study). These mice no longer underwent smoke exposure but received VC(S) or VC(L) treatment for 2 months. Morphometric analysis was performed, and measurements of oxidative stress, collagen synthesis, and vascular endothelial growth factor in the lungs were evaluated. Chronic smoke exposure caused emphysema (29.6% increases of mean linear intercepts [MLI] and 106.5% increases of destructive index compared with the air-only group) in 6-month-old SMP30-KO mice, and this emphysema closely resembled human chronic obstructive pulmonary disease. Smoke-induced emphysema persisted in the VC(L) group after smoking cessation, whereas VC treatment provided pulmonary restoration (18.5% decrease of MLI and 41.3% decrease of destructive index compared with VC(L) group). VC treatment diminished oxidative stress, increased collagen synthesis, and improved vascular endothelial growth factor levels in the lungs. Our results suggest that VC not only prevents smoke-induced emphysema in SMP30-KO mice but also restores emphysematous lungs. Therefore, VC may provide a new therapeutic strategy for treating chronic obstructive pulmonary disease in humans.

Budesonide/formoterol via Turbuhaler® versus formoterol via Turbuhaler® in patients with moderate to severe chronic obstructive pulmonary disease: phase III multinational study results.

BACKGROUND AND OBJECTIVE: The efficacy and tolerability of budesonide/formoterol versus formoterol in patients with moderate to severe chronic obstructive pulmonary disease (COPD) was evaluated. METHODS: In this randomized, double-blind, parallel-group, phase III study (NCT01069289), patients with moderate to severe COPD for ≥2 years received either budesonide/formoterol 160/4.5 µg two inhalations twice daily via Turbuhaler® or formoterol 4.5 µg two inhalations twice daily via Turbuhaler® for 12 weeks. Salbutamol was available as reliever medication. Primary outcome variable: change from baseline to average during treatment in pre-dose forced expiratory volume in 1 s (FEV1 ). RESULTS: One thousand two hundred ninety-three patients were randomized (budesonide/formoterol n = 636; formoterol n = 657). Both budesonide/formoterol and formoterol increased pre-dose FEV1 versus baseline (improvements of 4.6% and 1.5% over baseline, respectively), with the increase from baseline being significantly greater with budesonide/formoterol versus formoterol (budesonide/formoterol:formoterol ratio 1.032; 95% confidence interval: 1.013-1.052; P = 0.0011). The budesonide/formoterol group had a significantly prolonged time to first exacerbation versus the formoterol group (hazard ratio: 0.679; 95% confidence interval: 0.507-0.909; P = 0.0094) and significantly greater improvements in many secondary outcome measures. Both treatments were well tolerated; the incidence and type of adverse events were similar: most commonly reported (budesonide/formoterol vs formoterol): COPD (8.0% vs 9.4%) and nasopharyngitis (5.5% vs 4.9%). CONCLUSIONS: Budesonide/formoterol 160/4.5 µg two inhalations twice daily was effective and well tolerated in patients with moderate to severe COPD, offering benefits over formoterol alone in terms of improved lung function and reduced risk of exacerbation.

Efficacy and safety of indacaterol 150 and 300 µg in chronic obstructive pulmonary disease patients from six Asian areas including Japan: a 12-week, placebo-controlled study.

BACKGROUND AND OBJECTIVE: The efficacy and safety of indacaterol, a novel inhaled once daily ultra long-acting ß(2) -agonist was evaluated in COPD patients in six Asian countries/areas. This study was primarily designed to obtain the regulatory approval of indacaterol in Japan. METHODS: Moderate-to-severe COPD patients were randomized to indacaterol 150 µg, indacaterol 300 µg or placebo once daily. Efficacy variables: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), health status (St. George's Respiratory Questionnaire) and transition dyspnoea index at week 12. Safety/tolerability was evaluated. RESULTS: A total of 347 patients were randomized (96.5% male, mean (SD) age 66.7 (8.38) years, post-bronchodilator FEV(1) % predicted: 53.7 (12.50)); 88.8% completed. The least squares means (LSM) trough FEV(1) at week 12 for indacaterol 150 µg, indacaterol 300 µg and placebo were 1.34 L, 1.37 L and 1.17 L, respectively, with differences versus placebo exceeding the prespecified minimal clinically important difference of 0.12 L (0.17 L and 0.20 L for indacaterol 150 µg and 300 µg, respectively, both P < 0.001). The week 12 LSM transition dyspnoea index score was statistically superior for both indacaterol doses versus placebo (differences of 1.30 and 1.26, P < 0.001; both exceeding the minimal clinically important difference of 1). At week 12, both indacaterol doses provided statistically significant (P ≤ 0.005) and clinically meaningful (≥4 units) improvements in LSM St. George's Respiratory Questionnaire total score versus placebo (differences: -4.8 and -5.7 units). Adverse events for indacaterol (49.1%, both doses) were lower than placebo (59.0%) and were mostly mild/moderate in severity; no deaths were reported. CONCLUSIONS: Indacaterol provided clinically significant bronchodilation and improvements in dyspnoea and health status in Asian COPD patients.

Transdermal tulobuterol patch, a long-actingß(2)-agonist.

Tulobuterol patch (HokunalinTM Tape), which contains a ß(2)-adrenergic agonist, is the first bronchodilator to be available as a transdermal patch. This drug delivery system ensures that the time at which the peak drug concentration in the blood is reached coincides with the morning dip in respiratory function. The use of the patch also prevents excessive increase in blood drug concentrations, thereby reducing the incidence of systemic adverse reactions. Since 1998, when it was first approved in Japan and worldwide, the tulobuterol patch has been used widely in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD), and evidence collected since it was approved has confirmed its clinical efficacy and safety. Because the patch is easy to use and requires only once-daily application, treatment adherence of patients using the patch is good. In this article, we discuss the rationale behind the development of the tulobuterol patch, evaluate data on its clinical efficacy and safety in the treatment of asthma and COPD, and examine the treatment adherence in individuals using the patch.

Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.

BACKGROUND AND OBJECTIVE: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial. METHODS: Subgroup analysis from a randomized, double-blinded, placebo-controlled trial of tiotropium 18 µg daily in COPD. Primary end-point was rate of decline in FEV(1) . Secondary end-points included spirometry at individual time points, health-related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. RESULTS: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m(2) ; post-bronchodilator FEV(1) : 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV(1) although annual decline was less in Asian patients. Morning pre-bronchodilator FEV(1) and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57-0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62-1.05) and 0.85 (0.61-1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5-6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. CONCLUSIONS: In COPD patients from Asia, tiotropium improves lung function, improves health-related quality of life and reduces exacerbations over 4 years of treatment.

Efficacy and safety of inhaled formoterol 4.5 and 9 µg twice daily in Japanese and European COPD patients: phase III study results.

BACKGROUND: This study evaluated the efficacy and safety of the long-acting ß2-agonist formoterol in patients with moderate-to-severe COPD. METHODS: This double-blind, placebo-controlled, parallel-group, multinational phase III study randomized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 µg twice daily (bid) via Turbuhaler or placebo for 12 weeks. Salbutamol 100 µg/actuation via pMDI was permitted as reliever medication. The primary outcome variable was change (ratio) from baseline to treatment period in FEV1 60-min post-dose. RESULTS: 613 patients received treatment (formoterol 4.5 µg n = 206; 9 µg n = 199; placebo n = 208); 539 (87.9%) male; 324 (52.9%) Japanese and 289 (47.1%) European. End of study increases in FEV1 60-min post-dose were significantly greater (p < 0.001 for both) with formoterol 4.5 and 9 µg bid (113% of baseline for both) than with placebo, as were all secondary outcome measures. The proportion of patients with an improvement in St George's Respiratory Questionnaire score of ≥ 4 was 50.2% for formoterol 4.5 µg (p = 0.0682 vs. placebo), 59.2% (p = 0.0004) for 9 µg, and 41.3% for placebo. Reduction in reliever medication use was significantly greater with formoterol vs. placebo (9 µg: -0.548, p < 0.001; 4.5 µg: -0.274, p = 0.027), with 9 µg being significantly superior to 4.5 µg (-0.274, p = 0.029). Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups. CONCLUSIONS: Formoterol 4.5 µg and 9 µg bid was effective and well tolerated in patients with COPD; there was no difference between formoterol doses for the primary endpoint; however, an added value of formoterol 9 µg over 4.5 µg bid was observed for some secondary endpoints. TRIAL REGISTRATION: NCT00628862 (ClinicalTrials.gov); D5122C00001 (AstraZeneca Study code).

Bronchodilator efficacy of single doses of indacaterol in Japanese patients with COPD: A randomised, double-blind, placebo-controlled trial.

BACKGROUND: Indacaterol is an investigational, novel, inhaled once-daily ultra-long-acting beta-2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the 24-h bronchodilatory efficacy and safety of indacaterol in Japanese patients with COPD. METHODS: This Phase-II, randomised, placebo-controlled, crossover study comprised four double-blind, single-dose treatment periods (washout between periods: 14-28 days). Japanese patients aged 40-75 years with moderate-to-severe COPD were randomised to receive single doses of indacaterol (150, 300, or 600 microg) or placebo via a single-dose dry-powder inhaler. Efficacy (primary endpoint: standardised FEV(1)AUC(22-24h)) and safety were assessed for 24 h post-dose in each treatment period. RESULTS: Of the 50 patients randomised (92% male; mean age, 67.2 years), 45 completed the study. Standardised FEV(1)AUC(22-24h) was significantly higher for all indacaterol doses as compared with placebo, with clinically relevant differences of 130, 160, and 170 mL for 150, 300, and 600 microg, respectively (P < 0.001). The improvement in FEV(1) was seen as early as 5 min post-dose with indacaterol and sustained for 24 h (P < 0.001 vs placebo at all time points). All indacaterol doses were well tolerated and showed no clinically meaningful effect on pulse rate, blood pressure, QTc interval, and laboratory parameters when compared with placebo. CONCLUSIONS: In the Japanese COPD population studied, single doses of indacaterol (150, 300, and 600 microg) provided sustained 24-h bronchodilation, with onset of action within 5 min post-dose. All doses were well tolerated. These results are consistent with data from Caucasian populations.

Osteopontin expression in pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma.

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by fibrocellular intimal proliferation and thrombus formation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. Osteopontin (OPN) is a multifunctional cytokine and adhesive protein, and has been demonstrated to be implicated in fibrosis, neointima formation, arterial occlusion by thrombus, and tumor metastases in cooperation with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Herein is described an autopsy case of gastric adenocarcinoma with severe pulmonary hypertension due to PTTM. Histologically, tumor cell emboli markedly induced both fibromuscular intimal thickening and thrombosis, resulting in luminal stenosis and occlusion of small pulmonary arteries and arterioles. Tumor cells, both in the PTTM lesions and primary gastric carcinoma, had positive immunoreactivity for OPN, PDGF, and VEGF. In addition, proliferating fibromuscular intimal cells also showed expression of OPN, PDGF, and VEGF. These findings suggest that OPN may be involved in fibrocellular intimal proliferation and thrombus formation in PTTM together with PDGF and VEGF. To the best of the authors' knowledge this is the first report to demonstrate the possible involvement of OPN in PTTM. It is postulated that OPN is one of the candidate molecules for the development of PTTM.

Borderline pulmonary hypertension associated with chronic hypercapnia in chronic pulmonary disease.

Pulmonary hypertension (PH) due to lung diseases is classified as group 3 by the Dana Point classification. Given the basic pathophysiological conditions of group 3 lung diseases and the previously well-known concept of hypercapnic pulmonary vasoconstriction, chronic hypercapnia besides alveolar hypoxia might be another causative factor to increase mean pulmonary arterial pressure (PAm). Two hundred twenty-five subjects with chronic pulmonary diseases were assessed by a right heart catheterization and blood gas parameters. The subjects were classified into the following 4 groups: Hypercapnic Hypoxia (HCHX), Hypercapnic Normoxia (HCnx), Normocapnic Hypoxia (ncHX), and Normocapnic Normoxia (ncnx). Compared with ncnx, the HCHX, HCnx and ncHX groups all showed significantly higher PAm and met the criteria of borderline PH. Multiple regression analysis showed that PaCO2, as well as SaO2, was an independent variable for PAm. Given the poor prognosis with borderline PH, the elimination of excess pulmonary carbon dioxide in hypercapnia could be a considerable treatment strategy in chronic pulmonary disease.

Lung Fixation under Constant Pressure for Evaluation of Emphysema in Mice.

Emphysema is a significant feature of chronic obstructive pulmonary disease (COPD). Studies involving an emphysematous mouse model require optimal lung fixation to produce reliable histological specimens of the lung. Due to the nature of the lung's structural composition, which consists largely of air and tissue, there is a risk that it collapses or deflates during the fixation process. Various lung fixation methods exist, each of which has its own advantages and disadvantages. The lung fixation method presented here utilizes constant pressure to enable optimal tissue evaluation for studies using an emphysematous mouse lung model. The main advantage is that it can fix many lungs with the same condition at one time. Lung specimens are obtained from chronic cigarette smoke-exposed mice. Lung fixation is performed using specialized equipment that enables the production of constant pressure. This constant pressure maintains the lung in a reasonably inflated state. Thus, this method generates a histological specimen of the lung that is suitable to evaluate cigarette smoke-induced mild emphysema.

Isolated congenital spleen agenesis: a rare cause of chronic thromboembolic pulmonary hypertension in an adult.

This report describes a case of isolated congenital spleen agenesis complicated by chronic thromboembolic pulmonary hypertension (CTPH) in a 44-year-old female patient. The patient had increasing exertional dyspnoea and thrombocytosis. An echocardiogram showed severe pulmonary hypertension and right ventricular hypertrophy, and contrast-enhanced chest CT revealed multiple thromboemboli within both pulmonary arteries. A perfusion lung scan demonstrated multiple segmental defects and no spleen was detected by abdominal CT, ultrasonography or scintigraphy. Comprehensive clinical examinations disclosed no evidence of a thrombus elsewhere or of an associated malformation such as a cardiac anomaly. Anticoagulation therapy was started, and a perfusion lung scan revealed partial improvement of the hypoperfusion in the right lower lobe. However, repeat echocardiography showed the pulmonary hypertension persisting for 1 year. The multiple segmental defects in the perfusion lung scans were also persistent. Collectively, a diagnosis of CTPH with isolated congenital spleen agenesis was established. This is the first documented case of CTPH in an adult with isolated congenital asplenia. Although congenital spleen agenesis is a rare condition, this case report suggests that this possibility should be considered when a diagnosis of CTPH and thrombocytosis is made.

Downregulation of angiopoietin-1 and Tie2 in chronic hypoxic pulmonary hypertension.

BACKGROUND: Angiopoietins, newly discovered vascular-specific growth factors, and vascular endothelial growth factors (VEGF) play distinct and complementary roles in angiogenesis and vascular maturation. However, the exact roles of angiogenic factors in the adult pulmonary vasculature remain unclear. OBJECTIVE: To elucidate possible roles of angiopoietins and VEGF in the development of hypoxic pulmonary hypertension (PH), changes in the expression of angiogenic factors were examined. METHODS: The cellular distribution and expression of angiopoietins and their receptor Tie2 and VEGF were investigated by RT-PCR, immunoblot, and immunohistochemical methods in rat lung under normal and hypoxic conditions. RESULTS: During the development of PH with vascular remodeling characterized by a decrease in vessel density of intrapulmonary arteries, protein expression of angiopoietin-1 (Ang-1), Tie2, and VEGF significantly decreased in the pulmonary arteries, and Tie2 receptor was inactivated in the lung. The expression of angiopoietin-3 (Ang-3), an endogenous antagonist of Ang-1, significantly increased in the intima under hypoxic conditions. CONCLUSIONS: Since both Ang-1/Tie2 and VEGF promote angiogenesis and vascular survival, and play protective roles in the adaptation of microvascular changes during the onset of PH, the downregulation of both Ang-1/Tie2 and VEGF and upregulation of Ang-3 appear to be associated with vascular rarefaction and the development of hypoxic PH.

[Evaluation of clinical effectiveness of Pazufloxacin Mesilate in acute exacerbation of chronic respiratory diseases].

Patients with chronic respiratory disease have increased susceptibility to infection, because of impairment of the local immunologic defense mechanism in the airway system, which often results in acute exacerbation. Acute exacerbation of chronic respiratory disease is one of the most important predictors of increased morbidity and mortality, and thus the management in the acute phase is essential for better prognosis. Although the clinical guidelines for the management of respiratory tract infections published by the Japanese Respiratory Society recommend administering fluoroquinolones intravenously in case of hospitalized patients, the clinical evidence is still limited. In this study, we evaluated the efficacy of Pazufloxacin Mesilate (PZFX). an intravenous fluoroquinolone. in patients with chronic respiratory diseases complicated with acute exacerbation caused by acute respiratory infections. As a result, 16 out of 18 cases were successfully treated with PZFX. No adverse event was observed during this study. These results may support the validity of administering intravenous fluoroquinolone in hospitalized patients with acute exacerbation caused by infections, as recommended by the Japanese Respiratory Society.

COPD uncovered: a cross-sectional study to assess the socioeconomic burden of COPD in Japan.

Background: COPD remains a major health problem in Japan. Patients with COPD experience a reduced quality of life (QoL) and have a higher chance of work impairment and productivity loss. However, there is a lack of data on the impact of COPD in terms of QoL and work activity impairment in Japan. This study assessed the socioeconomic burden of COPD in Japan and the impact it may have on the working age population. Patients and methods: This was a 2-year retrospective chart review in COPD patients aged ≥40 years, with at least one health care visit to clinic or hospital in the previous 12 months. Patients were required to have available medical charts for at least the previous 24 months. Symptoms were assessed using COPD assessment test score; EuroQoL Group 5 Dimension (EQ-5D-5L) and work productivity and activity impairment general health questionnaires were used to evaluate health-related QoL and work productivity, and health care resource utilization data were obtained from clinical charts. Results: In total, 71 patients aged <65 years, and 151 patients aged ≥65 years were included; the majority of patients had moderate or severe airflow limitation. Exacerbations (moderate or severe) were reported by ~35% of patients in both age groups; 52.1% and 62.9% of patients in the <65-year and ≥65-year age groups had COPD assessment test scores ≥10. EQ-5D-5L index scores in the <65-year and ≥65-year age groups were 0.79 and 0.77, respectively. Work productivity and activity impairment scores were higher in <65-year age group. Annual costs of health care resource use per patient in the <65-year and ≥65-year age groups were ¥438,975 (US$4,389) and ¥467,871 (US$4,678), respectively. Costs due to productivity loss were estimated to be ¥5,287,024 (US$52,870) in the <65-year age group and ¥3,018,974 (US$30,187) in the ≥65-year age group. Conclusion: COPD represents a significant socioeconomic burden in Japan. Patients with COPD report significant use of health care resources. Higher impact on work impairment and productivity loss was observed frequently in the working age population.

Abrogation of the interaction between osteopontin and alphavbeta3 integrin reduces tumor growth of human lung cancer cells in mice.

Osteopontin (OPN) is a multifunctional cytokine involved in cell signaling by interacting with alphavbeta3 integrins. Recent clinical studies have indicated that OPN expression is associated with tumor progression and poor prognosis among patients with lung cancer. However, the biological role of OPN in human lung cancer has not yet been well-defined. The purpose of this study is to investigate and provide evidence for the causal role of OPN regarding tumor growth and angiogenesis in human lung cancer. In this study, we developed a stable OPN transfectant from human lung cancer cell line SBC-3 which does not express the intrinsic OPN mRNA. To reveal the in vivo effect of OPN on tumor growth of human lung cancer, we subcutaneously injected OPN-overexpressing SBC-3 cells (SBC-3/OPN) and control cells (SBC-3/NEO) into the nude mice. Transfection with the OPN gene significantly increased in vivo tumor growth and neovascularization of SBC-3 cells in mice. These in vivo effects of OPN were markedly suppressed with administration of anti-alphavbeta3 integrin monoclonal antibody or anti-angiogenic agent, TNP-470. Furthermore, recombinant OPN protein enhanced human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and this enhancement was significantly inhibited with the addition of anti-alphavbeta3 integrin antibody. Taken together, these results suggest that OPN plays a crucial role for tumor growth and angiogenesis of human lung cancer cells in vivo by interacting with alphavbeta3 integrin. Targeting the interaction between OPN and alphavbeta3 integrin could be effective for future development of anti-angiogenic therapeutic agents for patients with lung cancer.

IL-2-induced IL-9 production by allergen-specific human helper T-cell clones.

BACKGROUND: IL-9 is an important cytokine in allergic diseases such as asthma, atopic dermatitis, etc. T helper (Th) cells seem to be the main source of IL-9. Cellular and molecular mechanisms of IL-9 production by human Th cells have been poorly understood. METHODS: Dermatophagoides farinae(Der f)-specific Th clones were established from peripheral blood lymphocytes of atopic asthmatics, and cytokine synthesis in response to various stimuli was determined by specific ELISAs. RESULTS: IL-9 was produced by 14 of 27 human Th clones upon T cell receptor (TCR) stimulation, immobilized anti-CD3 antibody (Ab). IL-9 production was significantly enhanced by the addition of anti-CD28 Ab into the culture, indicating the role of costimulatory signal on IL-9 synthesis. Pharmacologically, IL-9 production was induced by ionomycin (IOM) alone, and enhanced by phorbol 12-myristate 13-acetate (PMA). rIL-2 induced IL-9 production by 8 out of 19 Th clones. IL-9 production by Th clones stimulated with immobilized anti-CD3 Ab was significantly suppressed by the addition of anti-IL-2 neutralizing Ab into the culture. CONCLUSION: Approximately half of the Der f-specific Th clones derived from atopic asthmatics produced IL-9 upon TCR stimulation. Ca(2+) signal, CD28 signal, and IL-2 receptor signal seem to play important roles in IL-9 production by human Th cells. Moreover, synthesis of IL-9, a Th2 cytokine, is dependent on IL-2, a Th1 cytokine, which is produced by Th cells themselves.