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BACKGROUND: Inhaled medication is the cornerstone of pharmacological treatment for asthma. Poor inhaler techniques are associated with poor asthma control and an increased risk of exacerbations. Leaflets and videos are provided by several pharmaceutical companies to explain the proper techniques to patients. We investigated the effects of instructional materials (leaflet and video) on the patient's inhaler techniques. METHODS: The subjects were 67 medical students at Kagoshima University. They all were provided with two types of inhalation devices: a dry powder inhaler (DPI) and a pressurized metered-dose inhaler (pMDI). The students were assigned to three groups: (1) leaflet, (2) video, and (3) combination (leaflet + video). Pulmonologists observed and assessed the students' use of the devices by using a validated checklist. The percentage of subjects who avoided critical errors was also assessed. Critical errors were errors that affected drug delivery to the lungs substantially. RESULTS: The percentage of overall competence and the number of steps that were mastered out of the 11 steps were higher in the combination group than those in the other two groups. However, only 40% in the combination group were able to successfully execute every critical step. The percentage of subjects who avoided critical errors was also higher in the combination group than in the other groups. CONCLUSIONS: A single form of instructional materials (leaflet or video) was insufficient for acquiring proper inhaler techniques. The combination of two learning materials may help patients with asthma acquire proper inhaler techniques and subsequently, improve their asthma control.

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BACKGROUND: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). OBJECTIVES: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy. METHODS: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects. RESULTS: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10-24 for rs9271588 and P = 2.96 × 10-24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10-9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQß1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10-8). CONCLUSIONS: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.

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Objective This multicenter, cross-sectional, non-interventional trial aimed to investigate adherence barriers to inhaled medicines when compared with oral medicines in Japanese patients with chronic obstructive pulmonary disease (COPD) and asthma. Methods The self-reporting "Adherence Starts with Knowledge 20" (ASK-20) questionnaire was administered for adherence barriers of inhaled and oral medicines to outpatients with regular clinic attendance. Results Patients with COPD and asthma reported different adherence barriers to inhaled medicines. Independent adherence barriers [odds ratio (95% confidence interval)] to inhaled medicines relative to those for oral medicines among patients with COPD and asthma were those related to item Q8 [ "I know if I am reaching my health goals"; 2.49 (1.39-4.47); p=0.0022] and item Q2 [ "I run out of my medicine because I do not get refills on time"; 2.69 (1.26-5.75); p=0.0127], respectively. Among patients with poor adherence to only inhaled medicines, those with COPD and asthma recognized item Q3 [ "consuming alcohol and taking medicines"; 6.63 (1.27-34.7); p<0.05] and item Q1 [ "forget to take medicines only sometimes"; 4.29 (1.83-10.0); p<0.05], respectively, were recognized as independent adherence barriers to inhaled medicines. The total ASK-20 scores and total barrier counts in patients with poor adherence to inhaled medicines were significantly higher than in those without poor adherence among patients with asthma (p=0.0057) but not those with COPD (p>0.05). Conclusion These results will aid in personalizing education on adherence to inhaled medicines among patients with COPD and asthma.

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BACKGROUND: It is crucial to develop novel diagnostic approaches for determining if peripheral lung nodules are malignant, as such nodules are frequently detected due to the increased use of chest computed tomography scans. To this end, we evaluated levels of napsin A in epithelial lining fluid (ELF), since napsin A has been reported to be an immunohistochemical biomarker for histological diagnosis of primary lung adenocarcinoma. METHODS: In consecutive patients with indeterminate peripheral lung nodules, ELF samples were obtained using a bronchoscopic microsampling (BMS) technique. The levels of napsin A and carcinoembryonic antigen (CEA) in ELF at the nodule site were compared with those at the contralateral site. A final diagnosis of primary lung adenocarcinoma was established by surgical resection. RESULTS: We performed BMS in 43 consecutive patients. Among patients with primary lung adenocarcinoma, the napsin A levels in ELF at the nodule site were markedly higher than those at the contralateral site, while there were no significant differences in CEA levels. Furthermore, in 18 patients who were undiagnosed by bronchoscopy and finally diagnosed by surgery, the napsin A levels in ELF at the nodule site were identically significantly higher than those at the contralateral site. In patients with non-adenocarcinoma, there were no differences in napsin A levels in ELF. The area under the receiver operator characteristic curve for identifying primary lung adenocarcinoma was 0.840 for napsin A and 0.542 for CEA. CONCLUSION: Evaluation of napsin A levels in ELF may be useful for distinguishing primary lung adenocarcinoma.

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Chronic obstructive pulmonary disease (COPD) is a progressive lung disease associated with significant morbidity and mortality. Although several oral phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of COPD, their use has been restricted because of side effects including nausea and emesis. We hypothesized that delivery of a dry powdered PDE4 inhibitor by inhalation would minimize systemic absorption and enable local PDE4 inhibition to suppress inflammation within the lung. Neutrophilic pulmonary inflammation was induced in mice by intratracheal administration of lipopolysaccharide. Mice were treated intratracheally with a new dry powder PDE4 inhibitor, E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino) carbonyl] benzoate). The pharmacokinetics, cell profiles and levels of cytokines, chemokines, and lipid mediators in bronchoalveolar lavage fluid (BALF), and lung histology were assessed. Intratracheal administration of E6005 to mice resulted in high concentrations of the compound in the lungs. Histological analysis of E6005-treated mice demonstrated reduced inflammation of lung tissue that correlated with a decrease in BALF levels of neutrophils, proinflammatory cytokines, chemokines, and cysteinyl leukotrienes. Thus, intratracheal administration of E6005 effectively suppresses neutrophilic pulmonary inflammation, suggesting that the new inhaled dry powder PDE4 inhibitor represents an alternative to the conventional oral formulation for treating COPD.

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BACKGROUND: Interstitial lung diseases (ILDs) are common in patients with connective tissue diseases (CTDs). Although the diagnosis of an underlying CTD in ILD (CTD-ILD) affects both prognosis and treatment, it is sometimes difficult to distinguish CTD-ILD from chronic fibrosing interstitial pneumonia (CFIP). B cell-activating factor belonging to the tumour necrosis factor family (BAFF) plays a crucial role in B cell development, survival, and antibody production. METHODS: We examined serum levels of BAFF, surfactant protein D (SP-D), and Krebs von den Lungen-6 (KL-6) in 33 patients with CTD-ILD, 16 patients with undifferentiated CTD-ILD, 19 patients with CFIP, and 26 healthy volunteers. And we analysed the relationship between serum BAFF levels and pulmonary function, as well as the expression of BAFF in the lung tissue of patients with CTD-ILD. RESULTS: Serum levels of BAFF were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. However, there were no significant differences in serum levels of SP-D and KL-6. Furthermore, serum BAFF levels in CTD-ILD patients were inversely correlated with pulmonary function. BAFF was strongly expressed in the lungs of CTD-ILD patients, but weakly in normal lungs. DISCUSSION: This is the first study to demonstrate that serum BAFF levels were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. Furthermore, serum BAFF levels were correlated with pulmonary function. We consider that serum BAFF levels in patients with CTD-ILD reflect the presence of ILDs disease activity and severity. CONCLUSION: These finding suggest that BAFF may be a useful marker for distinguishing CTD-ILD from CFIP.

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Lung cancer is clearly the primary cause of cancer-related deaths worldwide. Recent molecular-targeted strategy has contributed to improvement of the curative effect of adenocarcinoma of the lung. However, such current treatment has not been developed for squamous cell carcinoma (SCC) of the disease. The new genome-wide RNA analysis of lung-SCC may provide new avenues for research and the development of the disease. Our recent microRNA (miRNA) expression signatures of lung-SCC revealed that clustered miRNAs miR-1/133a were significantly reduced in cancer tissues. Here, we found that restoration of both mature miR-1 and miR-133a significantly inhibited cancer cell proliferation, migration and invasion. Coronin-1C (CORO1C) was a common target gene of the miR-1/133a cluster, as shown by the genome-wide gene expression analysis and the luciferase reporter assay. Silencing of CORO1C gene expression inhibited cancer cell proliferation, migration and invasion. Furthermore, CORO1C-regulated molecular pathways were categorized by using si-CORO1C transfectants. Further analysis of novel cancer signaling pathways modulated by the tumor-suppressive cluster miR-1/133a will provide insights into the molecular mechanisms of lung-SCC oncogenesis and metastasis.

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Pulmonary involvement has been identified in human T-lymphotropic virus type I (HTLV-I) carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the relationship between HTLV-I infection and lung disease is poorly understood. The occurrence of HTLV-I-specific immune responses in the lungs of patients infected with HTLV-I with pulmonary involvement was investigated. The frequency of HTLV-I-specific CD8+ cells and the amount of HTLV-I proviral DNA were determined in bronchoalveolar lavage fluid cells and peripheral blood mononuclear cells (PBMCs) from five patients with HAM/TSP and one HTLV-I carrier who had pulmonary involvement. HTLV-I-specific CD8+ cells were detected by flow cytometry using human leukocyte antigen/antigen complex multimers. The analysis of bronchoalveolar lavage fluid revealed lymphocytosis in five of six patients. HTLV-I provirus was detected in the bronchoalveolar lavage fluid cells of all patients, and the proviral load in these cells was comparable to that in PBMCs. The frequency of HTLV-I-specific CD8+ cells in the bronchoalveolar lavage fluid cells was 5.1 times higher than that in PBMCs. Immunohistochemically, clusters formed by HTLV-I-specific CD8+ cells were detected in lung tissue by in situ tetramer staining. No samples were available from patients infected with HTLV-I without lung disorders. Whether accumulation of CD8+ cells is specific to patients with pulmonary involvement remains unclear. These results indicate that HTLV-I-specific CD8+ cells accumulate and HTLV-I-infected cells exist in the lungs of patients infected with HTLV-I with pulmonary involvement.

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A 50-year-old man presented with visual disturbance at a local ophthalmology clinic. He was given a diagnosis of uveitis and treated with oral corticosteroids; however, his visual disturbance did not improve and he was admitted to our hospital. A chest CT scan showed a pulmonary nodule in the upper lobe of the right lung, and right hilar and mediastinal lymphadenopathy. Transbronchial biopsy yielded a diagnosis of squamous cell carcinoma, and an ophthalmologic examination revealed bilateral diffuse uveal melanocytic proliferation (BDUMP). BDUMP is a rare manifestation of paraneoplastic syndrome, and the characteristics of the condition have not yet been clarified in detail. BDUMP carries a very poor visual prognosis, and in the present case, the patient's visual disturbance progressed rapidly despite systemic chemotherapy and corticosteroid therapy.

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We report a rare case of a thigh abscess which appeared during treatment of miliary tuberculosis. A 72-year-old woman with a history of diabetes mellitus was being treated for systemic sclerosis with prednisolone. She was then admitted to our hospital with fever, and chest computed tomography showed an abnormal shadow. She was given a diagnosis of miliary tuberculosis, and antituberculous therapy was initiated with isoniazid, rifampicin, ethambutol and pyrazinamide. Although this combination of antituberculous drugs was effective, 3 months after the initiation of treatment, a collection of fluid appeared in her left thigh. Further examination revealed the fluid to be positive for Mycobacterium tuberculosis on PCR and negative on mycobacterial culture. We thus diagnosed this phenomenon to be a paradoxical reaction.

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A 62-year-old man with empyema caused by Aspergillus fumigatus was successfully treated with a combination of voriconazole (VRCZ) and micafungin (MCFG). Data regarding the penetration of antifungal agents into pleural fluid are limited. Thus, we measured the concentration of VRCZ and MCFG in his plasma and pleural fluid. Penetration of VRCZ and MCFG into the pleural fluid was excellent. Therefore, the combination therapy using VRCZ and MCFG may contribute to successful management of Aspergillus empyema.

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OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics of interstitial lung disease (ILD) patients with anti-aminoacyl-tRNA synthetase (anti-ARS) autoantibodies. Patients and Methods We examined 14 ILD patients with anti-ARS autoantibodies between 2004 and 2007 and retrospectively investigated their clinical, radiographic, and pathological findings. RESULTS: Anti-Jo-1 antibodies were the most common (10 of 14), followed by anti-OJ, anti-KS, and anti-EJ (1 each for 3 patients); 1 patient with polymyositis had both anti-Jo-1 and anti-PL-12 antibodies. Ten patients had a chronic clinical course, whereas 4 presented with subacute deterioration. Of 8 patients with myositis, 1 (12.5%) had myositis-preceding ILD, 3 (37.5%) had ILD-preceding myositis, and 4 (50%) had simultaneous onset. Chest high-resolution computed tomography frequently showed lung-base predominant ground glass opacities (GGO) with volume loss. The results of surgical lung biopsies indicated that 4 patients had nonspecific interstitial pneumonia (NSIP) and/or organizing pneumonia (OP) patterns. All but 1 received corticosteroid therapy, and 6 patients were also given cyclosporin. The mean duration of follow-up was 22 months (range, 5-47 months). ILD improved in 9 patients and stabilized in 3; however, in 1 patient, it initially improved during 6 months, then progressively worsened despite treatment, and finally resulted in death. CONCLUSION: These results indicate that ILD patients with anti-ARS antibodies usually have a chronic clinical course, lung-base predominant GGO with volume loss, NSIP and/or OP patterns, and a good response to corticosteroid treatment; however, some have a rapidly worsening course and recurrence, despite therapy.

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