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This study investigated the difference of measured values between two types of analyzer over a wider range of fractional exhaled nitric oxide （FeNO） levels than in previous reports because some asthma patients have high FeNO levels. The equation for conversion of measured FeNO levels between the two analyzers was also determined.Methods：Patients underwent assessment of FeNO for the diagnosis and management of asthma or for differential diagnosis of cough, FeNO levels were measured sequentially using both a stationary analyzer（NOA280i®, Sievers Inc, USA） and a hand-held analyzer（NIOX MINO®, Aerocrine Inc, Sweden）. FeNO levels were measured in a total of 167 subjects. Regression analysis of the FeNO data showed a strong positive correlation between values obtained with the two analyzers （r＝0.938, p＜0.0001）, and the regression line was calculated as：FeNO （NOA280i®）×0.63＋3.79＝FeNO （NIOX MINO®）. The correlation between the two analyzers was strongest at low FeNO values and it decreased as the FeNO level increased ［FeNO （NOA280i®）£50 （r＝0.730, p＜0.0001） FeNO （NOA280i®） 50 to £100 （r＝0.641, p＜0.0001）, FeNO （NOA280i®）＞100 to £150 （r＝0.607, p＝0.0008）, and FeNO （NOA280i®）＞150 （r＝0.523, p＝0.0180）］. Bland-Altman plot analysis between the two analyzers was 0.167 （95％ confidence interval＝－0.038 to 0.357, suggesting a positive difference.Some caution is needed because the correlation between the two analyzers is weaker when the FeNO level exceeds 150.

Introduction： A phase I trial was conducted to evaluate the feasibility of pemetrexed in combination with carboplatin followed by pemetrexed maintenance therapy in elderly patients with advanced non-small cell lung cancer （NSCLC）. The primary objective of this study was to determine the maximum tolerated dose （MTD） and the recommended dose （RD） of pemetrexed in combination with carboplatin.Methods：Chemotherapy-naïve elderly 13 patients （age, ≥70 years） with stage IIIB/IV non-squamous NSCLC were enrolled and received pemetrexed 500 mg/m2 and carboplatin at an area under the curve （AUC）dose of 5 mg/ml/min（level 1）or 6 mg/ml/min （level 2）. Pemetrexed with carboplatin was administered on day 1 of the 21-day cycle. The treatment schedule consisted of four cycles of pemetrexed with carboplatin. Patients who did not have progressive disease after completion of four cycles subsequently received pemetrexed maintenance therapy （500 mg/m2 every three weeks） until disease progression or unacceptable toxicity was noted.Results：Three patients were enrolled in level 1, in which no dose-limiting toxicity（DLT）was observed. The carboplatin dose was escalated to AUC 6. Two of 3 patients treated in level 2 had grade 4 thrombocytopenia of DLT. MTD was determined as level 2. Consequently, pemetrexed 500 mg/m2 with carboplatin AUC 5 was recommended as the dose for elderly patients with advanced non-squamous NSCLC. An additional 7 patients who received RD showed no DLT. Nine of 13 patients received 4 cycles of combination therapy, and 5 patients were continuously treated with pemetrexed maintenance therapy. Six patients achieved a partial response, and another 6 showed stable disease. The response rate and disease control rate were 46.2％ and 92.3％, respectively. The median progression-free survival for the enrolled patients was 134 days （95％ CI, 95 to 231 days）, and the median overall survival was 346 days （95％ CI, 151 to 549 days）.Conclusions：The combination therapy of pemetrexed 500 mg/m2 with carboplatin AUC 5 followed by pemetrexed maintenance therapy showed no severe adverse events and was feasible and well-tolerated for elderly patients with advanced non-squamous NSCLC.

Background Fractional exhaled nitric oxide concentration (FeNO) is widely used to support diagnosis and monitoring of bronchial asthma (BA). Tsoukias and George proposed a two‐compartment model (2CM) for assessing the alveolar concentration of NO, referred to as CANO(2CM), while Condorelli et al proposed a model based on the trumpet shape of the airway tree and axial diffusion (TMAD), referred to as CANO(TMAD). In addition, Högman et al proposed non‐linear model, referred to as CANO(non‐linear). Objective We examined associations between the expression of inducible nitric oxide synthase (iNOS) mRNA in airway cells (ACs) by bronchoscopy and NO‐parameters calculated by the three methods and identified which of them accurately reflected expression of iNOS mRNA from different airway portions. Methods We retrospectively analysed data of 18 patients with stable, mild‐moderate asthma, including 10 steroid‐naïve BA (snBA) patients. Samples were obtained from airway brushings and bronchoalveolar lavage (BAL). Expressions of iNOS protein in tissue samples were evaluated by immunostaining. The iNOS mRNA in ACs was measured by qPCR. NO‐parameters calculated by the three methods above and evaluated whether they were associated with iNOS mRNA in ACs derived from proximal (2nd carina), distal (10‐15th) airways and alveolar regions. Results Immunostaining revealed expression of iNOS proteins mainly in epithelial cells in the airways, while it was mainly expressed in macrophages in the alveolar region in the snBA group. The iNOS mRNA expression was increased in both proximal and distal ACs in the snBA group compared with steroid‐treated BA group (stBA). CANO(2CM) negatively associated with FEV 1 (%predicted) and also associated with iNOS mRNA in distal ACs significantly. However, CANO(TMAD) and CANO(non‐linear) showed no correlation with lung function nor iNOS mRNA expression in any portions of ACs. Conclusions These results suggested that CANO(2CM) reflected distal airway inflammation in steroid‐naïve asthma.

BACKGROUND: This study evaluated the efficacy of switching therapy from fluticasone propionate/salmeterol (FP/SM) or budesonide/formoterol (BD/FM) to fluticasone furoate and vilanterol (FF/VI) at the equivalent corticosteroid dose in a real-world setting. METHODS: A prospective, 3-month, open-label, parallel group, switching therapy trial was performed in symptomatic asthma patients under routine management. Patients using 1 puff of FP 250 µg/SM 50 µg b.i.d or 2 puffs of BD 160 µg/FM 4.5 µg b.i.d were switched to FF 100 µg/VI 25 µg once daily, while patients using 1 puff of FP 500 µg/SM 50 µg b.i.d or 4 puffs of BD 160/FM b.i.d was switched to FF 200 µg/VI 25 µg once daily. The primary outcome was improvement of the predicted forced expiratory volume in 1 second % (%FEV1), while secondary outcomes were improvement of asthma symptoms evaluated by the asthma control test (ACT) and fractional exhaled nitric oxide (FeNO). RESULTS: The %FEV1 was improved at 4 weeks after switching, and the improvement was maintained until 12 weeks. ACT also improved after switching. Patients with ACT 20. FeNO decreased from 8 weeks. CONCLUSIONS: In symptomatic asthma patients showing insufficient control, improvement of asthma was obtained by switching to FF/VI at the equivalent corticosteroid dose accompanied with the improvement of biomarkers. FF/VI can be a useful option for better control of asthma because of its high efficacy, long duration of action, and delivery via a single-action device.

Some patients with interstitial pneumonia (IP) have auto-antibodies, but do not fit the criteria for specific connective tissue diseases. Examination of auto-antibodies is recommended for diagnosis idiopathic pulmonary fibrosis. A prospective cohort study was performed in 285 patients with IP. Eleven auto-antibodies were assessed and patients were followed for 2 years. All 285 patients underwent the myositis panel test (MPT) for 11 auto-antibodies. Among them, 23.5% (67/285) of the patients had a positive MPT and 14.7% (42/285) had connective tissue diseases. Among the 49 MPT positive patients without connective tissue diseases, 29 patients (59.2%) were positive for Ro52, including 17 patients with Ro52 mono-positivity. Among interstitial pneumonia patients without connective tissue diseases, the Ro52 mono-positive patients showed worse at 2-years survival than those who were Ro52 negative (p = 0.022, HR = 5.88, 95% CI 1.29-26.75). Most of the Ro52 positive patients also showed a low titer of anti-nucleolar antibody. About 20% of IP patients had auto-antibodies detectable by the MPT, and Ro52 positive patients accounted for more than half of the MPT positive patients without connective tissue diseases. Detection of Ro52 auto-antibodies may be useful for assessing the risk of progression in idiopathic interstitial pneumonia patients without connective tissue diseases and a low anti-nucleolar antibody titer.

Induced pluripotent stem cells (iPSCs) are opening up new possibilities for medicine. Understanding the regulation of iPSC biology is important when attempting to apply these cells to disease models or therapy. Changes of lipid metabolism in iPSCs were investigated by matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF-IMS). Analysis revealed changes of the intensity and distribution of peaks at m/z 782.5 and 798.5 in iPSC colonies during spontaneous differentiation. Two phosphatidylcholines (PCs) were identified: C44H81NO8P, PC(36:4)[M+H]+ at m/z 782.5 and C42H82NO8P, PC(34:1)[M+K]+ at m/z 798.5. The intensity of PC(36:4) showed an inverse relation between undifferentiated and differentiated iPSC colonies. PC(34:1) displayed a diffuse distribution in undifferentiated iPSC colonies, while it showed a concentric distribution in differentiated iPSC colonies, and was localized at the border of the differentiated and undifferentiated areas or the border between undifferentiated iPSC and feeder cells. These findings suggested that the distribution of lipids changes during the growth and differentiation of iPSCs and that MALDI-TOF-IMS was useful for analyzing these changes. PC(36:4) might play a role in maintaining pluripotency, while PC(34:1) might play a role in the differentiation and spread of iPSCs.

Endothelial cells (EC) are involved in regulating several aspects of lipid metabolism, with recent research revealing the clinicopathological significance of interactions between EC and lipids. Induced pluripotent stem cells (iPSC) have various possible medical uses, so understanding the metabolism of these cells is important. In this study, endothelial phenotype cells generated from human iPSC formed cell networks in co-culture with fibroblasts. Changes of plasmalogen lipids and sphingomyelins in endothelial phenotype cells generated from human iPSC were investigated by reverse-phase ultra-high-pressure liquid chromatography mass spectrometry (UHPLC-MS/MS) analysis. The levels of plasmalogen phosphatidylethanolamines (38:5) and (38:4) increased during differentiation of EC, while sphingomyelin levels decreased transiently. These changes of plasmalogen lipids and sphingomyelins may have physiological significance for EC and could be used as markers of differentiation.

Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results.

To identify problems in early diagnosis of tuberculosis and to design countermeasures against the disease, we examined the status of active tuberculosis among patients admitted to a university hospital that did not have an isolation ward for tuberculosis. Between 2005 and 2007, we analyzed demographic characteristics, disease type, chest radiologic findings, and the process leading to diagnosis. Active tuberculosis was diagnosed after admission in 55 patients (34 males and 21 females): pulmonary tuberculosis, 26; tuberculous pleuritis, 13; tuberculous meningitis, 6; miliary tuberculosis, 4; tuberculous pericarditis, 3; lymph-node tuberculosis, 2; and tracheal and bronchial tuberculosis, 1. Although radiographic examinations provided abundant information, chest radiography showed normal findings in 7 patients (12.7%). Computed tomographic scanning was useful for detailed evaluation of abnormalities. Twenty patients (36.4%) were given diagnoses at departments other than ours (Department of Pulmonary Medicine). Numbers of days between hospital admission and diagnosis of tuberculosis (50th percentile/80th percentile) were 8.0/37.8 for miliary tuberculosis, 8.0/8.0 for tracheal and bronchial tuberculosis, 7.5/17.8 for tuberculous pleuritis, 7.0/8.8 for tuberculous pericarditis, 6.0/15.6 for pulmonary tuberculosis, 3.5/4.4 for lymph-node tuberculosis, and 1/1 for tuberculous meningitis. Early diagnosis of tuberculosis requires adherence to the following precautions. Tuberculosis should be suspected in any patient with respiratory symptoms. Sputum tests for acid-fast bacteria should be performed at least three times initially. If findings on chest X-ray films are equivocal, high-resolution computed tomography should be performed to confirm details of shadows and to detect minimal pulmonary shadows or cavitary lesions. Physicians from all specialties should be repeatedly informed about the risk of tuberculosis and should include tuberculosis in the differential diagnosis in patients suspected to have pulmonary diseases.

Background: Patients may receive negative results from a specific IgE (sIgE) test such as the ImmunoCAP (CAP) despite a documented history of systemic reaction to a Hymenoptera sting. Thus, further testing may be required using another serological method or venom skin prick tests to confirm allergy diagnosis and correct species. Objective: To evaluate the sensitivity and the specificity of CAP and IMMULITE 3gAllergy (IMMULITE) for detecting sIgE to Paper wasp (WA) and Yellow Jacket (YJ) venoms using patient clinical history as the comparator. Methods: Sera from 70 participants with a history of systemic reactions (SR) to WA and/or YJ stings were tested using CAP and IMMULITE. Fifty participants from this group had negative results on CAP. To assess specificity, sera from 71 participants who had never experienced either a WA or YJ sting were tested using CAP and IMMULITE. Fifty participants from this group tested positive using CAP. Results: In participants with a history of systemic reaction to a Hymenoptera sting, yet who tested negative for WA and/or YJ sIgE according to CAP, the positivity rate according to IMMULITE was 20-42% using 0.10 IUA/mL as the limit of detection (LoD), per the manufacturer’s specification. When the LoD for CAP (0.35 IUA/mL) was applied to the IMMULITE results, positivity according to IMMULITE was 14-26%. Overall, sensitivity, specificity, and agreement with SR were greater for IMMULITE than for CAP. For YJ: sensitivity (IMMULITE:CAP), 42.8%:28.5%; specificity, 53.5%:39.4%; agreement, 48.2%:34%. For WA, sensitivity (IMMULITE:CAP), 58.6%:28.5%; specificity, 49.3%:47.8%; agreement, 43.9%:38.3%. Conclusion: The IMMULITE performed well for detecting sIgE to Hymenoptera venom.

Background Type 2 helper T-cell cytokines including IL-13 play a central role in the pathogenesis of bronchial asthma (BA). During the course of our research, our attention was drawn to dipeptidyl peptidase-4 (DPP4) as one of the molecules that were induced from bronchial epithelial cells (BECs) by IL-13 stimulation. DPP4 could become a new biomarker or therapeutic target. The aim of this study was to investigate the expression of DPP4 in the asthmatic airway, and its role in the pathophysiology of asthma. Methods BECs were isolated from patients with inhaled corticosteroid-treated asthma (stBA) and inhaled corticosteroid-naïve asthma (snBA) using bronchoscopy. DPP4 mRNA expression in freshly isolated BECs and primary cultured BECs with or without IL-13 stimulation was investigated by microarray analysis and quantitative real-time PCR (qPCR). The distribution of DPP4 protein was determined by immunostaining of transbronchial lung biopsy specimens from asthma patients. The effect of recombinant human (rh) DPP4 on the proliferation of lung fibroblasts (HFL-1) and bronchial smooth muscle cells (BSMCs) was examined, as well as its effect on the production of fibronectin (FN). Results DPP4 mRNA was strongly expressed in freshly isolated BECs in snBA, and its expression was significantly enhanced by IL-13 stimulation. DPP4 mRNA expression in BECs of snBA significantly correlated with exhaled nitric oxide. Biopsied tissues of the asthmatic airway revealed strong expression of DPP4 protein in BECs from snBA subjects. rhDPP4 stimulated the proliferation of HFL-1 and BSMCs, and it also enhanced production of FN from these airway cells. Conclusion DPP4 may be involved in the pathologic features of asthmatic airway inflammation and cell proliferation and FN production. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0342-7) contains supplementary material, which is available to authorized users.