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Background: Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of idiopathic interstitial pneumonia, and its prevalence increases with age. In the era of pre-antifibrotic agents, the median survival time of Japanese patients with IPF is 35 months, with a 5-year survival rate in western countries ranging from 20% to 40%. The prevalence of IPF is highest in elderly patients aged ≥75 years; however, the efficacy and safety of long-term use of pirfenidone and/or nintedanib are not fully understood. Objective: This study aimed to determine the efficacy and safety of the sole use of antifibrotic agents (pirfenidone or nintendanib) for IPF in the elderly. Method: We retrospectively reviewed patients with IPF who were diagnosed and treated with either pirfenidone or nintedanib in our hospital between 2008 and 2019. We excluded patients with the subsequent use of both antifibrotic agents. We examined the survival probability and frequency of acute exacerbation, with focus on long-term use (≥1 year), elderly patients (≥75 years of age), and disease severity. Results: We identified 91 patients with IPF (male to female ratio: 63 to 28, age 42 to 90 years). The numbers of patients with disease severity classified by JRS (I/II/III/IV) and GAP stage (I/II/III) were (38/6/17/20) and (39/36/6), respectively. The survival probabilities were comparable between the elderly (n = 46) and non-elderly groups (n = 45, p = 0.877). After the initiation of antifibrotic agents, the cumulative incidence ratio of acute exacerbation of IPF was significantly lower in the early stage (GAP stage I, n = 20) than in the progressive stage of disease (GAP stages II and III, n = 20, p = 0.028). A similar trend was noted in the JRS disease severity classification (I, II vs. III, IV) (n = 27 vs. n = 13, p = 0.072). In the long-term treatment (≥1 year) group (n = 40), the survival probabilities at 2 and 5 years after treatment initiation were 89.0% and 52.4%, respectively, which did not reach the median survival rate. Conclusions: Even in elderly patients (≥75 years of age), antifibrotic agents demonstrated positive effects on survival probability and the frequency of acute exacerbation. These positive effects would be improved for earlier JRS/GAP stages or long-term use.

A 45-year-old man with allergic bronchopulmonary aspergillosis (ABPA) was treated with oral prednisolone (PSL) (30 mg/day), inhaled corticosteroids, and long-acting beta2-agonists. After confirmation of a PSL-dependent status (8 mg/day), subcutaneous injection with anti-interleukin (IL)-5 antibody (mepolizumab, 100 mg/month) was performed, and the PSL dose was tapered to 5 mg/day. However, ABPA recurred and proved refractory to oral itraconazole (200 mg/day). Alternative subcutaneous injection therapy with dupilumab (induction dose of 600 mg followed by a maintenance dose of 300 mg/2 weeks) enabled the successful withdrawal of oral PSL without clinical deterioration. This case demonstrates the potential utility of dupilumab for steroid-dependent ABPA via the synergistic suppression of IL-4 and IL-13 compared to monotherapy with anti-IL-5 antibody.

Rationale Severe eosinophilic asthma is characterized by airway eosinophilia and corticosteroid‐resistance, commonly overlapping with type 2 inflammation. It has been reported that chemokine (C‐C motif) ligand 5 (CCL5) is involved in the exacerbation of asthma by RNA virus infections. Indeed, treatment with a virus‐associated ligand and a T helper type 2 cell (Th2) cytokine can synergistically stimulate CCL5 production in bronchial epithelial cells. We aimed to evaluate the mechanisms underlying CCL5 production in this in vitro model and to assess the potential of Janus kinase 1 (JAK1) as a novel therapeutic target via the use of ruxolitinib. Methods We stimulated primary normal human bronchial epithelial (NHBE) cells and BEAS‐2B cells with poly(I:C) along with interleukin‐13 (IL‐13) or IL‐4, and assessed CCL5 production. We also evaluated the signals involved in virus‐ and Th2‐cytokine‐induced CCL5 production and explored a therapeutic agent that attenuates the CCL5 production. Results Poly(I:C) stimulated NHBE and BEAS‐2B cells to produce CCL5. Poly(I:C) and IL‐13 increased CCL5 production. Poly(I:C)‐induced CCL5 production occurred via the TLR3–IRF3 and IFNAR/JAK1–phosphoinositide 3‐kinase (PI3K) pathways, but not the IFNAR/JAK1–STATs pathway. In addition, IL‐13 did not augment poly(I:C)‐induced CCL5 production via the canonical IL‐13R/IL‐4R/JAK1–STAT6 pathway but likely via subsequent TLR3‐IRF3‐IFNAR/JAK1‐PI3K pathways. JAK1 was identified to be a potential therapeutic target for severe eosinophilic asthma. The JAK1/2 inhibitor, ruxolitinib, was demonstrated to more effectively decrease CCL5 production in BEAS‐2B cells than fluticasone propionate. Conclusion We have demonstrated that JAK1 is a possible therapeutic target for severe corticosteroid‐resistant asthma with airway eosinophilia and persistent Th2‐type inflammation, and that ruxolitinib has potential as an alternative pharmacotherapy., First, we focused on whether treatment with a virus‐associated ligand and type‐2 cytokine can synergistically stimulate CCL5 production in bronchial epithelial cells, in which we confirmed the synergistic effect. Second, we evaluated the mechanisms underlying the synergistical CCL5 production and found that the JAK1 is a novel therapeutic target for severe eosinophilic asthma. Finally, we have demonstrated that ruxolitinib is a potential therapeutic agent for severe corticosteroid‐resistant asthma with airway eosinophilia and persistent Th2‐type inflammation.

軍事研究の核心は兵器や兵器体系の開発にあって、人命殺傷と施設破壊という明確な目的をもち、かつ極度の秘密保持を要求される点に特徴がある。これに対して基礎研究の核心は自然界の理解にあって、研究それ自体が目的であり、発見された知識は公開されるのが原則である。両者は対極にあるように思え、一見すると簡単に結びつくことはないように見える。ところが、戦前の科学技術者である大河内正敏は、これらを大胆に結びつける仕組みを考案した。その舞台が財団法人理化学研究所(1917～1948)であった。, The core of military research is the development of weapons and weapons systems, which have the explicit purpose of killing lives and destroying facilities and is characterized by the need for extreme confidentiality. On the other hand, the core of pure research is the understanding of the natural world, the study itself is the purpose, and in principle, they should disclose the discovered knowledge. The two seem to be at the other end of the spectrum, and they don't seem to be easily connected. However, Masatoshi Okochi, a prewar science and technology engineer, devised a mechanism to connect these boldly. The stage was the Institute of Physical and Chemical Research (1917-1948).Based on these historical cases, researchers under modern Japanese science and technology policy will need to reconsider their freedom of research. If the investor of the research fund is war-oriented, can the researcher refuse the research related to the war? In the truest sense, if one wants to reject military research, each researcher must always be concerned about how their research results are applied and have a voice in their research results. If that doesn't happen, we need to find a way to report the results to the public in an easy-to-understand manner. When reporting, consider not only the merits of the research results but also the risks, and devise ways to raise public opinion on how to manage the research results. By doing so, it may be possible to restrain the movements of politicians, bureaucrats and military-industrial companies by public opinion in the unlikely event., 森田雅憲教授古稀祝賀記念号(Honorable issue in commemoration of Prof. Masanori Morita's 70 years of age), 軍事研究を哲学する : デュアルユースの観点から

Background and purpose of the study: Pseudomonas aeruginosa commonly colonizes the airway of patients with chronic obstructive pulmonary disease (COPD) and exacerbates their symptoms. P. ae...

A 77‐year‐old woman presented to our hospital with complaints of persistent cough and low‐grade fever for two months. On radiological analysis, she had moderate right‐sided pleural effusion with right hilar and subcarinal lymphadenopathies. Thoracentesis showed chylothorax of unknown cause. Bronchoscopy revealed a non‐specific inflammatory process. However, thoracoscopic surgery demonstrated a curiously enlarged lymphatic duct with its proximal portion compressed by subcarinal lymphadenopathies, pathologically diagnosed as granulomatous lymphadenitis. Hence, tuberculous lymphadenitis was proven to be the cause of chylothorax. Interestingly, cauterization of the lymphatic duct decreased the total amount of right‐sided pleural effusion along with a change in colour from milky yellow to red. These were in favour of tuberculosis (TB)‐associated chylothorax with the advent of the TB pleuritis. All symptoms and pleural effusion disappeared after the initiation of anti‐tuberculous drugs. The present case showed definite evidence of TB‐associated chylothorax development mechanism via compression of the lymphatic duct by mediastinal lymphadenopathies., We report a case of chylothorax due to tuberculosis lymphadenitis with distinct evidence of enlarged lymphatic duct macroscopically.

Background Neutrophilic inflammation is associated with poorly controlled asthma. Serum levels of sST2, a soluble IL-33 receptor, increase in neutrophilic lung diseases. We hypothesized that high serum sST2 levels in stable asthmatics are a predictor for exacerbation within a short duration. Methods This prospective observational study evaluated the serum sST2 levels of 104 asthmatic patients who were treated by a lung disease specialist with follow-ups for 3 months. Results High serum sST2 levels (> 18 ng/ml) predicted severe asthma exacerbation within 3 months. Serum sST2 levels correlated positively with asthma severity (treatment step), airway H2O2 levels, and serum IL-8 levels. High serum sST2 levels and blood neutrophilia (> 6000 /μl) were independent predictors of exacerbation. We defined a post-hoc exacerbation-risk score combining high serum sST2 level and blood neutrophilia, which stratified patients into four groups. The score predicted exacerbation-risk with an area under curve of 0.91 in the receiver operating characteristic curve analysis. Patients with the highest scores had the most severe phenotype, with 85.7% showing exacerbation, airflow limitation, and corticosteroid-insensitivity. Conclusions High serum sST2 levels predicted exacerbation within the general asthmatic population and, when combined with blood neutrophil levels, provided an exacerbation-risk score that was an accurate predictor of exacerbation occurring within 3 months. Electronic supplementary material The online version of this article (10.1186/s12931-018-0872-2) contains supplementary material, which is available to authorized users.

Objective We investigated a novel diagnostic scoring system to differentiate Legionella pneumophila pneumonia from Streptococcus pneumoniae pneumonia. Methods We retrospectively reviewed the clinical data of 62 patients with L. pneumophila pneumonia (L-group) and 70 patients with S. pneumoniae pneumonia (S-group). Results The serum sodium (Na) levels tended to be lower according to the severity [age, dehydration, respiratory failure, orientation disturbance, low blood pressure (A-DROP)] score in the L-group. On a multivariate analysis, we found that four factors were independent predictive markers for inclusion in the L-group: relative bradycardia [hazard ratio (HR) 5.177, 95% confidence interval (CI): 1.072-24.993, p=0.041], lactate dehydrogenase (LDH) levels ≥292 IU/L (HR 6.804, 95% CI: 1.629-28.416, p=0.009), C-reactive protein (CRP) levels ≥21 mg/dL (HR 28.073, 95% CI: 5.654-139.462, p

Background The impact of viral infections on acute exacerbations in idiopathic pulmonary fibrosis (IPF) and/or non-IPF interstitial lung disease (ILDs) has been scarcely described. Objectives To elucidate the frequency of virus infections in patients with IPF or non-IPF ILDs including idiopathic interstitial pneumonia (IIP) or connective tissue disease (CTD)-associated pneumonia, and its influence on their short-term mortality. Methods We prospectively enrolled adult patients with acute exacerbation of IPF and non-IPF ILDs who were admitted to the hospital during the last 3 years, and examined the respiratory samples obtained from nasopharyngeal, sputum, and bronchoalveolar lavage fluid. Results A total of 78 patients were identified, consisting of 27 patients with acute exacerbation of IPF and 51 patients with non-IPF ILDs (IIP: n = 27, CTD-associated IP: n = 24). Of all patients, 15 (19.2%) had viruses detected in their respiratory samples including the human herpesvirus 7 (HHV7; n = 4) and cytomegalovirus (CMV) plus HHV7 (n = 3). The proportion of virus infections in the IPF and non-IPF ILDs groups was comparable. The Kaplan-Meier survival curves over 60 days revealed a lower survival probability in the virus positive group (n = 15, 60%) than in the virus negative group (n = 60, 83.3%, p

Background: Increasing number of evidences suggest that IL-33/sST2 axis associates with occurring neutrophilic inflammation but its mechanism remains unknown. Objectives: We hypothesized that IL-33/sST2 balance regulates neutrophil-related cytokine production in bronchial epithelial cells. Methods: We cultured normal human bronchial epithelial (NHBE) cells to assess functions and production mechanisms of IL-33 and sST2. We measured IL-33 and sST2 levels in exhaled breath condensate (EBC) from bronchial asthma (BA), COPD, and asthma-COPD overlap (ACO) patients (n=143) and healthy control (HC) subjects (n=11) and in sputum from BA, COPD, and ACO patients (n=31). Results: In NHBE cells, IL-33 enhanced neutrophil-related (CXCL8, CXCL1, CXCL5, and GM-CSF) and Th17-related (CCL20 and IL-6) cytokine production, which was inhibited by excess sST2. Neutrophil elastase (NE) upregulated intracellular IL-33 expression and further NE-induced cell damage caused IL-33 release into extracellular space. IL-4 and -13 enhanced sST2 production. EBC IL-33 levels were higher in ACO patients than in others (ACO vs BA plus COPD plus HC: n=15 vs 143, P=0.0008). EBC sST2 levels were higher in asthmatics than in others (BA plus ACO vs COPD plus HC: n=111 vs 47, P=0.0036). Sputum IL-33 levels correlated positively with sputum CXCL8 (r=0.56, P=0.003, n=38) and CCL20 (r=0.44, P=0.0121, n=32) levels. Sputum sST2 levels correlated positively with %FEV1 (r=0.48, P=0.0197, n=28), indicating that sST2 was protective against tissue damage. Conclusion: IL-33/sST2 axis regulates neutrophil-related cytokine production in the human airways, where high IL-33 and sST2 levels suggest presence of neutrophilic and type-2 inflammation, respectively.

Neutrophilic airway inflammation plays a central role in chronic obstructive pulmonary disease (COPD). CXC chemokine ligand (CXCL)1 is a neutrophil chemokine involved in the pathogenesis of COPD. However, its clinical significance in COPD patients is poorly understood.To assess the production of CXCL1 by bronchial epithelial cells in response to lipopolysaccharide (LPS) and tumor necrosis factor (TNF)α.We measured sputum CXCL1 and CXCL8 levels in patients with COPD, asthma, and asthma-COPD overlap (ACO), and compared them to those of patients with interstitial pneumonia (IP). Using primary human bronchial epithelial cells and BEAS-2B cells, CXCL1 protein release and mRNA expression were measured after LPS or TNFα stimulation. We evaluated signal transduction mechanisms for CXCL1 production using nuclear factor-κ B (NF-kB) and mitogen-activated protein kinase (MAPK) inhibitors, and examined the effects of anti-inflammatory agents on CXCL1 production in BEAS-2B cells.Sputum CXCL1 levels in COPD and ACO patients were higher than in IP patients, whereas sputum CXCL8 levels were not. Sputum CXCL1 levels were not affected by inhaled corticosteroid usage, whereas sputum CXCL8 levels tended to be affected. LPS and TNFα stimulated CXCL1 production and mRNA expression in bronchial epithelial cells. NF-kB and MAPK p38 were involved in LPS-induced CXCL1 production. Therapeutic anti-inflammatory agents minimally attenuated CXCL1 production and considerably inhibited CXCL8 production in BEAS-2B cells.Sputum CXCL1 levels is a potentially better diagnostic marker for COPD than sputum CXCL8 levels, which is explained by that CXCL1 production in bronchial epithelial cells is less affected by therapeutic anti-inflammatory agents than CXCL8 production.

Immune checkpoint inhibitors (ICIs) have emerged as evolutionary treatments for malignant diseases. Although ICIs can cause immune-related adverse events (irAEs) in various organs, precise timing after ICI initiation has been scarcely reported. Elucidating the effects of irAEs, such as time to onset, involvement of major organs, influence on progression-free survival (PFS), and overall survival (OS), are critical issues for physicians. Furthermore, lung-irAE as a whole is not well known. We conducted a retrospective study of 156 patients who were treated with ICIs and compared 82 irAE patients with 74 non-irAE patients. This study clearly demonstrated that the preferred period after induction of ICIs was significantly longer in lung-irAE than in other major organs (skin, digestive tract, and endocrine). The effect of irAEs on PFS and OS was evident PFS in the irAE group (n = 82) (median 128 days, interquartile range [IQR] 62–269 days, P = .002) was significantly longer than that in the non-irAE group (n = 74) (median 53 days, IQR 33–151 days). Similarly, OS was significantly longer in the irAE group (median 578 days, IQR 274–1027 days, P = .007) than in the non-irAE group (median 464 days, IQR: 209–842 days). However, this positive effect of irAEs in the lungs was not proportional to the extent of severity. Lung-irAEs can occur at a later phase than non-lung-irAEs and seemed not to prolong OS and PFS. However, further studies are needed to support these findings.

Carcinomatous meningitis (CM) is a critical issue for physicians. However, no study has reported a simple and useful diagnostic or predictive marker for CM. This study aimed to elucidate the potential markers for diagnosing CM derived from cerebrospinal fluid (CSF). We retrospectively enrolled 78 lung cancer patients with suspected CM during the clinical course, including 42 CM and 36 non-CM patients. We compared the clinical and CSF findings, including carcinoembryonic antigen (CEA), between CM and non-CM patients, and explored the diagnostic markers for early identification of CM as well as the contributing factors for mortality. On CSF analysis, with cutoff values of CEA ≥5 ng/ml, total protein (TP) in CSF ≥45 g/dl, and total cell count (TCC) ≥7 cells/μL, the sensitivity, specificity, and area under the curve (AUC) for CM were 85.7%, 84.6%, and 0.887 (95% CI: 0.758–1.0, P patients’ age)” (n = 19, P = .008) showed significantly shorter 90-day survival probability than the residual patients (n = 20). None of the CSF parameters could predict the risk of mortality on Cox regression analysis. The cutoff value of CEA ≥5 ng/ml in CSF is a simple and useful method with a high diagnostic value for CM diagnosis, but not a suitable predicting factor for mortality. ‘TP in CSF >patients’ age” might be a novel factor for assessing short-term mortality.

During bronchoscopy, discomfort is mainly caused by an unavoidable cough; however, there are no reports of any predictive factors for strong cough during bronchoscopy identified before the procedure. To clarify the factors underlying the discomfort status and predictive factors for strong cough during bronchoscopy, we prospectively evaluated patients who underwent bronchoscopy at Kyorin University Hospital between March 2018 and July 2019. Before and after bronchoscopy, the enrolled patients answered a questionnaire regarding the procedure. At the same time, bronchoscopists evaluated cough severity using a four-grade cough scale. We evaluated patient characteristics and predictive factors associated with bronchoscopy from the perspective of discomfort and strong cough. A total of 172 patients were ultimately enrolled in this study. On multivariate logistic regression analysis, comparison of the subjective data between the discomfort and comfort groups revealed that factors that were more common in the former group were younger age (OR = 0.96, p = 0.002), less experienced bronchoscopist (OR = 2.08, p = 0.047), and elevation of cough score per 1 point (OR = 1.69, p < 0.001). Furthermore, the predictive factors for strong cough prior to performing bronchoscopy were female sex (OR = 2.57, p = 0.009), EBUS-TBNA (OR = 2.95, p = 0.004), and prolonged examination time of more than 36 min (OR = 2.32, p = 0.022). Regarding patients’ discomfort, younger age, less experienced bronchoscopist, and the elevation of cough score per 1 point were important factors for discomfort in bronchoscopy. On the other hand, female sex, EBUS-TBNA, and prolonged examination time were crucial factors for strong cough.

We studied the diagnostic value of cytokines, including vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and interleukin-8 (IL-8), and the ratio of lactate dehydrogenase (LDH) to adenosine deaminase (ADA) in pleural fluid. Prospective analysis of 44 inpatients or outpatients with pleural fluid, from December 2016 to March 2017 was conducted. We enrolled patients with malignant pleural effusion (MPE, N = 15), empyema (N = 11), parapneumonic effusion (PPE, N = 7), chronic renal failure (CRF)/chronic heart failure (CHF) (N = 7), and tuberculous pleural effusion (TBPE, N = 4). The pleural fluid values of IL-8 and VEGF were significantly higher in empyema patients than in CRF/CHF or PPE patients. In all patients, the pleural fluid VEGF and IL-8 values were significantly positively correlated (r = 0.405, p = 0.006; r = 0.474, p = 0.047, respectively). TGF-β was elevated in patients with empyema, PPE, TBPE, and MPE. The pleural LDH-to-ADA ratio in patients with MPE or empyema/PPE was significantly higher than in patients with CRF/CHF or TBPE. LDH and ADA levels correlated significantly only in patients with MPE (r = 0.648, p = 0.009) and empyema/PPE (r = 0.978, p

Background Immunoglobulin G4-related disease (IgG4-RD) is a rare multi-organ disorder. Physicians rarely encounter patients with IgG4-RD and its range of symptoms. Methods To elucidate the clinical characterization of IgG4-RD, along with the clinical significance of lung involvement, we retrospectively reviewed the medical records of patients who satisfied the comprehensive diagnostic criteria for IgG4-RD. Results We identified 52 patients with IgG4-RD. Of these, 32 patients underwent tissue biopsies, resulting in categorization as definite (n = 23) or possible (n = 9) IgG4-RD cases. Among the 23 definite IgG4-RD cases, those with positive lung involvement (n = 8) had significantly higher values of serum LDH (median 220 IU/L, interquartile range (IQR) 175–378 vs. median 184, IQR 136–249, p = 0.039), IgG (median 2769 mg/dL, IQR 2028–7807 vs. median 2048, IQR 1168–4376, p = 0.009), and soluble interleukin-2 receptors (median 1620 U/mL, IQR 871–2250 vs. median 733, IQR 271–1600, p = 0.003) than those with negative lung involvement (n = 15). Similarly, a significant number of patients with positive lung involvement were positive for rheumatoid factor (71.4% vs. 23.1%, p = 0.041) or hypocomplementemia (50% vs. 0%, p = 0.036). Sixteen patients also showed lung involvement (definite n = 8, possible n = 8); thoracic computed tomography (CT) of these patients revealed mediastinal lymphadenopathies (n = 14, 87.5%), ground glass opacity (n = 11, 68.8%), consolidation (n = 8, 50%), thickening of the bronchovascular bundles (n = 7, 43.8%), small nodules (n = 5, 31.3%), bronchiectasis (n = 4, 25%), and reticular shadows (n = 4, 25%), and pulmonary function tests, using a standard technique involving a single breath, revealed decreased diffusion capacity for carbon monoxide. Conclusions IgG4-RD is associated with diverse thoracic CT findings and a decreased diffusion capacity, and careful multidisciplinary assessment is needed to enable differentiation of IgG4-RD from lymphoproliferative disorders.

A 66-year-old man who suffered from an acute exacerbation of interstitial pneumonia developed a cavitary lesion after taking immunosuppressive drugs. He was diagnosed with cytomegalovirus (CMV) pneumonia. CMV was not thought to be the underlying cause of the cavitary lung lesions, as only six cases have been described thus far. However, this case clearly demonstrates that the development of cavitary lung lesions can be caused by CMV. Following CMV pneumonia, cavitary lesions again occurred in the patient's lungs that were thought to be the first case of cavitary lesions caused by Nocardia asiatica infection.

Background: Bronchial asthma (BA) is characterized by chronic airway inflammation. Although a majority of BA patients are controlled by standard treatment containing inhaled corticosteroids, some patients suffer acute exacerbation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells which are involved in the pathogenesis of BA. However, the role of ROS levels as a biomarker in BA patients is not yet clear. Aims and objectives: We tried to determine the role of ROS levels as a biomarker in the clinical settings of BA. Methods: We enrolled patients with BA from 2013 through 2015 at the Department of Respiratory Medicine, Kyorin University Hospital. Pulmonary function tests, FeNO, serum reactive oxygen metabolite (ROM) levels and serum IL-6 and IL-8 were measured. Serum ROM levels were measured by d-ROMs test. Results: A total of 110 patients with BA were recruited. Serum ROM levels correlated with WBC (rs = 0.273, P = 0.004), neutrophil (rs = 0.235, P = 0.014), CRP (rs = 0.403, P P 1 (rs = -0.306, P = 0.001, rs = - 0.240, P = 0.012, respectively). Serum ROM levels were significantly higher in patients with severe exacerbation group than in patients without exacerbation group ( P = 0.025). Receiver-operating characteristics analysis showed that ROM levels associated with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597 to 0.801, P = 0.025). Conclusions: ROM levels might reflect neutrophilic inflammation, and correlated with airway obstruction. This biomarker may be useful for predicting severe exacerbations of BA.

Background and Purpose Bronchial asthma (BA) is a chronic airway disease characterized by airway hyperresponsiveness and remodeling, which are intimately linked to chronic airway inflammation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells that are involved in the pathogenesis of BA. However, the role of ROS in the management of BA patients is not yet clear. We attempted to determine the role of ROS as a biomarker in the clinical setting of BA. Subjects and Methods We enrolled patients with BA from 2013 through 2015 and studied the degrees of asthma control, anti-asthma treatment, pulmonary function test results, fractional exhaled nitric oxide (FeNO), serum reactive oxygen metabolite (ROM) levels, and serum levels of interleukin (IL)-6 and IL-8. Results We recruited 110 patients with BA. Serum ROM levels correlated with white blood cell (WBC) count (rs = 0.273, p = 0.004), neutrophil count (rs = 0.235, p = 0.014), CRP (rs = 0.403, p < 0.001), and IL-6 (rs = 0.339, p < 0.001). Serum ROM levels and IL-8 and CRP levels negatively correlated with %FEV1 (rs = -0.240, p = 0.012, rs = -0.362, p < 0.001, rs = -0.197, p = 0.039, respectively). Serum ROM levels were significantly higher in patients who experienced severe exacerbation within 3 months than in patients who did not (339 [302–381] vs. 376 [352–414] CARR U, p < 0.025). Receiver-operating characteristics analysis showed that ROM levels correlated significantly with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597–0.801, p = 0.025). Conclusions Serum levels of ROM were significantly associated with the degrees of airway obstruction, WBC counts, neutrophil counts, IL-6, and severe exacerbations. This biomarker may be useful in predicting severe exacerbations of BA.

高度な科学技術の産物が、自動車や家庭用電気製品の形をとって、我々の生活の様々な領域を取り囲む時代にあって、我々はそこから利便性だけでなくリスクをも受け取るようになった。本論では、人工物の特性を技術的媒介性、技術的忘却性、技術的盲目性の三つの概念によって分析し、技術製品が我々の生活の中で果たす役割を論じるとともに、技術製品市場システムそのものの弱点についても検討する。その上で、このシステムを健全に機能させるためには、科学者や技術者のみならず消費者の倫理が必要である事が論じられる。, The diffusion of technological artifacts means that social mass aggregation gets to share a way of looking at the world and a way of life unconsciously. We would like to give the name `Techno-Public' to people who have no alternative but to buy technological goods to access technology. Their view of the world and their way of life are mediated by technology in large part. They have to depend on experts' knowledge to maintain their artificial environment. Their attitude to technology is very passive. Hence it is possible to say that all their passivity would be the cause of market failure. In this essay, to keep our social security, we would like to discuss about the necessity of ethics not only for scientists and engineers whose responsibility is concerned with technological products, but also for consumers (`Techno-Public') whose responsibility is concerned with choices of technological goods., 論説(Article)

研究ノート

現代社会に流通している多くの商品を見ると、それらが最新の科学技術を元に開発されたものである場合が多い。ある種の商品がランドマーク商品として不可逆的に普及し、消費者の生活スタイルを変容させていく現象を考えようとするとき、その原因を科学技術の特性との関連から分析する必要があるのではないだろうか。本論文では、科学技術が生み出した人工物の特性を「具忘性」と「技術的媒介」という概念で表し、これらを用いて商品のランドマーク化について考察する。, How does a commodity which has been developed through new technology prevail into the society? A certain kind of artifact has a special puissance to change our lifestyle. Here we should analyze the essence of the puissance in connection with the characteristic of technology, because almost all contemporary commodities are invented as technological artifacts. In this paper, we will try to identify the features of technological artifacts by two concepts such as `Inherent Oblivity' and `Technological Mediation'. They would give a new aspect for thinking how some sort of commodity prevails into the society irreversibly and how it changes our style of life., 研究ノート

Background: Bronchial asthma (BA) is a common disease that is characterized by airway inflammation. Recently many patients achieve good control with anti-inflammatory treatment. However some patients have persistent symptoms and airflow limitation even during such intervention. Therefore, pursuing appropriate biomarkers reflecting severity is crucial for disease monitoring. Oxidative stress is attracting attention as one of the important pathophysiological factors in BA. Aims and objectives: We investigated the magnitudes of oxidative stress and other biomarkers in patients with BA to clarify relationship between severity and various biomarkers. Methods: We enrolled patients who attended our hospital due to BA from January 2012 to January 2015. Oxidative stress was evaluated by reactive oxygen metabolite (ROM) levels using the d-ROMs test (Diacron International, Grosetto, Italy). We examined characteristics of clinical history and laboratory findings. Results: One hundred and six patients (67 women, mean age: 52.3±16.5, 12 current smokers, 23 ex-smokers) were included in this study. Thirty four patients had airflow limitation (FEV1/FVC < 0.7). ROM levels were negatively correlated with %FEV1 (r = -0.21, p < 0.05). Serum IL-8 concentrations were also negatively correlated with FEV1/FVC (r = -0.37, p < 0.05) and %FEV1 (r = -0.42, p < 0.05). WBC and eosinophil counts, FeNO levels were not correlated with FEV1/FVC and %FEV1. Conclusions: ROM levels and serum IL-8 concentrations had significantly negative correlation with degrees of airflow limitation. These biomarkers may be useful in the management of BA.

Background Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. Methods C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. Results The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. Conclusion We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice.

Introduction: A reversed halo sign (RHS) has diverse differential diagnoses such as cryptogenic organizing pneumonia, fungal, bacterial and mycobacterial infections, and systemic and neoplastic diseases. However, no report has been described regarding an RHS associated with infective endocarditis (IE). Case presentation: A 43‐year‐old man was transferred to our hospital because of persistent pyrexia, chest pain with multiple cavitary lung lesions for a month. He was diagnosed with tricuspid native valve IE caused by massive vegetations in the context of CA‐MRSA (staphylococcal cassette chromosome mec type II, sequence type 91, clonal complex 509) infection with multiple pulmonary septic emboli, manifesting as an atypical RHS. Conclusion: The present case showed huge tricuspid native valve IE associated with community‐acquired meticillin‐resistant Staphylococcus aureus (CA‐MRSA), which was analysed successfully by multilocus sequence typing.

A 66-year-old man who suffered from an acute exacerbation of interstitial pneumonia developed a cavitary lesion after taking immunosuppressive drugs. He was diagnosed with cytomegalovirus (CMV) pneumonia. CMV was not thought to be the underlying cause of the cavitary lung lesions, as only six cases have been described thus far. However, this case clearly demonstrates that the development of cavitary lung lesions can be caused by CMV. Following CMV pneumonia, cavitary lesions again occurred in the patient's lungs that were thought to be the first case of cavitary lesions caused by Nocardia asiatica infection.

Objective and design:The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. Material:A human alveolar epithelial cell line A549 was usedinvitro.Methods:Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed. Results:Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cellsin vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. Conclusion:These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition.

Summary We studied the risk factors associated with resistance to imipenem, levofloxacin and gentamicin in Pseudomonas aeruginosa isolated from blood cultures of 175 patients in a hospital in Japan. Imipenem resistance was associated with transfer from another hospital, and receiving antifungal medication. Gentamicin resistance was associated with previous administration of a penicillin. No specific risk factors were associated with levofloxacin resistance.

The efficacy, safety and usefulness of a highly purified concentrate of porcine factor VIII (MTI-9002; Hyate: C) was evaluated in 30 treatment episodes with 12 hemophilia A patients having inhibitor to human factor VIII in 11 institutes in Japan. A total of 44 infusions was given. Results were as follows.1. The hemostatic efficacy was evaluated at 8 hours and 24 hours after the first infusion in each treatment episode. In 22 of 30 episodes (73.3%), excellent to good responses were obtained at both times. General hemostatic efficacy of each episode was also evaluated. In 26 of 30 episodes (86.7%), excellent to good responses were obtained.2. When more units were infused than the calculated neutralizing dose based on the titer of porcine factor VIII inhibitor at the time of pre-infusion, an adequate rise in factor VIII: C was almost always seen after infusion of MTI-9002. However, even if factor VIII: C level remained low, desired hemostasis was occasionally obtained.3. There were 8 infusions for 8 treatment episodes in 5 patients where a definite relationship between MTI-9002 and adverse reactions could not be eliminated. Since those patients treated with hydrocortisone responded well soon, it seemed that adverse reactions could be prevented and treated with hydrocortisone.4. For patients who have difficulty controlling bleeding and low inhibitor cross-reactivity, it was felt that MTI-9002 was extremely useful.

In order to reduce risk factors in the treatment of hemophilia B with prothrombin complex concentrates, a new coagulation factor IX concentrate (GA-1013) was developed by Green Cross Corporation, Osaka, Japan. This product is prepared by immunoaffinity chromatography using a monoclonal antibody (3A6) and virally inactivated by solvent/detergent treatment. GA-1013 has a specific activity of 173 factor IX units/mg of protein, representing a 13, 700 fold purification from cryosupernatant.A multicenter clinical study was conducted in 24 previously treated and 1 previously untreated hemophilia B patients with no inhibitor to evaluate the safety and efficacy of GA-1013. We determined the half life and in vivo recovery of this FIX concentrate.The mean age of the patients was 29.0 years with a range of 9 months 62 years. The mean T1/2 value (n=22) was 20.3±8.93hr and the mean in vivo recovery rate was 69.0±20.12% calculated from the labelled FIX: C content (47.6±14.46% calculated from the actual FIX: C content).A total of one hundred and seventy-six bleeding episodes were assessed during the 6 months treatment, chiefly on a demand basis. Hemostatic effectiveness was confirmed with an efficacy rate of 93.7% (165/176). No adverse reactions attributed to GA-1013 were obserbed in any infusion. Neither FIX inhibitors nor antibodies to mouse or goat protein were detected. No significant changes attributed to GA-1013 were seen in vital signs or in laboratory findings including CBC, blood chemistries, virological parameters and immunological data (CD4 and CD8 counts, lymphocyte blastogenesis index and serum immunoglobulins at 1, 3 and 6 months).These results suggest that monoclonal antibody-purified coagulation FIX concentrate (GA-1013) is safe and efficacious as replacement therapy for hemophilia B.

This is a case report of a hemophilia B patient who became seropositive for HIV-1 more than 3 and a half years after switching to heat-treated prothrombin complex concentrates. This 17 year old boy has been treated in our institution since 1973, when he was a year of age. He became HIV-1 seropositive for the first time in July, 1990. Because of the delayed HIV seroconversion, we studied his serum samples stored separately, using RNA-PCR (polymerase chain reaction) method. All of his serum samples tested were positive for RNA sequences of HIV, and the earliest positive sample was obtained in August of 1985. In Japan, prothrombin complex concentrates were switched to heat-treated ones, in January, 1986. Therefore, we conclude that this is a case of hemophilia who seroconverted after a prolonged window period, showing that silent infection is also possible in hemophilia patients at risk as well as in homosexual men, although the incidence must be low (less than 1%).