Search

Objectives: This study aimed to compare the measurements of the peripapillary nerve fiber layer (RNFL) thickness obtained by OCT in patients with TAO and healthy controls and to correlate these parameters with the severity of the orbital disease.Methods: The cross-sectional single-center study consisted of 74 patients (45 with TAO and 29 healthy controls). Patients with TAO underwent a complete ophthalmological examination and were divided according to the clinical activity score (CAS) and European Group Graves' Orbitopathy severity (EUGOGO) classification. Spectral-domain OCT assessed the measurements of the peripapillary RNFL. Results: There was no statistical difference between the groups regarding demographic characteristics and comorbidities (p>0.05%). According to CAS, 93.3% of patients with TAO were in the inactive phase. By the EUGOGO, 27% had mild TAO, 66% had moderate-to-severe, and 7% had very severe disease. The mean peripapillary RNFL thickness was thinnest in the temporal quadrant in the TAO group (pConclusion: These results suggest that OCT can be a valuable tool in detecting early changes in peripapillary RNFL in patients with TAO, even in the inactive phase when neuropathy is not yet clinically detectable. These parameters appear to be potential adjuncts in the follow-up of patients, especially when there is a risk of visual loss.

Purpose: This study aimed to identify patient’s reason for no-show at a university eye clinic after ophthalmic examination via a mobile ophthalmic unit, which provides comprehensive ophthalmic care to underserved communities in a region of Brazil. Methods: In 2017/2018, this prospective observational study searched for no-shows at referrals to a university eye clinic after an outreach program screening via a mobile ophthalmic unit in 10 municipalities in the central-western region of São Paulo, Brazil. A total of 1,928 patients underwent a comprehensive eye examination at no cost, and 37.1% of them needed referral to a university eye clinic for specialized examinations or surgeries. We used the following two main tools: (1) comparative analysis between patients who attended the referral and those who did not; (2) active search using a questionnaire to assess reasons for no-show. Results: Attendance to referrals was not influenced by age, gender, distance from the university hospital, number of ophthalmologists in the municipality, average family income, and visual acuity. The main cause for referrals was cataract (350 cases). No-show was most common among glaucoma/suspected glaucoma (54.1%) cases, followed by strabismus (45%) and anterior segment disease (33.6%) cases. Many patients who did not attend the referral sought another service. Conclusion: Patient’s issues and lack of knowledge regarding their ophthalmic condition are the main reasons for no-show at referrals for free ophthalmic care. Thus, educational campaigns are needed to achieve consistently high attendance to prevent avoidable blindness. RESUMO Objetivo: Avaliar as razões para não comparecimento à clínica oftalmológica da universidade após triagem oftalmológica realizada usando uma unidade móvel oftalmológica que fornece exame oftalmológico para comunidades não assistidas em uma região do Brasil. Métodos: Foi realizado um estudo observacional prospectivo no ano de 2017/2018 para avaliar as razões que fizeram com que os indivíduos triados usando uma unidade móvel oftalmológica e referenciados para a clínica oftalmológica da universidade não comparecessem à consulta agendada. A triagem foi feita em 10 municípios da região centro-oeste do estado de São Paulo, Brasil. Todos os 1.928 participantes fizeram o exame oftalmológico sem custo e 37,1% deles necessitaram de encaminhamento para a clínica oftalmológica da universidade para exames especializados ou cirurgias. O estudo usou duas ferramentas: (1) análise comparativa entre os dados dos indivíduos encaminhados que compareceram ao agendamento com os que não compareceram; (2) busca ativa dos indivíduos que não compareceram à consulta agendada, aplicando-se um questionário para avaliar os motivos para o não comparecimento. Resultados: Fatores como idade, sexo, distância entre a cidade de origem e o hospital universitário, número de oftalmologistas na cidade de procedência, renda familiar média e acuidade visual não influenciaram no comparecimento ao encaminhamento. Catarata foi a maior causa para o encaminhamento (350 casos). O não comparecimento foi maior nos portadores de glaucoma/glaucoma suspeitos (54,1%), estrabismo (45%) e afecções do segmento anterior (33,6%). Muitos indivíduos que não compareceram ao serviço de referência procuraram por outro local para o atendimento oftalmológico. Conclusão: O não comparecimento para tratamento oftalmológico sem custo depende de fatores relacionados ao paciente ou à falta de conhecimento das próprias condições oftalmológicas. Campanhas educativas nas comunidades assistidas devem ser feitas para alcançar maior comparecimento às consultas e melhor prevenir a cegueira evitável.

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Yu Fujita, Hirofumi Utsumi, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata Tel +81-3-3433-1111 (ex 3271)Fax +81-3-3433-1020Email t-numata@jikei.ac.jpBackground: In Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain.Methods: To elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy.Results: Thirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness.Conclusion: Switching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective.Keywords: benralizumab, dupilumab, mepolizumab, omalizumab, switching

For the hydrogen tanks of type 2 and 3, the metal lining and composite wrapping are bonded together by adhesive. To ensure the safety of these tanks for long-term use, nondestructive testing (NDT) and nondestructive evaluation (NDE) of their plastic composite/metal adhesive bonds are required. However, up to now, there is no effective NDT method for the debonding detection of hydrogen tanks of type 2 and 3. In this study, we propose the use of electromagnetic-pulse-induced acoustic testing (EPAT) to generate guided waves in plastic composite/metal adhesive bonding to detect debonding in adhesive parts. The EPAT method can excite the electromagnetic force from outside of the plastic composite material without contact, thereby directly exciting sound waves on the metal contacting the plastic composite. Through reasonable design, the intensity of the pulsed magnetic field can pass through a very thick plastic composite material and directly induces guided waves in the inner side metal. Therefore, EPAT method has the potential to detect the debonding of plastic composite/metal adhesive bonding in hydrogen tanks of type 2 and type 3 at the site of use. EPAT testing of acrylic/aluminum, glass-fiber-reinforced plastic/aluminum, and carbon-fiber-reinforced plastic/aluminum specimens was performed. The testing signals were analyzed in the time domain and frequency domain. The results indicate that the time-domain signals exhibited guided wave dispersion characteristics. In addition, the guided wave signals showed significant differences between the specimen with debonding and that without debonding, which could be used for the detection of debonding. In addition, different frequency guided waves had different sensitivities to debonding defects.

We report the case of a 56-year-old man with chronic myeloid leukemia (CML) who developed dasatinib-induced interstitial lung disease (ILD) 7 years after starting dasatinib, a BCR-ABL1 inhibitor. The patient presented with dyspnea. Chest imaging showed diffuse ground-glass opacities. A surgical lung biopsy showed cellular non-specific interstitial pneumonia (NSIP). Corticosteroid treatment ameliorated his condition. Bosutinib, another BCR-ABL1 inhibitor, was successfully re-instituted. The present case and relevant literature suggest that dasatinib-induced ILD can present as NSIP after an extended period, responds to corticosteroids, and is amenable to re-challenge at a lower-dose or with alternative BCR-ABL1 inhibitors.

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Department of Respiratory Diseases, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata, Department of Respiratory Diseases, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku Tokyo, 105-8461, Japan, Tel +81-3-3433-1111 (ext. 3271), Fax +81-3-3433-1020, Email t-numata@Jikei.ac.jpBackground: Treatment with dupilumab, an anti-interleukin (IL)-4 receptor α monoclonal antibody that blocks both the IL-4 and IL-13 pathways, has demonstrated efficacy for the treatment of severe asthma (SA) with type 2 inflammation. However, few studies have focused on the efficacy of this biologic for the treatment of SA in a real-world setting.Methods: From April 2019 to December 2021, 26 Japanese patients with SA received dupilumab at Jikei University Hospital. We retrospectively evaluated the number of moderate-to-severe exacerbations, pulmonary function, maintenance dose of corticosteroids, biomarkers, and adverse events.Results: During a mean follow-up period of 12.6 months, 10 patients received dupilumab as the first biologic, and 16 switched to dupilumab from other biologics. Dupilumab treatment significantly reduced the number of annual exacerbations from 3.4 ± 4.1 to 1.6 ± 2.7 (/person-year, p < 0.01) at the last follow-up regardless of previous biologic use. The Asthma Control Test score significantly improved in all patients by six months after administration but tended to worsen by 24 months in patients with previous biologic use. On the other hand, blood eosinophil counts (BECs) transiently increased and peaked three to six months after administration. The peak timing can be affected by previous biologic use. Adverse events included wheezing immediately after injection, hypereosinophilia, mild conjunctivitis, and relapse of chronic eosinophilic pneumonia in the patient switched from benralizumab.Conclusion: Dupilumab treatment was useful for patients with SA in a real-world setting. However, the BEC should be monitored carefully, especially in patients who previously received anti-IL-5/IL-5 receptor antibody.Keywords: dupilumab, severe asthma, exacerbation, transient eosinophilia, real-world

Introduction: Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes, and galectin-3 and tripartite motif proteins (TRIM)16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome selective autophagy for maintaining lysosome function. Methods: To examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis, using human bronchial epithelial cells (HBEC) and lung tissues. Results: CS extract (CSE) induced LMP as detected by galectin-3 accumulation and TRIM16 was involved in CSE-induced lysophagy. Impaired lysophagy was associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed increase in lipofuscin, aggresome, and galectin-3 puncta reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. HBEC isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Conclusion: Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Materials composed of metals and plastic composites joined through adhesive bonding are being increasingly used. However, debonding of such materials may occur during manufacture or use. Non-destructive testing of adhesive bonding structures is required to evaluate their debonding. Herein, electromagnetic pulse-induced acoustic testing (EPAT) was used to detect debonding at the adhesive joint in plastic composite/metal specimens. EPAT uses a pulsed excitation current to generate guided waves in a specimen to detect debonding without contact, which makes it suitable for testing from the plastic composite side. Simulations were performed to analyze acrylic/aluminum (Al) and carbon fiber-reinforced plastic (CFRP)/Al specimens. The results showed that the Lorentz force in the z direction was the dominant mechanism in the generation of guided waves, and mainly the A0-mode Lamb wave was excited. The simulation and experimental results revealed that for specimens where the mechanical parameters of the plastic composite layer differed greatly from those of the metal, such as the acrylic/Al specimen, debonding could only be detected directly above debonding. Therefore, it is necessary to evaluate the debonding position by scanning the receiver sensor. Conversely, for specimens with reasonably similar mechanical parameters of the plastic composite and metal layers, like the CFRP/Al specimen, the debonding position could be evaluated by scanning the receiver sensor or excitation coil.

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)–induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

This paper describes the detectability of eddy current testing (ECT) using directional eddy current for detection of in-plane fibre waviness in unidirectional carbon fibre reinforced plastic (CFRP) laminate. Three different types of probes, such as circular driving, symmetrical driving and uniform driving probe, were proposed, and the waviness angle was extracted from the contour map of the ECT signal by applying a Canny filter and a Hough transform. By comparing both the waviness angle estimated by ECT and that obtained by an X-ray CT image, the standard deviation (precision) and root mean square error (accuracy) were evaluated to discuss the detectability of these probes. The directional uniform driving probe shows the best detectability and can detect fibre waviness with a waviness angle of more than 2° in unidirectional CFRP. The probe shows a root mean square error of 1.90° and a standard deviation of 4.49° between the actual waviness angle and the angle estimated by ECT. This article is part of the theme issue ‘Advanced electromagnetic non-destructive evaluation and smart monitoring’.

Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of CMA; downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non–small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that LAMP2A expression is elevated in NSCLC cell lines and patient's tumors, conferring poor survival and platinum resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC‐bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC., Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of chaperone‐mediated autophagy (CMA). Downregulation of LAMP2A leads to CMA blockade. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes through CMA modulation and represents a promising new target against chemoresistant non–small cell lung cancer (NSCLC).

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient’s respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure.

Mepolizumab significantly reduces the number of annual exacerbations (AEs) and the maintenance dose of systemic corticosteroids (CSs) in patients with severe eosinophilic asthma (SEA). However, there are few studies based on real life with a long-term observational period in Japan. Between July 2016 and December 2019, 24 Japanese patients received mepolizumab at Jikei University Hospital for at least 12 months. We retrospectively evaluated these characteristics, AEs and CS doses. To elucidate the predictors of the enhanced responders, we performed multivariate logistic regression analysis. After introduction, asthma symptoms improved and were maintained for over a year. The number of AEs and CS doses significantly decreased. In the subgroup analysis, the younger than 65 years-old, body mass index (BMI) < 25 kg/m2, eosinophilic chronic rhinosinusitis, or eosinophil count ≥ 400/mm3 exhibited effective reductions in either AEs or CS doses with mepolizumab treatment. The percentage change in the AEs (≤ −75%) was significantly decreased in the patients with a BMI < 25 using multivariate logistic regression analysis (odds ratio 31, 95% confidence interval: 1.4–700, P = 0.03). In real-life, BMI < 25 could be a predictor for reductions in AEs with mepolizumab treatment in the patients with SEA. Abbreviations IL, interleukin; CS, corticosteroid; SEA, severe eosinophilic asthma; BMI, body mass index; ECRS, eosinophilic chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps

Introduction: Sarcopenia characterized by the loss of skeletal muscle mass and strength is prevalent in COPD. Sarcopenia has a huge impact on physical activity and is associated with increased mortality in COPD, but detailed molecular mechanism is still unclear. Increased reactive oxygen species (ROS) production and altered mitochondrial function has been reported in limb skeletal muscle of COPD. Previous study reported that muscle-specific depletion of autophagy was associated with increased ROS production in skeletal muscle. Although we have demonstrated the involvement of impaired Parkin-mediated mitochondria-selective autophagy, mitophagy in COPD pathogenesis, participation of mitophagy in sarcopenia progression associated with cigarette smoke (CS) exposure remains to be elucidated. Methods: Myoblasts were isolated from mouse limbs. CS extracts (CSE) was used to examine the effect of CS on myotube differentiation, reflecting myogenesis ability of myoblasts. Wild type (WT) myoblasts and Parkin knockout (KO) derived myoblasts were treated with 0.5 % CSE. Fusion index (the degree of differentiation from myoblast to myotube) and quantitative reverse transcription (RT)-PCR for myogenin (a marker for myotube differentiation) were performed. Results: Fusion index was significantly reduced by CSE exposure in WT myoblasts. Parkin KO myoblasts also showed reduced fusion index even in the absence of CSE. The expression levels of myogenin mRNA were decreased in CSE-exposed WT myoblasts and in Parkin KO myoblasts without CSE treatment. Conclusion: These results suggest that Parkin-mediated mitophagy may have a regulatory role in myogenesis during CS exposure as a part of sarcopenia pathogenesis in COPD.

International audience

Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

We describe a small electromagnetic acoustic transducer (EMAT) that is different from traditional large EMATs. The maximum vertical magnetic flux density decreases quickly, and its distribution becomes very uneven with increasing lift-off distance of the permanent magnet. To increase the magnetic field strength of a small magnet without increasing the thickness of the magnet configuration, we propose a different permanent magnet configuration. With the same lift-off distance of the magnet, the increase in the maximum vertical magnetic flux density is about 20% when using this configuration. When this lift-off distance is 1.5 mm, the configuration increases the amplitude of the received signal by 71.4% for an aluminium specimen; in contrast, only a 29.0% increase is achieved with a low-carbon steel specimen. This is because, in the latter, the vertical magnetic flux density is less than 0.66 T. The interplay between the Lorentz force and magnetostrictive force leads to a decrease in the efficiency of both forces in generating ultrasonic waves.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)–induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)–treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain–containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β–mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-β–induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-β–induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-β signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.

Background Several major randomized control studies have demonstrated that mepolizumab, an anti-IL-5 monoclonal antibody, is effective for patients with severe eosinophilic asthma who show exacerbation or require systemic corticosteroid maintenance therapy. However, the predictive factors of the response to mepolizumab other than blood eosinophil count are unclear in clinical practice. Objective To elucidate the predictive factors of the response to mepolizumab for patients with severe eosinophilic asthma. Methods From July 2016 to December 2017, 28 patients with severe asthma received mepolizumab in our hospital. To determine the predictive factors, we retrospectively evaluated patient characteristics, comorbidities, biomarkers, pulmonary function, maintenance dose of systemic corticosteroids and number of exacerbations. Results The response rate to mepolizumab treatment was 70% (19/27; one pregnant woman was excluded from analysis). Compared with 11 patients without eosinophilic chronic rhinosinusitis (ECRS), 16 patients with ECRS showed significantly improved systemic corticosteroid-sparing effects [− 71.3 ± 37.0% vs − 10.7 ± 20.1%, P = 0.006], change from baseline FeNO [− 19 ± 57 (%) vs 30 ± 77 (%), P = 0.023] and symptoms [14 patients (88%) vs five patients (45%), P = 0.033]. ECRS was identified as a predictive factor of the response to mepolizumab in a multivariate logistic regression analysis [odds ratio = 22.5, 95% CI (1.5–336), P = 0.024]. Of the eight patients previously administered omalizumab, five responded to mepolizumab. Staphylococcus aureus enterotoxin B IgE results were negative in 80% of responders (P = 0.14). Conclusion Both groups showed improved symptom scores and a decreased number of exacerbations. Mepolizumab substantially improved the clinical variables of patients with eosinophilic asthma complicated with ECRS.

Small airway chronic inflammation is a major pathologic feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Dendritic cells (DCs) accumulate around small airways in COPD. DCs are critical mediators of Ag surveillance and Ag presentation and amplify adaptive immune responses. How DCs accumulate around airways remains largely unknown. We use 2-photon DC imaging of living murine lung sections to directly visualize the dynamic movement of living DCs around airways in response to either soluble mediators (IL-1β) or environmental stimuli (cigarette smoke or TLR3 ligands) implicated in COPD pathogenesis. We find that DCs accumulate around murine airways primarily by increasing velocity (chemokinesis) rather than directional migration (chemotaxis) in response to all three stimuli. DC accumulation maximally occurs in a specific zone located 26–50 μm from small airways, which overlaps with zones of maximal DC velocity. Our data suggest that increased accumulation of DCs around airways results from increased numbers of highly chemokinetic DCs entering the lung from the circulation with balanced rates of immigration and emigration. Increases in DC accumulation and chemokinesis are partially dependent on ccr6, a crucial DC chemokine receptor, and fibroblast expression of the integrin αvβ8, a critical activator of TGF-β. αvβ8-Mediated TGF-β activation is known to enhance IL-1β–dependent fibroblast expression of the only known endogenous ccr6 chemokine ligand, ccl20. Taken together, these data suggest a mechanism by which αvβ8, ccl20, and ccr6 interact to lead to DC accumulation around airways in response to COPD-relevant stimuli.

Chronic airway inflammation and fibrosis, known as airway remodeling, are defining features of chronic obstructive pulmonary disease and are refractory to current treatments. How and whether chronic inflammation contributes to airway fibrosis remain controversial. In this study, we use a model of chronic obstructive pulmonary disease airway disease utilizing adenoviral delivery of IL-1β to determine that adaptive T cell immunity is required for airway remodeling because mice deficient in α/β T cells (tcra−/−) are protected. Dendritic cells (DCs) accumulate around chronic obstructive pulmonary disease airways and are critical to prime adaptive immunity, but they have not been shown to directly influence airway remodeling. We show that DC depletion or deficiency in the crucial DC chemokine receptor ccr6 both protect from adenoviral IL-1β–induced airway adaptive T cell immune responses and fibrosis in mice. These results provide evidence that chronic airway inflammation, mediated by accumulation of α/β T cells and driven by DCs, is critical to airway fibrosis.

Introduction: Downregulation of lamin B1 has been recognized to be a crucial step for development of full senescence. Accelerated cellular senescence linked to dysregulated autophagy and mTOR activation have been implicated in COPD pathogenesis. We have demonstrated reduced lamin B1 was associated with COPD pathogenesis through activating mTOR during cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). Methods: To further elucidate the mechanisms for lamin B1 downregulation related to autophagy, confocal microscopic evaluation and immunoprecipitation were performed in HBEC. DNA microarray and mass spectrometry were examined. C57BL/6J mice were exposed to cigarette smoke over a 6-month period as COPD model. Results: LaminB1 reduction during CSE exposure was recovered by lysosomal protease inhibitors and ATG5 knockdown. Confocal microscopic evaluation detected cytoplasmic colocarization between lamin B1 and LC3, reflecting autophagic degradation. DNA microarray and mass spectrometry demonstrated decrease in DEPTOR expression, an mTOR inhibitor by lamin B1 knockdown, which was responsible for subsequent autophagy impairment and cellular senescence. Lamin B1 knockdown also enhanced histone modification of H4K20me3. Decreased lamin B1 and DEPTOR with concomitantly increased p62 reflecting insufficient autophagic degradation were demonstrated in lung homogenate from cigarette smoke exposed-mice. Conclusion: These findings suggest CSE-induced autophagic degradation is involved in the mechanisms of lamin B1 reduction. Phenotypic alterations linked to cellular senescence can be attributed to epigenetic histone modifications by reduced laminB1.

Background Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. Methods Transforming growth factor-β (TGF-β)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. Results We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-β. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. Conclusions These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.

Background: Prostaglandin E2 (PGE2) is metabolized to prostaglandin E-major urinary metabolite (PGE-MUM). Enhanced cyclooxygenase-2 (COX-2) expression demonstrated in lung adenocarcinoma indicates increased PGE-MUM levels in patients with lung adenocarcinoma. Objectives: We aimed to elucidate the clinical usefulness of measuring PGE-MUM as an indicator of tumor burden in patients with lung adenocarcinoma. Methods: PGE-MUM was measured by a radioimmunoassay in control healthy volunteers (n = 124) and patients with lung adenocarcinoma (n = 54). Associations between PGE-MUM levels and clinical characteristics of the patients (including lung cancer stage and TNM factors (T: Tumor, N: Node, M: Metastasis) were examined. Results: PGE-MUM levels were significantly elevated in patients with lung adenocarcinoma. A PGE-MUM level of 14.9 &mu, g/g∙Cr showed 70.4% sensitivity and 67.7% specificity for the diagnosis of lung adenocarcinoma. PGE-MUM levels tended to be positively correlated with cancer progression as determined by the TNM staging system. Advanced stage (stage III, stage IV, and recurrence) was significantly associated with high PGE-MUM levels by logistic regression analysis. No apparent correlation was demonstrated between PGE-MUM and carcinoma embryonic antigen (CEA) levels. Conclusions: PGE-MUM can be a promising biomarker reflecting the systemic tumor burden of lung adenocarcinoma.

© 2017 the American Physiological Society. Small airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in α/β T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A (il17ra). Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including γδ T cells, type 3 innate lymphoid cells, polymorphonuclear cells, and CD8+ T cells. Antibody neutralization of IL-17RA or IL-17A confirmed that IL-17A was the relevant pathogenic IL-17 isoform and IL-17RA was the relevant receptor in airway inflammation and fibrosis. These results demonstrate that the IL-17A/IL-17 RA axis is crucial to murine airway fibrosis. These findings suggest that IL-17 might be targeted to prevent the progression of airway fibrosis in COPD.

Background Fatigue is an important clinical state and limits physical, mental activities in the patients with chronic lung diseases. However mechanisms and evaluation methods of fatigue are not well established. Recently reactivation of human herpesvirus (HHV)6/7 and HHV6 related molecules, named SITH-1 (Small protein encoded by the Intermediate Stage Transcript of HHV6-1) and its serum antibody (aSITH-1Ab) have been studied as novel biomarkers for fatigue.1),2) Fatigue due to chronic stress can cause increase of HHV6/7 DNAs in saliva, and aSITH-1Ab in blood of patients with mental disturbance. The HHV-related biomarkers could be good candidates to evaluate the pathological fatigue. Method To evaluate fatigue state, patients in stable conditions with COPD, asthma (BA) and BA COPD overlap syndrome (ACOS) were enrolled. The fatigue markers, depression score, and inflammation markers were measured. Result 60 patients were enrolled (mean age=60±14.8y, M/F=45/15, COPD/BA/ACOS=15/32/14). The rates (%) of high HHV DNA in saliva, meaning fatigue state, in COPD/BA/ACOS were 40/36/30, for both viruses equally. aSITH-1Ab positive rates (%) in COPD/BA/ACOS were 15.8/57.9/26.3. The markers for systemic inflammation were higher in COPD/ACOS than BA alone. Conclusion 30∼40% of the patients with COPD/BA/ACOS were estimated as fatigue. The patients with COPD (COPD/ACOS) showed higher systemic inflammation than BA alone, whereas those with BA (BA/ACOS) showed higher prevalence of mental disturbance than COPD alone. 1) Kondo K. et al. Journal of Virology 2002; 76: 4145-4151 2) Kondo K. et al. US Patent Application US 2013/0137088 A1 May 30, 2013.

Background The postoperative pulmonary complication (PPC) is an important surgical risk as common as the cardiac one, containing atelectasis, pneumonia, and respiratory failure. Objective The purpose of this study is to evaluate the risk factors for PPC in the patients with major respiratory underlying diseases such as bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) in our university hospital. Methods Totally 10699 patients were surgically treated in our university hospital from April to December in 2014. Among them, there were 68 COPD patients and 181 BA ones studied here. Eight of 68 COPD patients (11.8%) had PPC with 6 consolidations and 2 consolidations + respiratory failures, whereas 16 of 181 BA patients (8.8%) had PPC with 14 asthma attacks and 2 consolidations. We retrospectively evaluated physiological background, pulmonary function, duration of surgery, and perioperative specific treatment for pulmonary diseases to analyze the risk for PPC in these patients. Results In the BA patients, smoking index> 20 pack-year was significantly associated with PPC [OR (95%CI) = 11.7(2.6-52.1), P= 0.0013]. In the COPD patients, induction of COPD specific treatment and duration of surgery >300minites were significantly associated with PPC [OR (95%CI) = 0.09(0.01-0.63), P= 0.016; OR (95%CI) = 9.5(1.4-65.3), P= 0.022, respectively] Conclusions To prevent PPC, smoking cessation in BA and induction of specific treatment and shortening of surgery time in COPD were critically important.

RESUMO Objetivo: Avaliar a utilidade do tonômetro de ar (TA) em estudos populacionais em indivíduos suspeitos de hipertensão ocular, comparando os valores com os fornecidos pelo tonômetro de aplanação de Goldmann (TG). Métodos: Estudo transversal, de amostra probabilística, composta por 11.452 indivíduos e"20 anos, compondo-se uma subamostra dos que apresentaram valores de pressão intraocular (PIO) obtidos com o TA e"20mmHg, nos quais a PIO foi repetida com o TG. Os resultados dos dois tonmetros foram comparados considerando sexo, cor da pele referida, lateralidade, relação escavação/disco (Â0,6; entre e"0,6 e

An 87-year-old man was admitted to Jikei University Hospital presenting with fever and fatigue. Physical examinations revealed inspiratory coarse crackles on the left lung field. A chest CT detected a tumour-like consolidation around the thoracic aorta (figure 1A). Biochemical examinations found a high number of white blood cells and elevated C-reactive protein level, and a diagnosis of pneumonia was made. Penicillin antibiotics (ampicillin/sulbactam) were administered. Two days later, methicillin-sensitive Staphylococcus aureus (MSSA) was detected in two sets of blood cultures. An echocardiogram showed no vegetation and a urine culture was negative. A sputum culture was unobtainable, but pneumonia was the only focus of infection for the MSSA. Penicillin antibiotics were continued, but the patient suddenly developed cardiopulmonary arrest …

A 76-year-old man with ulcerative colitis presented with a 1-week history of low-grade fever and progressive dyspnea. He was taking infliximab for the ulcerative colitis. He was known to be negative for human immunodeficiency virus. Computed tomography (CT) of the chest revealed infiltrates in the