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Background: Contrast extravasation ("blush") on contrast-enhanced computed tomography (CECT) indicates active bleeding, but diagnostic angiography (AG) following CECT sometimes differs from the CECT findings in patients with pelvic fractures. This study aimed to evaluate the concordance rate between blush on CECT and AG based on pelvic anatomical location., Methods: This retrospective single-center study included patients (18 years or older) with pelvic fractures between 2015 and 2023 who had AG after CECT. Angiography was performed in patients with blush or hematoma on CECT, or unstable hemodynamics due to pelvic fracture. Pelvic bleeding regions were categorized separately into left and right as anterior internal iliac artery and posterior internal iliac artery based on pelvic arterial anatomy. The concordance rate between blush on CECT and AG was assessed using the k statistic., Results: A total of 87 patients with pelvic fractures were included. Among these, 75 (86%) had blush on CECT, and 12 (14%) had no blush on CECT. The concordance rate was 83% (95% confidence interval, 0.03-0.57; k = 0.30) when assessed on an individual patient basis and 53% (95% confidence interval, 0.24-0.44; k = 0.34) when evaluated by anatomical regions on a unilateral half of the pelvis. The concordance rate for the anatomical hemipelvis evaluation was significantly lower compared with the individual evaluation ( p < 0.001). Thirty-three percent of patients with unilateral blush on CECT showed new contralateral blushes during AG., Conclusion: The location of active bleeding often differs between CECT and AG, indicating that bleeding may change intermittently and at various sites over time. This suggests the importance of evaluating both sides of the pelvic arteries during AG rather than solely relying on CECT findings., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 American Association for the Surgery of Trauma.)

Background: There are cases of idiopathic interstitial pneumonias (IIPs) that do not meet the diagnostic criteria for connective tissue disease but have clinical features suggestive of autoimmune process. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept for these patients. Although several prospective studies on IPAF have been conducted, its clinical significance in cryptogenic organizing pneumonia (COP) remains unclear. Methods : Patients aged ≥20 years with suspected COP were prospectively enrolled between June 2018 and December 2022. Among the enrolled patients, those diagnosed with COP based on computed tomography (CT) and bronchoalveolar lavage (BAL) findings were compared between the IPAF and non-IPAF groups. Results : A total of 56 patients were enrolled in this study. Of these, 30 were diagnosed with COP and included in the analysis. Clinical and serological features were positive in two and six patients, respectively. Each feature was exclusive, and eight patients (26.7%) were diagnosed with IPAF. There were no differences between the IPAF and non-IPAF groups in terms of clinical features, including BAL findings, laboratory data, CT findings, and clinical course. During the one-year follow-up period, the frequency of COP exacerbation did not differ between the IPAF and non-IPAF groups, and no cases of systemic autoimmune disease or death occurred in either group. Conclusions : The COP characteristics of the IPAF and non-IPAF groups are similar in all aspects, and distinguishing between the two groups may be of little significance.

Background: Because exacerbation of severe asthma decreases patients' quality of life, this study aimed to identify predictive factors for asthma exacerbation., Methods: Japanese patients with severe asthma requiring treatment according to the Global Initiative for Asthma (GINA) guidelines ≥ Step 4 between January 2018 and August 2021 were prospectively enrolled and followed up for one year at facilities participating in the Okayama Respiratory Disease Study Group (Okayama Severe Asthma Research Program)., Results: A total of 85 patients (29 men and 56 women) were included. The median age was 64 (interquartile range [IQR], 51-72) years. Treatment according to GINA Steps 4 and 5 was required in 29 and 56 patients, respectively, and 44 patients (51.8%) were treated with biologics. The median peripheral-blood eosinophil count, fractional exhaled nitric oxide, IgE level, and percent predicted FEV 1 (%FEV 1 ) at enrollment were 204 (IQR, 49-436)/μL, 28 (IQR, 15-43) ppb, 172 (IQR, 56-473) IU/mL, and 80.0 (IQR, 61.1-96.1) %, respectively. Exacerbation during the previous year, asthma control test (ACT) score <20, %FEV 1 <60%, and serum IL-10 level >6.7 pg/mL were associated with exacerbation during the observation period., Conclusions: Exacerbation during the previous year, low ACT score, and low %FEV 1 were predictive factors of future exacerbation, even in a cohort with >50% of patients treated with biologics. Furthermore, high serum IL-10 levels might be a new predictive factor., Competing Interests: Declaration of competing interest HH has received grants from Novartis Pharma K.K., outside the submitted work. AK received speaker fees from AstraZeneca K.K., GlaxoSmithKline K.K., Novartis Pharma K.K., and Sanofi K.K., NM received speaker fees from AstraZeneca K.K., Boehringer Ingelheim K.K., GlaxoSmithKline K.K., Novartis Pharma K.K., and Sanofi K.K.. The rest of the authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Owing to the miniaturization of diagnostic ultrasound scanners and their spread of their bedside use, ultrasonography has been actively utilized in emergency situations. Ultrasonography performed by medical personnel with focused approaches at the bedside for clinical decision-making and improving the quality of invasive procedures is now called point-of-care ultrasonography (POCUS). The concept of POCUS has spread worldwide; however, in Japan, formal clinical guidance concerning POCUS is lacking, except for the application of focused assessment with sonography for trauma (FAST) and ultrasound-guided central venous cannulation. The Committee for the Promotion of POCUS in the Japanese Association for Acute Medicine (JAAM) has often discussed improving the quality of acute care using POCUS, and the "Clinical Guidance for Emergency and Point-of-Care Ultrasonography" was finally established with the endorsement of JAAM. The background, targets for acute care physicians, rationale based on published articles, and integrated application were mentioned in this guidance. The core points include the fundamental principles of ultrasound, airway, chest, cardiac, abdominal, and deep venous ultrasound, ultrasound-guided procedures, and the usage of ultrasound based on symptoms. Additional points, which are currently being considered as potential core points in the future, have also been widely mentioned. This guidance describes the overview and future direction of ultrasonography for acute care physicians and can be utilized for emergency ultrasound education. We hope this guidance will contribute to the effective use of ultrasonography in acute care settings in Japan., Competing Interests: Dr. Akio Kimura is an Editorial Board member of AMS Journal and a co‐author of this article. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication. The Japanese version of this paper was published in the July 2022 issue of the Journal of the Japanese Association for Acute Medicine (JJAAM). The authors have obtained permission for the secondary publication of the English version of the editors of the JJAAM., (© 2024 The Author(s). Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Filamentous fungi produce numerous industrially important enzymes. Among them, Aspergillus oryzae-derived enzymes are widely used in various fermentation applications. In this study, we constructed self-cloning strains that overproduce multiple biomass-degrading enzymes under the control of a strong promoter of α-amylase-coding gene (amyB) using the industrial strain A. oryzae AOK11. Two strains (strains 2-4 and 3-26) were introduced with different combinations of genes encoding xylanase (xynG1), phytase (phyA), pectin lyase (pelA), and polygalacturonase (pgaB). These strains had at least one copy of each enzyme gene derived from the expression cassette in the genome. The transcription levels of enzyme-coding genes introduced were more than 100-fold higher than those in the parent strain. Reflecting the high transcription levels, the activities of the enzymes derived from the expression cassettes of these two strains were significantly higher than those of the parent strain in both liquid and solid-state cultures. Even in ventilated solid-state cultures that were scaled up using mechanical equipment for practical applications, the two strains showed significantly higher enzyme activity than the parent strain. These results indicate that these strains constructed using a safe self-cloning technique represent industrially valuable practical strains that can be used in the food and livestock industries., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Objective: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality., Methods: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome., Results: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not., Conclusion: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population., Competing Interests: K.M. have received personal fees from Nippon Shinyaku Co td and AstraZeneca. N.T. have received grants and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer-Ingelheim Japan, and Ono Pharmaceutical; grants from Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; and personal fees from MSD and Bristol-Myers Squibb Company Japan outside the submitted work. None declared (S.S., R. S., J. I., G. K., T. K., T. T., K. K., T. K., Y. N., H. H., D. H., N. M.) This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Miyake et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The endocardial anchoring technique is a novel modification of total anomalous pulmonary venous return repair that involves creation of an L-shaped flap of the pulmonary venous confluence, subsequently anchoring it to the endocardium. A wide and smooth pathway can be expected from the theoretical advantages of this technique, namely, a smooth inner surface of the anchored flap and traction force to extend the orifice of the connection. An application of this technique for a rare variant of supracardiac total anomalous pulmonary venous return suggests its potential to be an alternative to the conventional repair, especially in patients with a curved pulmonary venous confluence., (© 2024 The Author(s).)

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-β, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-β and other cytokines, including interleukin (IL)-1β, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-β, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis., Competing Interests: Conflict of Interest Satoru Senoo, Hisao Higo, and Akihiko Taniguchi have no conflict of interest. Katsuyuki Kiura reports lecture fees from MSD K.K. outside of the submitted work. Katsuyuki Kiura also reports grants from Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Bristol-Myers Squibb K.K. outside of the submitted work. Yoshinobu Maeda reports lecture fees from Novartis Pharma K.K. outside of the submitted work. Yoshinobu Maeda also reports grants from Novartis Pharma K·K./AstraZeneca K·K./Astellas Pharma/Chugai Pharmaceutical Co., Ltd./Nippon Shinyaku Co., Ltd./Otsuka Pharmaceutical Co., Ltd./Eisai Co., Ltd./Chugai Pharmaceutical Co., Ltd./Nippon Shinyaku Co., Ltd./Takeda Pharmaceutical Company Limited/Kyowa Kirin Co., Ltd./Astellas Pharma outside of the submitted work. Nobuaki Miyahara reports grants from Novartis Pharma K·K, AstraZeneca K·K., Boehringer Ingelheim Co., Ltd., and GlaxoSmithKline Pharmaceuticals Co., Ltd./ROHTO Pharmaceutical Co., Ltd. outside of the submitted work., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Dupilumab is a fully humanized monoclonal antibody that blocks interleukin-4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics., Methods: This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded., Results: The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV 1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/μL), but all were asymptomatic and able to continue dupilumab therapy., Conclusions: Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval.

Background: Older individuals increasingly require emergency abdominal surgeries. They are susceptible to surgical stress and loss of independence in performing daily activities. We hypothesized that the psoas muscle volume would be significantly associated with postoperative functional decline (FD) in older patients undergoing emergency abdominal surgery and aimed to evaluate the use of the psoas muscle volume on computed tomography (CT) scans., Methods: A retrospective, single-center study of patients aged ≥ 65 years who had undergone emergency abdominal surgery between January 2019 and June 2021 was performed. We assessed patients' activities of daily living using the Barthel Index. FD was defined as a ≥ 5-point decrease between preoperative and 28-day postoperative values. The psoas muscle volume was measured by CT, which was used for diagnosis, and normalized by height to calculate total psoas muscle index (TPI). We evaluated associations between FD and TPI using receiver operating characteristics (ROC) analysis and multiple logistic regression analysis., Results: Of 238 eligible patients, 71 (29.8%) had clinical postoperative FD. Compared to the non-FD group, the FD group was significantly older and had a higher proportion of females, higher Charlson Comorbidity Index, lower body mass index, higher American Society of Anesthesiology score, lower serum albumin level, and lower TPI. ROC analyses revealed that TPI had the highest area under the curve (0.802; 95% confidence interval [CI], 0.75-0.86). A multivariable logistic regression model revealed that low TPI was an independent predictor of postoperative FD (odds ratio, 0.14; 95% CI, 0.06-0.32)., Conclusions: TPI can predict postoperative FD due to emergency abdominal surgery. Identification of patients who are at high risk of FD before surgery may be useful for enhancing the regionalized system of care for emergency general surgery., (© 2023. The Author(s).)

Neuropeptide Y (NPY), a 36 amino acid residue polypeptide distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1β concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1β concentrations in the lungs. Moreover, IL-1β neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1β release, and Y1 receptor antagonists inhibited IL-1β release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1β concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays a protective role against pulmonary fibrosis by suppressing IL-1β release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.

Anti-asparaginyl transfer RNA (tRNA) synthetase (KS) antibodies, detected in <5% patients with anti-aminoacyl-tRNA synthetase antibody syndrome, are strongly associated with interstitial pneumonia but not myositis and skin symptoms. A recent report suggested that most patients with interstitial pneumonia and anti-KS antibody (KS-ILD) may present with chronic disease. We herein report a rare case of severe acute respiratory failure in a KS-ILD patient requiring extracorporeal membrane oxygenation (ECMO). ECMO is useful for facilitating not only lung rest until recovery but also the definitive diagnosis and treatment of ILD. KS-ILD can develop acutely with fulminant respiratory failure, as observed in this case.

Robust and automated image segmentation in high-throughput image-based plant phenotyping has received considerable attention in the last decade. The possibility of this approach has not been well studied due to the time-consuming manual segmentation and lack of appropriate datasets. Segmenting images of greenhouse and open-field grown crops from the background is a challenging task linked to various factors such as complex background (presence of humans, equipment, devices, and machinery for crop management practices), environmental conditions (humidity, cloudy/sunny, fog, rain), occlusion, low-contrast and variability in crops and pose over time. This paper presents a new ubiquitous deep learning architecture ThelR547v1 (Thermal RGB 547 layers version 1) that segmented each pixel as crop or crop canopy from the background (non-crop) in real time by abstracting multi-scale contextual information with reduced memory cost. By evaluating over 37,328 augmented images (aug1: thermal RGB and RGB), our method achieves mean IoU of 0.94 and 0.87 for leaves and background and mean Bf scores of 0.93 and 0.86, respectively. ThelR547v1 has a training accuracy of 96.27%, a training loss of 0.09, a validation accuracy of 96.15%, and a validation loss of 0.10. Qualitative analysis further shows that despite the low resolution of training data, ThelR547v1 successfully distinguishes leaf/canopy pixels from complex and noisy background pixels, enabling it to be used for real-time semantic segmentation of horticultural crops.

Neuropeptide Y (NPY) is a neuropeptide widely expressed in not only the central nervous system but also immune cells and the respiratory epithelium. Patients with chronic obstructive pulmonary disease (COPD) reportedly exhibit decreased NPY expression in the airway epithelium, but the involvement of NPY in the pathophysiology of COPD has not been defined. We investigated the role of NPY in elastase-induced emphysema. NPY-deficient (NPY -/- ) mice and wild-type (NPY +/+ ) mice received intratracheal instillation of porcine pancreas elastase (PPE). The numbers of inflammatory cells and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates were determined along with quantitative morphometry of lung sections. Intratracheal instillation of PPE induced emphysematous changes and increased NPY levels in the lungs. Compared with NPY +/+ mice, NPY -/- mice had significantly enhanced PPE-induced emphysematous changes and alveolar enlargement. Neutrophilia seen in BAL fluid of NPY +/+ mice on day 4 after PPE instillation was also enhanced in NPY -/- mice, and the enhancement was associated with increased levels of neutrophil-related and macrophage-related chemokines and IL-17A as well as increased numbers of type 3 innate lymphoid cells in the airways. Treatment with NPY significantly reduced PPE-induced emphysematous changes. Conversely, treatment with a NPY receptor antagonist exacerbated PPE-induced emphysematous changes. These observations indicate that NPY has protective effects against elastase-induced emphysema and suggest that targeting NPY in emphysema has potential as a therapeutic strategy for delaying disease progression.

Aim: Limited information exists on the factors associated with prolonged procedural time in embolization for trauma patients. We clarified the clinical application of embolization in trauma patients and factors associated with a prolonged procedure time., Methods: Medical records of 162 trauma patients who underwent embolization between January 2007 and December 2020 at a regional trauma care center were reviewed retrospectively. Patients were divided into four embolized body regions: chest, abdomen, pelvis, and other. Patient demographics, trauma mechanism, physiology, trauma severity, embolization procedures, and 30-day mortality were examined. The outcomes were identifying an embolized body region, embolized arteries, and procedure time. Multiple regression model was created to investigate the factors associated with prolonged procedural time in embolization., Results: Embolization was mainly undertaken in pelvic fractures ( n  = 96, 59%) and abdominal organ injuries ( n  = 57, 35%) and extended to the chest ( n  = 17, 10%), and other ( n  = 20, 12%). Approximately 13% ( n  = 21) of patients underwent embolization in two or more regions. Embolization was more strictly performed in minor artery injuries, for example, external iliac ( n  = 15, 16%) and lumbar artery ( n  = 22, 23%) branches in pelvic fractures, and inferior phrenic artery ( n  = 2, 3.5%) branches in liver injuries. Multiple regression model indicated that the number of embolized arteries ( P  = 0.021) and number of embolized regions ( P  < 0.001) were associated with prolonged procedural time in embolization., Conclusions: Embolization for trauma patients extended to various trauma regions. In time-sensitive embolization, emergency interventional radiologists showed superior knowledge of expected embolizing arteries and factors associated with procedure time., (© 2022 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF)., Methods: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC)., Results: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions., Conclusions: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF., (© 2022. The Author(s).)

Acute exacerbation of idiopathic pulmonary fibrosis has a poor prognosis associated with neutrophilic inflammation. Interleukin-23 is a proinflammatory cytokine involved in neutrophilic inflammation. However, little is known about its role in acute exacerbation of pulmonary fibrosis. This study was performed to determine the role of interleukin-23 in acute exacerbation of pulmonary fibrosis. For assessment of acute exacerbation of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Cytokine levels were measured in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients with or without acute exacerbation. Interleukin-23, -17A, and -22 levels were increased in the airway of mice with acute exacerbation of pulmonary fibrosis. Interleukin-23p19-deficient mice with acute exacerbation of pulmonary fibrosis had markedly reduced airway inflammation and fibrosis associated with decreased levels of interleukin-17A and -22 compared with wild-type mice. Treatment with an anti-interleukin-23 antibody attenuated airway inflammation and fibrosis and reduced interleukin-17A and -22 levels in mice with acute exacerbation of pulmonary fibrosis. T-helper type 17 cells were the predominant source of interleukin-17A in mice with acute exacerbation of pulmonary fibrosis. Interleukin-23 levels in bronchoalveolar lavage fluid tended to be higher in idiopathic pulmonary fibrosis patients with than without acute exacerbation. The data presented here suggest that interleukin-23 is essential for the development of acute exacerbation of pulmonary fibrosis and that blockade of interleukin-23 may be a new therapeutic strategy for acute exacerbation of pulmonary fibrosis.

Mucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA+PTX). CBDCA+PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma.

Background: IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear., Methods: We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33 -/- mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again., Results: Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33 -/- mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33 -/- and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33 -/- mice than WT mice. IL-33 -/- mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE., Conclusion: These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor ( EGFR ), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult., (Copyright © 2020, Spandidos Publications.)

Quercetin is a flavonol that is known to have numerous beneficial biological effects such as an anti-fibrotic effect. Epithelial-mesenchymal transition (EMT) of alveolar type II epithelial cells is one of major causes of pulmonary fibrosis. However, the effect of quercetin on drug-induced EMT in alveolar type II cells is not known. In this study, we examined the effect of quercetin on bleomycin (BLM)-induced EMT using RLE/Abca3 cells having alveolar type II cell-like phenotype. BLM induced EMT-like morphological changes, downregulation of an epithelial marker E-cadherin, and upregulation of a mesenchymal marker α-smooth muscle actin in RLE/Abca3 cells. In addition, BLM increased the levels of phosphorylated Smad2 and Slug mRNA expression, and enhanced nuclear translocation of β-catenin, suggesting that BLM induced EMT in RLE/Abca3 cells via Smad and β-catenin signaling pathways. However, when the cells were co-treated with quercetin, quercetin suppressed all of these EMT-related changes induced by BLM. Furthermore, BLM increased the intracellular level of reactive oxygen species, which was also suppressed by quercetin. These results suggest that quercetin may be a possible candidate for preventing pulmonary fibrosis caused by drugs., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%., Methods: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months., Results: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib., Conclusions: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment., Competing Interests: Takuo Shibayama has received research funding from Nippon Boeringer Ingerheim Co., Ltd. Kanehiro Arihiko has received honoria from Nippon Boeringer Ingerheim Co., Ltd. Katsuyuki Kiura has received research funding and donation from Nippon Boeringer Ingerheim Co., Ltd. The other authors have nothing to declare.

BACKGROUND Patients with coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 can rapidly progress to acute respiratory distress syndrome (ARDS). Because clinical diagnosis of ARDS includes several diseases, understanding the characteristics of COVID-19-related ARDS is necessary for precise treatment. We report 2 patients with ARDS due to COVID-19-associated pneumonia. CASE REPORT Case 1 involved a 72-year-old Japanese man who presented with respiratory distress and fever. Computed tomography (CT) revealed subpleural ground-glass opacities (GGOs) and consolidation. Six days after symptom onset, reverse transcription-polymerase chain reaction (RT-PCR) testing confirmed the diagnosis of COVID-19-associated pneumonia. He was intubated and received veno-venous extracorporeal membrane oxygenation (ECMO) 8 days after symptom onset. Follow-up CT revealed large diffuse areas with a crazy-paving pattern and consolidation, which indicated progression of COVID-19-associated pneumonia. Following treatment with antiviral medications and supportive measures, the patient was weaned off ECMO after 20 days. Case 2 involved a 70-year-old Asian man residing in Canada who presented with cough, malaise, nausea, vomiting, and fever. COVID-19-associated pneumonia was diagnosed based on a positive result from RT-PCR testing. The patient was then transferred to the intensive care unit and intubated 8 days after symptom onset. Follow-up CT showed that while the initial subpleural GGOs had improved, diffuse GGOs appeared, similar to those observed upon diffuse alveolar damage. He was administered systemic steroid therapy for ARDS and extubated after 6 days. CONCLUSIONS Because the pattern of symptom exacerbation in COVID-19-associated pneumonia cases seems inconsistent, individual treatment management, especially the CT-based treatment strategy, is crucial.

Background: Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline., Methods: This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled., Results: We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009)., Conclusions: We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone., Competing Interests: Conflict of Interest The authors declare that they have no known competing financial interests., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to investigate the longitudinal association of the combination of poor appetite (PA) and low masticatory function (LMF) with sarcopenia in community-dwelling older adults., Methods: In total, 173 community-dwelling Japanese adults aged ≥ 75 years participated in the 3-year cohort study. Appetite assessment using the Simplified Nutritional Appetite Questionnaire (SNAQ) and masticatory function assessment using spectrophotometric measurement of differences in gum colour before and after masticating colour-changeable chewing gum (ΔE*ab) were performed at baseline. SNAQ score of ≤ 14 was defined as PA. The lowest tertile of ΔE*ab was defined as LMF. Follow-up examinations were administered annually over a 3-year period to determine sarcopenia incidence, which was defined by the criteria proposed by the Asian Working Group for Sarcopenia. Adjusted hazard ratios (HRs) of sarcopenia incidence according to the presence of PA and LMF were calculated using Cox proportional hazards regression models., Results: At baseline, 81 participants (46.8%) had neither PA nor LMF, 34 (19.7%) had PA alone, 35 (20.2%) had LMF alone, and 23 (13.3%) had both PA and LMF. On follow-up, 31 participants (17.9%) developed sarcopenia. After adjusting for covariates, the adjusted HR for sarcopenia in participants with both PA and LMF was 4.4 (95% confidence interval = 1.6-12.2) compared with those without PA or LMF. PA or LMF alone was not significantly associated with sarcopenia development., Conclusions: Coexisting PA and LMF increase the risk of sarcopenia development among community-dwelling Japanese adults aged ≥ 75 years., (© 2020 John Wiley & Sons Ltd.)

An engineering tool for controlling flux distribution on metabolic pathways to an appropriate state is highly desirable in bioproduction. An optogenetic switch, which regulates gene expression by light illumination is an attractive on/off switchable system, and is a promising way for flux control with an external stimulus. We demonstrated a light-inducible flux control between glycolysis and the methylglyoxal (MGO) pathway in Escherichia coli using a CcaS/CcaR system. CcaR is phosphorylated by green light and is dephosphorylated by red light. Phosphorylated CcaR induces gene expression under the cpcG2 promoter. The tpiA gene was expressed under the cpcG2 promoter in a genomic tpiA deletion strain. The strain was then cultured with glucose minimum medium under green or red light. We found that tpiA messenger RNA level under green light was four times higher than that under red light. The repression of tpiA expression led to a decrease in glycolytic flux, resulting in slower growth under red light (0.25 hr -1 ) when compared to green light (0.37 hr -1 ). The maximum extracellular MGO concentration under red light (0.2 mM) was higher than that under green light (0.05 mM). These phenotypes confirm that the MGO pathway flux was enhanced under red light., (© 2019 Wiley Periodicals, Inc.)

Moment equations were developed on the basis of the Einstein equation for diffusion and the random walk model to analytically determine the rate constant for the interfacial solute permeation from a bulk solvent into molecular aggregates (k in ) and the inverse rate constant from the molecular aggregates to the bulk solvent (k out ). The moment equations were in good agreement with those derived in a different manner. To demonstrate their effectiveness in one concrete example, the moment equations were used to analytically determine the values of k in and k out of three electrically neutral solutes, i.e. resorcinol, phenol, and nitrobenzene, from the first absolute (μ 1A ) and second central (μ 2C ) moments of their elution peaks, as measured by electrokinetic chromatography (EKC), in which the sodium dodecyl sulfate (SDS) micelles were used as a pseudostationary phase. The values of k in and k out should be determined with no chemical modifications and no physical action with the molecular aggregates because they are dynamic systems formed through weak interactions between the components. The moment analysis of the elution peak profiles measured by EKC is effective to unambiguously determine k in , k out , and the partition equilibrium constant (k in /k out ) under appropriate experimental conditions., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dynamically controlling cellular metabolism can improve a cell's yield and productivity towards a target compound. However, the application of this strategy is currently limited by the availability of reversible metabolic switches. Unlike chemical inducers, light can readily be applied and removed from the medium multiple times without causing chemical changes. This makes light-inducible systems a potent tool to dynamically control cellular metabolism. Here we describe the construction of a light-inducible metabolic switch to regulate flux distribution between two glycolytic pathways, the Embden-Meyerhof-Parnas (EMP) and oxidative pentose phosphate (oxPP) pathways. This was achieved by using chromatic acclimation sensor/regulator (CcaSR) optogenetic system to control the expression of pgi, a metabolic gene which expression determines flux distribution between EMP and oxPP pathways. Control over these pathways may allow us to maximize Escherichia coli's yield on highly-reduced compounds such as mevalonate. Background pgi expression of the initial CcaSR construct was too high to significantly reduce pgi expression during the OFF-state. Therefore, we attenuated the system's output leakage by adjusting plasmid copy number and by tagging Pgi with ssRA protein degradation signal. Using our CcaSR-pgi ver.3, we could control EMP:oxPP flux ratio to 50:49 and 0.5:99 (of total glycolytic flux) by exposure to green and red light, respectively., (Copyright © 2019 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

We herein report a case of the beneficial effect of osimertinib readministration in non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A 69-year-old non-smoking woman was diagnosed with advanced NSCLC harboring an EGFR exon19 deletion and T790M. She was treated with osimertinib for two years but eventually acquired resistance. After 1.5 years of salvage chemotherapies, osimertinib was re-administered. She has been effectively and safely treated with osimertinib readministration for over 10 months. A prospective study is warranted to evaluate the efficacy and safety of osimertinib readministration in NSCLC with EGFR mutations.

Squamous cell carcinoma of the lung is associated with smoking in its development and comprises about 20-30% of all lung cancers. Its treatment strategy had been limited for the past decades, inevitably resulting in the poor outcome. However in the 2010s, it has dramatically changed mainly with the recent clinical introduction of immune checkpoint inhibitors. In this review, we will introduce various clinical studies involving squamous cell carcinoma of the lung.

Pulmonary pleomorphic carcinoma (PPC) is a rare very aggressive subtype of non-small cell lung cancer. We herein report a case of PPC that showed a rapid response to nivolumab. The patient, whose multiple tumors had progressed very aggressively, was treated with nivolumab, an anti-programmed cell death-1 (PD-1) antibody. The tumors dramatically shrank after one cycle of nivolumab. The tumors were positive for programmed cell death ligand 1 (PD-L1). An immunohistochemical analysis revealed numerous PD-1 + , CD68 + and CD206 + macrophages. This PD-1 antibody may be a good treatment option, especially in tumors that express PD-L1 and which show PD-1 + macrophage infiltration.

Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the NPY Y 1 receptor. NPY modulates these cells via its Y 1 receptor; however, involvement of NPY in the pathophysiology of bronchial asthma, particularly airway hyperresponsiveness (AHR), has not been defined. NPY-deficient and wild-type mice were intranasally sensitized and challenged to house dust mite (HDM) extract, and airway responses were monitored. After sensitization and challenge, NPY-deficient mice showed significantly lower AHR than wild-type mice, and numbers of eosinophils and levels of type 2 cytokines [interleukin (IL)-4, IL-5, and IL-13] in bronchoalveolar lavage fluid were significantly lower. Type 2 cytokine production from splenic mononuclear cells of HDM-sensitized mice was also significantly lower in NPY-deficient mice. Flow cytometry analysis showed that the number of CD4 T cells and CD11c + antigen-presenting cells (APCs) was significantly lower in the lungs of NPY-deficient mice than in wild-type mice following sensitization and challenge. Significantly fewer CD11c + APCs phagocytosed HDM in the mediastinal lymph nodes of NPY-deficient mice than in those of wild-type mice. Treatment with BIBO-3304, a NPY receptor antagonist, significantly suppressed development of HDM-induced AHR and inflammation in wild-type mice. These data identify an important contribution of NPY to allergen-induced AHR and inflammation through accumulation of dendritic cells in the airway and promotion of the type 2 immune response. Thus, manipulating NPY represents a novel therapeutic target to control allergic airway responses.

Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined., Methods: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction., Results: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice., Conclusion: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has been proven to result in a survival benefit for the treatment of patients with HER2-positive advanced gastric cancer (AGC). However, data are lacking for the treatment of those with disseminated intravascular coagulation (DIC) and diffuse bone marrow carcinomatosis. A 77-year-old woman presented with back pain and fatigue since 2 months. Esophagogastroduodenoscopy showed a scirrhous lesion in the gastric corpus, which was biopsied and identified as signet-ring cell carcinoma with HER2 overexpression on immunohistochemistry. Laboratory testing, bone scintigraphy, and bone marrow biopsy were conducted, and she was diagnosed with HER2-positive AGC with DIC and diffuse bone marrow carcinomatosis. She underwent chemotherapy with the following regimen: oral administration of 80 mg/m2 S-1 for 2 weeks and 6 mg/kg trastuzumab infusion on day 6 every 3 weeks, which significantly improved the DIC. She was discharged from the hospital 73 days after admission and survived for 438 days after diagnosis. To the best of our knowledge, this is the first case report in which HER2-positive AGC complicated by DIC with diffuse bone marrow carcinomatosis was successfully treated with combined chemotherapy consisting of S-1 plus trastuzumab.

Eight 5-arylimino-3,4-tetramethylene-1,3,4-thiadiazolidine-2-thiones and eight 4-aryl-1,2- tetramethylene-1,2,4-triazolidine-3,5-dithiones were synthesized and their phytotoxic activities were investigated using sawa millet (Echinochloa utilis), green microalgae (Scenedesmus acutus) and protoporphyrinogen-IX oxidase isolated from etiolated corn (Zea mays) seedlings. 5-Arylimino-3,4-tetramethylene-1,3,4-thiadiazolidine-2-thiones showed strong phytotoxic activities and the same herbicidal mode of action as known for peroxidizing herbicides. 5-Arylimino-3,4-tetramethylene-1,3,4-thiadiazolidine-2-thiones were not or very little converted into 4-aryl-1,2-tetram ethylene-1,2,4-triazolidine-3,5-dithiones either with E. utilis seedlings present for 7 days, with S. acutus cells, or using glutathione 5-transferase (GST) and glutathione (GSH). The phytotoxic activities of 4-aryl-1,2-tetram ethylene-1,2,4-triazolidine- 3,5-dithiones were stronger than those of 5-arylimino-3,4-tetram ethylene-1,3,4-thiadiazolidine- 2-thiones [cf. Sato, Y., et al., Z. Naturforsch. 49c, 49-56 (1994)]., (© 1946 – 2014: Verlag der Zeitschrift für Naturforschung.)

A total of 18 rainfed upland New Rice for Africa (NERICA) varieties were categorized as the heavy panicle and low tillering types and early heading, in compared with 32 different varieties. These chromosome components were clarified using 243 SSR markers which showed polymorphism among NERICA varieties and their parents, CG 14 (O. glaberrima Steud.) and one of the recurrent parents, WAB-56-104 (O. sativa L.). NERICA varieties were classified into three groups, which corresponded with these parents' continuation including two exceptions, NERICAs 14 and 17, by a cluster analysis using polymorphism data of SSR markers and 14 differential markers among them were selected to classify NERICA varieties. However, three groups: NERICAs, 3 and 4, NERICAs, 8, 9 and 11 and NERICAs, 15 and 16 were not distinguishable. Association analysis was carried out for characterization of NERICA varieties by using SSR markers genotype and phenotype of agronomic traits. A total of 131 quantitative trait loci between SSR markers and 11 agronomic traits were detected. The characteristics of early maturity and heavy panicle of upland NERICA varieties were succeeded from Asian rice varieties and the characteristics of high dry matter production and late heading were introduced from CG 14 and the other varieties.

To evaluate whether neuropathic pain affects autonomic nervous activities, we investigated daily change in cardiovascular parameters and plasma norepinephrine (NE) in free-moving rats after chronic constriction injury (CCI) on the sciatic nerve. Arterial blood pressure (BP), heart rate (HR), and the power spectrum of pulse interval variability were analyzed. Daily change in motor activity and nociceptive behavior was also measured from some CCI rats. In others, NE from daily blood samples was quantified and spontaneous pain was evaluated by daily monitoring of foot guarding behavior. We identified three stages in the daily change of cardiovascular parameters and plasma NE level over 3 weeks following CCI. The first stage (up to 3 days after the surgery) was characterized by increased MAP and HR, especially in the daytime, even though plasma NE was unchanged and motor activity decreased. The second stage (mid first to mid second postoperative weeks) was characterized by increased daytime MAP and HR, and the animals developed punctate hyperalgesia in the affected hindpaw. An NE surge that may have been related to spontaneous pain was present 3-5 days after CCI. The third stage, which appeared after the second postoperative week, was characterized by normalized MAP and decreased HR, and increased high-frequency (0.8-3.0Hz) power in pulse interval variability, which is an index of cardiac parasympathetic tone. These results demonstrated that cardiovascular function was kept high through sympathetic and non-sympathetic activity for 2 weeks after CCI, followed by a predominance of parasympathetic tone.

This study was conducted to clarify the development of free neuromasts with growth of the barramundi, Lates calcarifer. A pair of free neuromasts was observed behind the unpigmented eyes in newly hatched eleutheroembryos with a mean total length of 1.93 mm, and two-hour-old eleuthero-embryos could respond to an approaching pipette. At 2 days after hatching, the egg yolk sac was mostly consumed, the eyes were pigmented, and the larvae commenced feeding on rotifers. Free neuromasts increased in number with growth and commenced developing into canal neuromasts in barramundi 15 days old with a mean total length of 8.07 mm. The average length of the major axis of the trunk free neuromasts attained approximately 12.9-15.5 microm, and the number of sensory cells was 15.4-17.5 at 15-20 days old. Developed cupulae of free neuromasts were observed in 1-day-old eleutheroembryos. The direction of maximum sensitivity of free neuromasts, determined from the polarity of the sensory cells, coincided with the minor axis of the lozenge-shaped outline of the apical surface of the free neuromasts. The polarity of trunk neuromasts was usually oriented along the antero-posterior axis of the fish body, but a few had a dorso-ventral direction. On the head, free neuromasts were oriented on lines tangential to concentric circles around the eye.

Background: We histologically evaluated the epithelia of the gallbladder (GB) and bile duct (BD) in patients with anomalous arrangement of the pancreaticobiliary ductal system (AAPB), with regard to the shape of the common BD (CBD)., Methods: The GB and BD were studied histologically using surgical materials from 44 patients with AAPB: 27 with a dilated CBD (D-type) and 17 with a nondilated CBD (N-type)., Results: GB cancer and BD cancer were found in 11.1% and 3.7% of D-type and 17.6% and 0% of N-type respectively. Hyperplastic epithelium and atypical epithelium of the GB were frequently seen in both D-type (46%, 46%) and N-type (82%, 70%), while such epithelia of the BD were only seen in D-type (10%, 35%). The Ki67 labeling index of the nonneoplastic epithelium of the GB was high in both D-type (13.0%) and N-type (9.7%), though that of the BD was high in D-type (12.5%) but low in N-type (1.8%). The prevalences of pyloric gland metaplasia, intestinal metaplasia, and p53 protein overexpression of the nonneoplastic epithelium did not show any significant differences between D-type and N-type., Conclusions: It is suggested that the BD epithelium of N-type probably has a lower potential for developing malignancy than that of D-type, while the GB epithelia of both D-type and N-type have a high potential for developing malignancy. This might support the selection of simple cholecystectomy as the treatment of choice in AAPB patients of N-type, although further investigation of the BD epithelium is required in a larger number of such patients.

This study was carried out to clarify the efficacy of magnetic resonance cholangiopancreatography (MRCP) in the diagnosis of biliary tract diseases, Three hundred and eleven patients who underwent MRCP and ERCP during the period from January 1999 to December 1999 at our institution were included in the study. Two gastroenterologists who were blinded to results of direct cholangiography and final diagnoses interpreted MRCP images prospectively. The biliary duct was visualized by MRCP and ERCP in 99.4% and 89.5% of the cases, respectively. The sensitivity, specificity, and accuracy of MRCP in the diagnosis of choledocholithiasis were 95%, 97%, and 97%, respectively. MRCP depicted the presence of strictures with a sensitivity, specificity, and accuracy of 97%, 96%, and 96%, respectively. There were three false-positive cases because of artifacts from arterial compression, The accuracy of MRCP and ERCP in differentiation of benign strictures from malignant ones was 85% and 96%, respectively. Based on these results, it is concluded that MRCP has high capability in visualization of the biliary tree, and in detection of stones and strictures, To avoid over and under-diagnosis, awareness of some pitfalls inherent in, MRCP is important. We suggest that MRCP should be recommended for patients with suspicion of biliary tract diseases in the initial stage of making diagnosis.

To clarify the significance of magnetic renonance cholangiopancreatography (MRCP) in the acute phase of acute cholecystitis, MRCP was carried out in forty-five patients with acute cholecystitis in their acute phase. The MR pericholecystic high signal was observed in 38 of the 45 patients (84%). Enlargement of the gallbladder, presence of gallstones, and impacted stones was seen in 71%, 53%, and 18%, respectively. The MR pericholecystic high signal was classified into four categories: type 0, not observed; type 1, a liner high signal; type 2, a band-like high signal; type 3, a radiating high signal. In patients who showed a type 3 MR pericholecystic high signal, 91% required percutaneous transhepatic gallbladder drainage, and most of the gallbladders were diagnosed as necrotic cholecystitis by histology. The accuracy of MRCP for the diagnosis of choledocholithiasis was 96%. It was suggested that MRCP for patients with acute cholecystitis in the acute phase provides useful information for planning the treatment.

A 58-year-old man was admitted to our hospital suffering from intermittent claudication and angiogram revealed complete obstruction of the left common iliac artery. The essential thrombocythemia was diagnosed from platelet count over 1,000,000/mm3 as well as bone marrow finding. After the platelet count was reduced into normal range by administration of ranimustine (MCNC), abdominal aorta-femoral artery bypass grafting using 8mm-diameter Gelseal graft was successfully performed without any complications such as thrombus formation or bleeding. Coldness and cyanotic discoloration of the lower extremities were diminished with the decrease in platelet count. He was discharged in satisfactory condition and has been on postoperative control with warfarin, ticlopidine chloride and aspirin therapy.