Absolute Quantification of Pure Free Radical Reagents by Combination of the Effective Magnetic Moment Method and Quantitative Electron Paramagnetic Resonance Method.

An absolute quantitative analysis of free radicals by combining the effective magnetic moment method and the quantitative electron paramagnetic resonance [qEPR] method is proposed. This combined method utilizes the advantages of both the analytical methods and compensates for their disadvantages. In the effective magnetic moment method, the magnetic moment under a constant magnetic field is measured accurately using a superconducting quantum interference device. The qEPR method compares a "primary standard sample" and "secondary standard sample". The effective magnetic moment method was used to determine the purity of the primary standard sample. The qEPR method realizes a simple purity analysis of free-radical reagents with traceability to the International System of Units (SI). The purity of the free radicals by the qEPR method for pure 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate [4HTB], 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine [TEMPOL], and di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium [DPPH] reagents was obtained with a relative expanded uncertainty of 0.7% for 4HTB to 1.5% for the DPPH. These small uncertainties were almost equal to those of the purity of the primary standard samples and were achieved by adopting in-plane positioning of the measured sample perpendicular to the cylindrical axis of the sample space of the superconducting quantum interference device. Some purity values of the free radicals for these reagents differed from those stated by the manufacturers. This combined method enables short-time quality control of pure radical reagents, instead of quality control by separation analytical methods or titrations.

Role of FK506 Binding Protein on Tacrolimus Distribution in Red Blood Cells.

PURPOSE: Tacrolimus is distributed mainly in red blood cells (RBCs) after transfer into blood. This study aimed to evaluate the effect of FK506-binding proteins (FKBPs) on RBC distribution of tacrolimus in a physiological environment. METHODS: Human RBCs were isolated from fresh blood samples from healthy volunteers. The effect of FKBPs on each process of the RBC distribution of tacrolimus was evaluated in vitro. Effect of intracellular FKBPs was assessed by inhibition experiment with rapamycin, which competitively inhibits the binding of tacrolimus to FKBPs. Effect of extracellular FKBPs was examined by pre-exposure of RBCs to FKBP and preincubation of tacrolimus with FKBP. RESULTS: Pretreatment with rapamycin significantly reduced the rate of tacrolimus distribution in RBCs in a concentration-dependent manner. Pre-exposure of RBCs to FKBP12 followed by exposure to tacrolimus significantly decreased tacrolimus distribution in RBCs in a concentration-dependent manner. In addition, preincubation of tacrolimus with FKBP12 significantly reduced the rate of tacrolimus distribution in RBCs. CONCLUSIONS: FKBP played an important role in the distribution of tacrolimus in RBCs. The effect of intracellular and extracellular FKBPs on RBC distribution of tacrolimus in circulating blood was substantial. FKBP was shown as a potential biomarker for predicting the pharmacokinetics and pharmacodynamics of tacrolimus.

Elevated levels of periostin and TGF-ß1 in the bronchoalveolar lavage fluid of patients with idiopathic eosinophilic pneumonia.

BACKGROUND: Periostin is induced in bronchial epithelial cells and fibroblasts by various stimuli including interleukin (IL)13 and transforming growth factor (TGF)-ß1, and is involved in allergic diseases such as asthma and atopic dermatitis, playing an important role in tissue remodeling and fibrosis. The role of periostin in the pathogenesis of eosinophilic lung diseases, however, is unclear. OBJECTIVE: To examine the contribution of periostin to eosinophilic inflammation of the lung in humans, we evaluated periostin, IL-13, and TGF-ß1 levels in the bronchoalveolar lavage fluid (BALF) of patients with eosinophilic pneumonia (EP). METHODS: Periostin, IL-13, and TGF-ß1 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute EP, chronic EP, idiopathic pulmonary fibrosis (IPF), and sarcoidosis. Further, we analyzed the relationship between periostin, IL-13, and TGFß-1, levels and the number of inflammatory cells in the BALF. RESULTS: The absolute number of eosinophils, and the periostin, IL-13, and TGF-ß1 levels in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. Concentrations of periostin significantly correlated with the concentrations of TGF-ß1, but not those of IL-13, in the BALF of patients with EP. Periostin levels also significantly correlated with the absolute number of eosinophils in the BALF of patients with IPF, but not EP. CONCLUSIONS: Our findings suggest that TGF-ß1 might increase the production of periostin in the lungs of patients with EP. Periostin might contribute the pathogenesis of not only EP, but also IPF.

Drug-drug interactions among drugs prescribed for nontuberculous mycobacterial infection and epilepsy: A case report.

WHAT IS KNOWN AND OBJECTIVE: Multi-drug combinations often make chemotherapy difficult owing to drug-drug interactions (DDIs). We report a rare and difficult-to-treat case due to DDIs between drugs for Mycobacterium avium complex (MAC) infection and antiepileptic drugs. CASE DESCRIPTION: A 70-year-old Japanese woman was diagnosed as having pulmonary MAC disease. She had a history of symptomatic epilepsy, which was successfully treated with phenytoin and phenobarbital. Serum phenytoin concentrations increased upon the initiation of MAC infection treatment. WHAT IS NEW AND CONCLUSION: We evaluated DDIs and adjusted the dosage of drugs by monitoring the serum drug level.

Improvement of Reproducibility of Magnetic Moment Detected by a SQUID Magnetometer Through Radial Offset Measurement on a YIG Sphere.

We report here on the reproducibility of measurements on a second-order gradiometer superconducting quantum interference device magnetometer of two different yttrium iron garnet spheres, both having a diameter of 1 mm: 1) the National Institute of Standards and Technology magnetic moment standard reference material (SRM) and 2) a commercial sample. It has been suggested that rotating the sample rod around its axis can move the sample center toward the center of the second-order gradiometer coil. The observed value of the magnetic moment will be theoretically a minimum when the radial offset is 0, and this value will increase in a "quadratic" manner with the radial offset. When the magnetic moment of the SRM was repeatedly measured as a function of rotation angle φ from 0° to 360°, we observed a sinusoidal variation in the measured values. The radial offset dependence of the observed magnetic moment was experimentally confirmed by the measurements of the commercial sphere placed in a hole in several cylindrical containers, wherein the distance between the center of the hole and the center of the container was r. The r-dependence of the minimum from each φ-dependent measurement series is qualitatively consistent with the theoretical curve. When the φ-dependent measurements for the SRM in a capsule were repeated 12× over 21 months, the relative standard deviation of the minimums improved up to 0.1%. Knowledge of these facts will be necessary for the accurate measurement of the magnetic moment of other sample forms (e.g., powders).

Malignant mesothelioma with squamous differentiation.

AIMS: We report the autopsy findings of a 58-year-old man with malignant mesothelioma in the left pleural cavity. METHODS AND RESULTS: The patient had a history of asbestos exposure, and the chest computed tomography scan on initial admission demonstrated an extrapleural sign, suggesting a nodular lesion in the chest wall. However, no nodular lesions were detectable in either of his lungs. In spite of chemotherapy, he died 4 months after the initial admission. An autopsy revealed markedly thickened pleura in a large section of the left pleural cavity without visible intrapulmonary primary tumour lesions. Histological examination of a biopsy specimen obtained prior to chemotherapy and that of an autopsy specimen showed that the pleural tumour was composed of a mixture of mesothelioma and tumour cells with squamous differentiation mimicking squamous cell carcinoma. CONCLUSIONS: To the best of our knowledge, this is the first case report of mesothelioma with extensive squamous differentiation in the English-language literature. The extensive squamous differentiation reminiscent of squamous cell carcinoma can be a pitfall in the pathological diagnosis of pleural cytology and that of biopsy specimens from patients with mesothelioma. Here, we report autopsy findings of a case of malignant mesothelioma with portions of extensive squamous differentiation, mimicking a squamous cell carcinoma.

Factors associated with pneumococcal vaccination in elderly people: a cross-sectional study among elderly club members in Miyakonojo City, Japan.

BACKGROUND: Pneumonia is the third leading cause of death in Japan. All elderly people aged 65 years or older are recommended to receive a pneumococcal vaccine. A subsidy for part of the cost of routine pneumococcal vaccination in this age group was introduced in 2014. Factors related to vaccination behavior among elderly adults have not been well reported. The purpose of this study was to investigate factors associated with vaccine uptake among elderly people in Japan. METHODS: We conducted a cross-sectional study, using a self-administered questionnaire among elderly club members aged 65 years or older in one city of Japan in April 2017. The participants were selected from among all elderly club members in the study area. Variables extracted from the questionnaire were analyzed using logistic regression analysis. RESULTS: A total of 208 elderly club members participated in the study. The mean age (± SD) was 77.2 (± 5.3) years. The pneumococcal vaccination rate was 53.2%. Logistic regression analysis revealed three variables that had a significant association with pneumococcal vaccination: a recommendation for vaccination from medical personnel (aOR 8.42, 95% CI 3.59-19.72, p <  0.001), receiving influenza vaccination in any of the previous three seasons (aOR 3.94, 95% CI 1.70-9.13, p = 0.001), and perception of the severity of pneumonia (aOR 1.23, 95% CI 1.03-1.48, p = 0.026). CONCLUSIONS: Although the pneumococcal vaccination rate in this study was increased compared with previous reports, almost half of study participants had not yet received vaccination. Our findings could be helpful for developing vaccination strategies to increase the vaccine coverage in the elderly population.

Possible Role of IL-25 in Eosinophilic Lung Inflammation in Patients with Chronic Eosinophilic Pneumonia.

PURPOSE: Interleukin (IL)-25 and IL-33 induce IL-5 production by various types of cells, such as type 2 helper T (Th2) cells and type 2 innate lymphoid cells. The number of Th2 cells and concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) are increased in patients with eosinophilic pneumonia (EP). To examine the contribution of IL-25 and IL-33 to eosinophilic inflammation of the lung in humans, we evaluated IL-5, IL-25 and IL-33 levels in the BALF of patients with EP. METHODS: IL-5, IL-25, and IL-33 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), idiopathic pulmonary fibrosis (IPF), and sarcoidosis. RESULTS: The absolute number of eosinophils, and IL-5 levels, but not IL-33 levels, in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. IL-25 levels in the BALF were significantly higher in patients with CEP, but not in patients with AEP, than in patients with IPF and sarcoidosis. The absolute number of eosinophils was significantly correlated with the IL-5 concentration in the BALF of patients with EP. IL-5 concentrations were significantly correlated with IL-25 concentrations in the BALF of patients with CEP, but not in patients with AEP. IL-5 levels were not correlated with IL-33 levels in the BALF of patients with EP. CONCLUSIONS: Our findings suggest that IL-25 plays an important role via IL-5 in eosinophilic lung inflammation in patients with CEP.

Clinical application of ghrelin for chronic respiratory failure.

Chronic respiratory failure, which is often caused by chronic obstructive pulmonary disease, chronic lower respiratory tract infection, or interstitial pneumonia, often leads to cachexia with disease progression. Patients who have chronic respiratory failure with cachexia exhibit increased morbidity. Although cachectic status is an important clinical problem, there are no effective therapies for cachexia. Ghrelin has various effects, including increasing food intake, attenuating sympathetic nerve activity, inhibiting inflammation, increasing cardiac output, and controlling fat utilization. These effects of ghrelin are ideal targets for the treatment of severely wasting chronic respiratory disease. In a few clinical studies, including a small randomized controlled trial, ghrelin administration to cachectic patients with chronic respiratory failure improved exercise tolerance, dyspnea, and appetite. The patients in these studies gained muscle mass and weight. In another study of chronic lower respiratory tract infection with cachexia, ghrelin suppressed airway inflammation by decreasing neutrophil accumulation in the airway, resulting in improvements in oxygenation and exercise tolerance. Although further clinical investigations are needed to clarify its usefulness, ghrelin is expected to become a novel therapy for cachectic patients with chronic respiratory failure.

Ghrelin does not influence cancer progression in a lung adenocarcinoma cell line.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced in the human stomach. Although ghrelin has therapeutic potential for cancer cachexia, ghrelin treatment may have a concern about accelerating cancer progression. Here, using the human lung adenocarcinoma cell line HLC-1, we investigated the effects of ghrelin on molecular mechanisms linked to cancer progression, including cell viability, proliferation, resistance to apoptosis, and mitochondrial activity. Both types of mouse alveolar epithelial cells (types I and II) expressed the GHSR, as did the human normal airway cell lines BEAS-2B and HLC-1. Treatment with ghrelin (10-2, 10-1, 1, 10 µM) did not affect cell viability or proliferation. Pretreatment of HLC-1 cells with ghrelin (10 µM) did not affect resistance to paclitaxel-induced apoptosis. The parameters of mitochondrial respiration, including basal respiration, proton leak, ATP production, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration, of the HLC-1 cells pretreated with or without ghrelin were unchanged. Taken together, ghrelin does not influence cancer progression in lung adenocarcinoma cells.

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections.

Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence-clearance-regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice.

Ghrelin is a 28-amino-acid peptide that stimulates the release of pituitary growth hormone. Because of its orexigenic effects, ghrelin is being developed as a therapeutic option for postoperative support and treatment of anorexia-cachexia syndrome of cancer patients. However, ghrelin has a multiplicity of physiological functions, and it also affects cell proliferation. Therefore, the effects of ghrelin administration on carcinogenesis and cancer progression in patients susceptible to cancer should be clarified. In this study, we examined the effects of ghrelin on cancer promotion in vivo using murine intestinal carcinogenesis models. Intestinal tumorigenesis was examined to determine the effects of either exogenous ghrelin administration or ghrelin deficiency following deletion of the Ghrl gene. Two murine intestinal tumorigenesis models were used. The first was the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced inflammation-associated colon carcinogenesis model and the second was the Apc(Min/+) genetic cancer susceptibility model. In AOM/DSS-treated mice, administration of ghrelin significantly suppressed tumor formation in the colon. In contrast, ghrelin administration did not affect the number of intestinal tumors formed in Apc(Min/+) mice. The absence of endogenous ghrelin did not affect the incidence of intestinal tumors in either AOM/DSS-treated mice or Apc(Min/+) mice, though tumor size tended to be larger in Ghrl(-/-) colons in the AOM/DSS model. No tumor-promoting effect was observed by ghrelin administration in either tumorigenesis model. In summary, this study provides in vivo experimental evidence for the usefulness of ghrelin administration in the chemoprevention of inflammation-associated colorectal carcinogenesis and may suggest its safety in patients under colitis-associated cancer susceptibility conditions.

Ghrelin administration for chronic respiratory failure: a randomized dose-comparison trial.

BACKGROUND: Repeated ghrelin administration leads to improvements in symptoms, muscle wasting and exercise tolerance in cachectic patients with pulmonary disease. We investigated the optimal ghrelin dose for underweight patients with chronic respiratory failure. METHODS: In this multicenter, randomized, dose-comparison exploratory study, 44 cachectic patients with chronic respiratory failure were randomly assigned pulmonary rehabilitation with intravenous twice-daily administration of 1 or 2 µg/kg ghrelin for 3 weeks. The primary endpoint was improvement in 6-min walking distance (6 MWD). The secondary endpoint was change in peak VO2. RESULTS: Twenty-one patients were assigned to the 1 µg/kg ghrelin group and 23 to the 2 µg/kg ghrelin group. Change from baseline 6 MWD after treatment was similar between groups(1 µg/kg: 53.9 m, 2 µg/kg: 53.9 m, p = 0.99). Mean change in peak VO2 was significantly greater in the 2 µg/kg group (63.1 ml/min) than in the 1 µg/kg group (-63.8 ml/min, p = 0.048). Food intake and lean body mass significantly increased in both groups, and the St. George Respiratory Questionnaire score, body weight, and body mass index were remarkably improved in only the 2 µg/kg group, although there was no significant difference between groups. No treatment-related serious events were reported for either group. CONCLUSION: Improvements in the oxygen uptake capacity were greater in patients receiving 2 µg/kg ghrelin twice daily for 3 weeks than in those receiving 1 µg/kg, although exercise tolerance was similar between groups at the end of the 3-week treatment period. Thus, a twice daily dose of 2 µg/kg ghrelin is recommended over 1 µg/kg ghrelin for patients with chronic respiratory failure and weight loss.

Autopsy analyses in acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. However, few studies have so far reviewed analyses of autopsy findings in patients with AE-IPF. METHODS: We retrospectively reviewed 52 consecutive patients with AE-IPF who underwent autopsies at five university hospitals and one municipal hospital between 1999 and 2013. The following variables were abstracted from the medical records: demographic and clinical data, autopsy findings and complications during the clinical course until death. RESULTS: The median age at autopsy was 71 years (range 47-86 years), and the subjects included 38 (73.1%) males. High-dose corticosteroid therapy was initiated in 45 (86.5%) patients after AE-IPF. The underling fibrotic lesion was classified as having the usual interstitial pneumonia (UIP) pattern in all cases. Furthermore, 41 (78.8%) patients had diffuse alveolar damage (DAD), 15 (28.8%) exhibited pulmonary hemorrhage, nine (17.3%) developed pulmonary thromboembolism and six (11.5%) were diagnosed with lung carcinoma. In addition, six (11.5%) patients developed pneumothorax prior to death and 26 (53.1%) developed diabetes that required insulin treatment after the administration of high-dose corticosteroid therapy. In addition, 15 (28.8%) patients presented with bronchopneumonia during their clinical course and/or until death, including fungal (seven, 13.5%), cytomegalovirus (six, 11.5%) and bacterial (five, 9.6%) infections. CONCLUSIONS: The pathological findings in patients with AE-IPF represent not only DAD, but also a variety of pathological conditions. Therefore, making a diagnosis of AE-IPF is often difficult, and the use of cautious diagnostic approaches is required for appropriate treatment.

Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity.

RATIONALE: Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. OBJECTIVES: To determine the role of epithelial Pten in ALI and lung fibrosis. METHODS: Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Δ/Δ) (SOPten(Δ/Δ)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: SOPten(Δ/Δ) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Δ/Δ) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-ß1 expressions. Akt inactivation definitively saved SOPten(Δ/Δ) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. CONCLUSIONS: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.

Clinical usefulness of the two-question assessment tool for depressive symptoms in Japanese patients with chronic obstructive pulmonary disease.

PURPOSE: Depressive symptoms are highly prevalent in patients with chronic obstructive pulmonary disease (COPD) and have been associated with poor outcomes. Developing a concise questionnaire to measure depressive symptoms in COPD patients is needed in outpatient settings. We evaluated the clinical usefulness of a concise two-question instrument to assess depressive symptoms in patients with COPD. METHODS: The study was conducted as a cross-sectional analysis in patients with COPD. All patients completed a self-reported questionnaire consisting of the two-question instrument, as well as a shortened version of the Center for Epidemiologic Studies Depression Scale (CESD-10) to measure depressive symptoms. Performance of the two-question instrument was evaluated using the results for CESD-10 as standard. We also measured patients' health-related quality of life using the Medical Outcomes Study 8-Item Short-Form Health Survey (SF-8) to determine whether the instrument was related to SF-8. RESULTS: Sensitivity of the two-question instrument in the detection of depressive symptoms was 73.3 % (95 % confidence interval [CI] 51-95.7), specificity was 73 % (95 % CI 58.7-87.3), and area under the receiver operating characteristics curve was 0.73 (95 % CI 0.59-0.87). When study patients were divided into two groups with a cutoff of 1 point on the two-question instrument, scores for all subscales of the SF-8 except "bodily pain" were significantly lower in patients with than without depressive symptoms. CONCLUSIONS: This concise two-question instrument is useful as assessment of depressive symptom in patients with COPD in busy outpatient settings.

A possible role of galectin-9 in the pulmonary fibrosis of patients with interstitial pneumonia.

BACKGROUND: Galectin-9 (Gal-9) is a ß-galactoside-binding protein that induces biological reactions, such as cell activation, chemoattraction, and apoptosis. We evaluated the role of Gal-9 in the pathogenesis of interstitial pneumonia (IP). METHODS: Gal-9 levels in the bronchoalveolar lavage fluid (BALF) of patients with IP associated with collagen vascular disease (CVD-IP) and with idiopathic interstitial pneumonias (IIPs), including idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (idiopathic NSIP), were estimated by enzyme-linked immunosorbent assay. Gal-9 expression in the lungs of these patients was evaluated using immunohistochemistry. The effect of Gal-9 on the growth and apoptosis of human lung fibroblast cells was assessed in vitro. RESULTS: Gal-9 levels in the BALF were significantly higher in patients with CVD-IP than in patients with IIPs. Gal-9 levels significantly correlated with both the total cell count and the absolute number of lymphocytes in the BALF of patients with IIPs and CVD-IP. Strong reactivity with anti-Gal-9 antibody was observed in the cytoplasm of alveolar macrophages, lymphocytes, and type II pneumocytes in the lungs of patients with IP. Gal-9 expression in those cells was more remarkable in patients with CVD-IP than in patients with IPF and idiopathic NSIP. Gal-9 suppressed the growth of human lung fibroblast cells in a dose- dependent manner. Gal-9 induced apoptosis of human lung fibroblast cells in a dose-dependent manner. CONCLUSIONS: Our findings suggest that the expression level of Gal-9 in the lung is increased in patients with CVD-IP and that Gal-9 may have a protective role against pulmonary fibrosis of these patients.

Developing Artificial Intelligence Models for Extracting Oncologic Outcomes from Japanese Electronic Health Records.

INTRODUCTION: A framework that extracts oncological outcomes from large-scale databases using artificial intelligence (AI) is not well established. Thus, we aimed to develop AI models to extract outcomes in patients with lung cancer using unstructured text data from electronic health records of multiple hospitals. METHODS: We constructed AI models (Bidirectional Encoder Representations from Transformers [BERT], Naïve Bayes, and Longformer) for tumor evaluation using the University of Miyazaki Hospital (UMH) database. This data included both structured and unstructured data from progress notes, radiology reports, and discharge summaries. The BERT model was applied to the Life Data Initiative (LDI) data set of six hospitals. Study outcomes included the performance of AI models and time to progression of disease (TTP) for each line of treatment based on the treatment response extracted by AI models. RESULTS: For the UMH data set, the BERT model exhibited higher precision accuracy compared to the Naïve Bayes or the Longformer models, respectively (precision [0.42 vs. 0.47 or 0.22], recall [0.63 vs. 0.46 or 0.33] and F1 scores [0.50 vs. 0.46 or 0.27]). When this BERT model was applied to LDI data, prediction accuracy remained quite similar. The Kaplan-Meier plots of TTP (months) showed similar trends for the first (median 14.9 [95% confidence interval 11.5, 21.1] and 16.8 [12.6, 21.8]), the second (7.8 [6.7, 10.7] and 7.8 [6.7, 10.7]), and the later lines of treatment for the predicted data by the BERT model and the manually curated data. CONCLUSION: We developed AI models to extract treatment responses in patients with lung cancer using a large EHR database; however, the model requires further improvement.

The use of artificial intelligence (AI) to derive health outcomes from large electronic health records is not well established. Thus, we built three different AI models: Bidirectional Encoder Representations from Transformers (BERT), Naïve Bayes, and Longformer to serve this purpose. Initially, we developed these models based on data from the University of Miyazaki Hospital (UMH) and later improved them using the Life Data Initiative (LDI) data set of six hospitals. The performance of the BERT model was better than the other two, and it showed similar results when it was applied to the LDI data set. The Kaplan­Meier plots of time to progression of disease for the predicted data by the BERT model showed similar trends to those for the manually curated data. In summary, we developed an AI model to extract health outcomes using a large electronic health database in this study; however, the performance of the AI model could be improved using more training data.

[Educational usefulness of lung auscultation training with an auscultation simulator].

OBJECTIVE: We examined the educational usefulness of lung auscultation training with an auscultation simulator "Mr. Lung". METHODS: Auscultation training was conducted for fifth-year students of the Medical Department of the University of Miyazaki, and consisted of a lecture by a pulmonologist (Board Certified Member of the Japanese Respiratory Society) and skill training using Mr. Lung for a total of 90 min. We compared the percentages of students who correctly identified 4 adventitious sounds before and after training. We also investigated the responses to a self-report questionnaire on self-evaluation after training, auscultation experiences before training, and opinions regarding medical education with the simulator. RESULTS: The subjects' correct answer rate before training was 40% or less and that for the correct identification of rhonchi was the lowest (5%). The correct answer rate, which was not influenced by previous experience of auscultation, significantly increased after training (80% or more). In the self-report questionnaire, about 90% of the students answered that the ability to identify lung sounds by auscultation was necessary for all doctors and that the simulator was effective for acquiring this skill. CONCLUSION: The auscultation simulator may be useful for medical students not only to enhance auscultatory skills but also to realize the importance of auscultation in clinical examination.

A case of bilateral invasive mucinous adenocarcinoma of the lung with severe productive cough and dyspnea successfully treated with palliative lung lobectomy.

Invasive mucinous adenocarcinoma (IMA) of the lung is a chemo-refractory type of lung cancer with frequent intrapulmonary dissemination. Patients with IMA of the lung often suffer from a productive cough and rapid deterioration of performance status (PS). There is currently no standard therapeutic strategy against this unrelenting condition. Here we report a patient with bilateral IMA of the lung with severe productive cough and dyspnea successfully controlled by palliative lung lobectomy. A 67-year-old Japanese man presented with a 3-month history of productive cough. Chest computed tomography (CT) revealed a mass lesion in the left lower lobe and a small nodule and multiple thin-walled cystic lesions in the right lung. He was diagnosed with stage IIB IMA of the lung. Over the next two weeks, his productive cough and dyspnea drastically worsened and his PS declined from 0 to 4. Chest CT showed increases in size of both the nodule and cystic lesions in the right lung and the mass lesion in the left lower lobe. He was re-diagnosed as stage IVA. Given the extreme heterogeneity of the tumor distribution, we decided to perform palliative resection of the left lower lobe. After the surgery, he experienced complete relief of respiratory symptoms, and his PS improved dramatically, enabling chemotherapy. Thirty-one months after surgery, he maintains good PS. In conclusion, our report suggests that aggressive introduction of palliative lung lobectomy played a substantial role for in the excellent outcome of our patient with relatively well confined, advanced-stage IMA.