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Seigo Miyoshi,1 Hitoshi Katayama,1 Minoru Matsubara,2 Takahide Kato,1 Naohiko Hamaguchi,1 Osamu Yamaguchi1 1Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; 2Department of Internal Medicine, Sumitomo Besshi Hospital, Niihama, Ehime 792-8543, JapanCorrespondence: Seigo MiyoshiDepartment of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, JapanTel +81-89-960-5303Fax +81-89-960-5306Email seigom@m.ehime-u.ac.jpBackground and Objective: Spirometry is sometimes difficult to perform in elderly patients and patients with cognitive impairment. Forced oscillometry (FOT) is a simple, noninvasive technique used for measuring respiratory impedance. The aim of this study was to develop regression equations to estimate vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1.0) on the basis of FOT indices and to evaluate the accuracy of these equations in patients with asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD).Materials and Methods: We retrospectively included data on 683 consecutive patients with asthma (388), COPD (128), or ILD (167) in this study. We generated regression equations for VC, FVC, and FEV1.0 by multivariate linear regression analysis and used them to estimate the corresponding values. We determined whether the estimated data reflected spirometric indices.Results: Actual and estimated VC, FVC, and FEV1.0 values showed significant correlations (all r > 0.8 and P < 0.001) in all groups. Biases between the actual data and estimated data for VC, FVC, and FEV1.0 in the asthma group were − 0.073 L, − 0.069 L, and 0.017 L, respectively. The corresponding values were − 0.064 L, 0.027 L, and 0.069 L, respectively, in the COPD group and − 0.040 L, − 0.071 L, and − 0.002 L, respectively, in the ILD group. The estimated data in the present study did not completely correspond to the actual data. In addition, sensitivity for an FEV1.0/FVC ratio of < 0.7 and the diagnostic accuracy for the classification of COPD grade using estimated data were low.Conclusion: These results suggest that our method is not highly accurate. Further studies are needed to generate more accurate regression equations for estimating spirometric indices based on FOT measurements.Keywords: forced expiratory volume in 1 second, forced oscillation technique, forced vital capacity, spirometry, vital capacity

Shoichiro Yamamoto,1 Seigo Miyoshi,1 Hitoshi Katayama,1 Mikio Okazaki,2 Hisayuki Shigematsu,2 Yoshifumi Sano,2 Minoru Matsubara,3 Naohiko Hamaguchi,1 Takafumi Okura,1 Jitsuo Higaki1 1Department of Cardiology, Pulmonology, Hypertension, and Nephrology, 2Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, 3Department of Internal Medicine, Sumitomo Besshi Hospital, Niihama, Japan Purpose: Spirometry is sometimes difficult to perform in elderly patients and in those with severe respiratory distress. The forced-oscillation technique (FOT) is a simple and noninvasive method of measuring respiratory impedance. The aim of this study was to determine if FOT data reflect spirometric indices.Patients and methods: Patients underwent both FOT and spirometry procedures prior to inclusion in development (n=1,089) and validation (n=552) studies. Multivariate linear regression analysis was performed to identify FOT parameters predictive of vital capacity (VC), forced VC (FVC), and forced expiratory volume in 1 second (FEV1). A regression equation was used to calculate estimated VC, FVC, and FEV1. We then determined whether the estimated data reflected spirometric indices. Agreement between actual and estimated spirometry data was assessed by Bland–Altman analysis.Results: Significant correlations were observed between actual and estimated VC, FVC, and FEV1 values (all r>0.8 and P0.8 and P

Seigo Miyoshi,1 Takahide Kato,1 Hitoshi Katayama,1 Ryoji Ito,1 Yosuke Mizuno,2 Takafumi Okura,1 Jitsuo Higaki1 1Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan; 2Department of Molecular Pathology, Ehime University Graduate School of Medicine, Ehime, Japan Abstract: EGFR mutant lung cancer responds to EGFR tyrosine kinase inhibitors (TKIs), but all patients eventually develop resistance to EGFR-TKIs. Herein we report a case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-TKI with MET amplification and epithelial-to-mesenchymal transition (EMT). A 73-year-old woman was diagnosed with adenocarcinoma harboring an EGFR exon 19 deletion. She received gefitinib as second-line therapy. Tumors were reduced 1 month after gefitinib therapy. However, only a few months later, chest computed tomography results indicated cancer progression. Gefitinib therapy was stopped and docetaxel therapy started. However, she died 13 days after admission. Microscopic examination of postmortem specimens revealed a diffuse proliferation of atypical giant cells in primary and metastatic lesions, but no adenocarcinomatous components as in the antemortem specimens. Immunohistochemical analyses showed that antemortem tumor specimens were positive for CDH1 but negative for VIM. In contrast, postmortem tumor specimens were positive for VIM but negative for CDH1. Genetic analyses revealed MET amplification. We concluded that resistance to EGFR-TKI might be caused by MET amplification and EMT. To our knowledge, no clinical studies have reported that MET amplification and EMT together may be associated with acquired resistance to EGFR-TKI. Second biopsy after the development of EGFR-TKI resistance may be recommended to determine the best therapeutic strategy. Keywords: epidermal growth factor receptor tyrosine kinase inhibitor, MET amplification, epithelial-to-mesenchymal transition

Seigo Miyoshi,1 Ryoji Ito,1 Hitoshi Katayama,1 Kentaro Dote,2 Mayuki Aibiki,3 Hironobu Hamada,1,4 Takafumi Okura,1 Jitsuo Higaki1 1Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, 2Intensive Care Division, Ehime University Hospital, 3Department of Emergency and Critical Care Medicine, School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, 4Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi, Minami-ku, Hiroshima, Japan Background: Neutrophil elastase, alveolar thrombin generation, and fibrin deposition play crucial roles in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). However, the usefulness of combination therapy with a selective neutrophil elastase inhibitor, sivelestat, and recombinant human soluble thrombomodulin (rhTM) for patients with ARDS and DIC remains unknown. Methods: We conducted a retrospective data analysis of 142 ARDS patients with DIC to assess the effects of sivelestat combined with rhTM. Patients were divided into four groups: control (no sivelestat or rhTM treatment), sivelestat treatment alone, rhTM treatment alone, and combined treatment with sivelestat and rhTM. A Cox proportional hazard model was used to assess subject mortality rates. The efficacy of these drugs was evaluated based on survival rate, number of ventilator-free days, and change in PaO2/FIO2 (P/F) ratios and DIC scores before and at 7 days after a diagnosis of ARDS with DIC. Results: Multivariate analysis showed that patient age, combination therapy, gas exchange, organ failure, cause, associated disease score, and serum C-reactive protein levels were predictors of mortality for patients with ARDS and DIC. As compared with untreated controls, combination therapy significantly improved the 60-day survival rate of patients with ARDS and DIC. There were significantly more ventilator-free days for those who received combination therapy than for untreated controls. P/F ratios and DIC scores were significantly improved with sivelestat alone, rhTM alone, or their combination as compared with untreated controls. Conclusion: Our results suggest that combined treatment with sivelestat and rhTM has beneficial effects on survival and the respiratory and DIC status of patients with ARDS and DIC. Keywords: sivelestat, recombinant human soluble thrombomodulin, disseminated intravascular coagulation, acute respiratory distress syndrome

Seigo Miyoshi,1 Hironobu Hamada,1,2 Ryoji Ito,1 Hitoshi Katayama,1 Kazunori Irifune,1 Toshimitsu Suwaki,3 Norihiko Nakanishi,4 Takanori Kanematsu,5 Kentaro Dote,6 Mayuki Aibiki,7 Takafumi Okura,1 Jitsuo Higaki1 1Department of Integrated Medicine and Informatics, Ehime University, Graduate School of Medicine, Toon, 2Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 3Department of Respiratory Medicine, Sumitomo Besshi Hospital, Niihama, 4Department of Respiratory Medicine, Ehime Prefectural Central Hospital, Matsuyama, 5Department of Respiratory Medicine, Matsuyama Red Cross Hospital, Matsuyama, 6Intensive Care Division, Ehime University Hospital, Toon, 7Department of Emergency Medicine, School of Medicine, Ehime University, Toon, Japan Background: Neutrophil elastase plays a crucial role in the development of acute lung injury (ALI) in patients with systemic inflammatory response syndrome (SIRS). The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat. Methods: This was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs) and changes in PaO2/FIO2 (ΔP/F) before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL. Results: There were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated patients than in the control patients. However, there was no significant difference in the patient survival rate between the two groups. Sivelestat was more effective in ALI patients with a PaO2/FIO2 ratio ≥140 mmHg or sepsis. Sivelestat significantly prolonged survival and led to higher VFDs and increased ΔP/F in septic patients and patients with initial serum procalcitonin levels ≥0.5 ng/mL. Conclusion: The results may facilitate a future randomized controlled trial to determine whether sivelestat is beneficial for ALI patients with sepsis. Keywords: systemic inflammatory response syndrome, procalcitonin, ventilator-free days, neutrophil elastase

Introduction. Amniotic membrane contains a multipotential stem cell population and is expected to possess the machinery to regulate immunological reactions. We investigated the safety and efficacy of allogeneic amniotic membrane-derived mesenchymal stromal cell (AMSC) transplantation in a porcine model of chronic myocardial ischemia as a preclinical trial. Methods. Porcine AMSCs were isolated from amniotic membranes obtained by cesarean section just before delivery and were cultured to increase their numbers before transplantation. Chronic myocardial ischemia was induced by implantation of an ameroid constrictor around the left circumflex coronary artery. Four weeks after ischemia induction, nine swine were assigned to undergo either allogeneic AMSC transplantation or normal saline injection. Functional analysis was performed by echocardiography, and histological examinations were carried out by immunohistochemistry 4 weeks after AMSC transplantation. Results. Echocardiography demonstrated that left ventricular ejection fraction was significantly improved and left ventricular dilatation was well attenuated 4 weeks after AMSC transplantation. Histological assessment showed a significant reduction in percentage of fibrosis in the AMSC transplantation group. Injected allogeneic green fluorescent protein (GFP)-expressing AMSCs were identified in the immunocompetent host heart without the use of any immunosuppressants 4 weeks after transplantation. Immunohistochemistry revealed that GFP colocalized with cardiac troponin T and cardiac troponin I. Conclusions. We have demonstrated that allogeneic AMSC transplantation produced histological and functional improvement in the impaired myocardium in a porcine model of chronic myocardial ischemia. The transplanted allogeneic AMSCs survived without the use of any immunosuppressants and gained cardiac phenotype through either their transdifferentiation or cell fusion.

Crude fat content of longissimus (ribeye) muscle of beef cattle was predicted from a ratio of fat area (RFA) to area of ribeye muscle calculated from computer image analysis (CIA). Cross sections of 64 ribeyes taken from the 6-7th rib from cattle at experiment station A and cross sections of 94 ribeyes taken from the 6-7th rib from cattle at Experiment Station B were used in this study. Slices (1 to 1.5 cm in thickness) of just the Longissimus dorsi were homogenized and sampled for chemical estimation of crude fat content using petroleum ether. Crude fat content as determined from chemical analysis was used as the true estimate of fat content. A CCD (charge-coupled device) camera was used as the input device at Experiment Station A, and a single-lens reflex camera was used at Experiment Station B to photograph ribeyes for CIA. The contour comparison method, which assigns a threshold value for each marbling particle, was used to obtain accurate binarization in this study. Minimum and maximum of chemical measurements of crude fat were 2.1 and 39.8%, and for CIA calculation of the RFA were 6.1 and 56.8%, respectively. This range covered almost the complete range of the beef marbling standard used in carcass grading in Japan. The equation for the regression of the crude fat content (Y) on RFA (X) calculated from CIA for all of the data was Y = .793X- 3.04 with r(super 2) = .96. Regression equations for prediction of crude fat percentage from RFA taking into consideration the effect of experiment station were Y = .741X - 2.22 with r(super 2) = .91 for Experiment Station A, and Y = .782X - 2.54 with r(super 2) = .91 for Experiment Station B. Analysis of covariance showed that the effects of experiment stations on intercepts and slopes were not significant (P > .10). The ranges of differences between actual and predicted crude fat content from the prediction equation that was calculated without consideration of the effect of station were - 6.4 to 4.0%. CIA of cross sections of the ribeye muscle seems to have potential for prediction of crude fat content. Key Words: Animal Fat, Carcasses, Imagery

A theoretical model of the x-ray responses of silicon surface-barrier (SSB) detectors was developed under a configuration of a widely used detector structure for plasma x-ray diagnostics. The model consisted of a signal contribution from thermally diffusing charge created in the field-free substrate region within a diffusion length from the depletion layer. This was accompanied signal contributions coming from charge created in the depletion layer. The model was found to predict a large signal contribution from the charge-diffusion effect on the SSB responses to high-energy x-rays.