Researcher Profile and Settings

Master

Affiliation (Master)

• Hokkaido University Hospital　Division of Hospital Safety Management

Affiliation (Master)

• Hokkaido University Hospital　Division of Hospital Safety Management

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Profile and Settings

Profile and Settings

• Name (Japanese)

  Nasuhara

• Name (Kana)

  Yasuyuki

• Name

  200901079494254291

Achievement

Research Interests

• patient safety   呼吸器内科学   

Research Areas

• Life sciences / Healthcare management, medical sociology
• Life sciences / Respiratory medicine

Research Experience

• 2017/07 - Today Hokkaido University Hokkaido University Hospital
• 2008/04 - 2017/06 Hokkaido University Hokkaido University Hospital
• 2005 - 北海道大学病院 講師
• 2005 - Lecturer

Education

• 1988/03 - Today  Hokkaido University  School of Medicine

Awards

• 2005 ベルツ賞
  

Published Papers

• Associations of COVID-19 symptoms with omicron subvariants BA.2 and BA.5, host status, and clinical outcomes in Japan: a registry-based observational study.

  Sho Nakakubo, Naoki Kishida, Kenichi Okuda, Keisuke Kamada, Masami Iwama, Masaru Suzuki, Isao Yokota, Yoichi M Ito, Yasuyuki Nasuhara, Richard C Boucher, Satoshi Konno

  The Lancet. Infectious diseases 2023/06/30 

  BACKGROUND: Previous SARS-CoV-2 infection and vaccination, coupled with the rapid evolution of SARS-CoV-2 variants, have modified COVID-19 clinical manifestations. We aimed to characterise the clinical symptoms of COVID-19 individuals in omicron BA.2 and BA.5 Japanese pandemic periods to identify omicron and subvariant associations between symptoms, immune status, and clinical outcomes. METHODS: In this registry-based observational study, individuals registered in Sapporo's web-based COVID-19 information system entered 12 pre-selected symptoms, days since symptom onset, vaccination history, SARS-CoV-2 infection history, and background. Eligibility criteria included symptomatic individuals who tested positive for SARS-CoV-2 (PCR or antigen test), and individuals who were not tested for SARS-CoV-2 but developed new symptoms after a household member tested positive for SARS-CoV-2. Symptom prevalence, variables associated with symptoms, and symptoms associated with progression to severe disease were analysed. FINDINGS: Data were collected and analysed between April 25 and Sept 25, 2022. For 157 861 omicron-infected symptomatic individuals, cough was the most common symptom (99 032 [62·7%] patients), followed by sore throat (95 838 [60·7%] patients), nasal discharge (69 968 [44·3%] patients), and fever (61 218 [38·8%] patients). Omicron BA.5 infection was associated with a higher prevalence of systemic symptoms than BA.2 in vaccinated and unvaccinated individuals (adjusted odds ratio [OR] for fever: 2·18 [95% CI 2·12-2·25]). Omicron breakthrough-infected individuals with three or more vaccinations or previous infection were less likely to exhibit systemic symptoms (fever 0·50 [0·49-0·51]), but more likely to exhibit upper respiratory symptoms (sore throat 1·33 [1·29-1·36]; nasal discharge 1·84 [1·80-1·89]). Infected older individuals (≥65 years) had lower odds for all symptoms. However, when symptoms were manifest, systemic symptoms were associated with increased odds for severe disease (dyspnoea 3·01 [1·84-4·91]; fever 2·93 [1·89-4·52]), whereas upper respiratory symptoms were associated with decreased odds (sore throat 0·38 [0·24-0·63]; nasal discharge 0·48 [0·28-0·81]). INTERPRETATION: Host immunological status, omicron subvariant, and age were associated with a spectrum of COVID-19 symptoms and outcomes. BA.5 produced a higher systemic symptom prevalence than BA.2. Vaccination and previous infection reduced systemic symptom prevalence and improved outcomes but increased upper respiratory tract symptom prevalence. Systemic, but not upper respiratory, symptoms in older people heralded severe disease. Our findings could serve as a practical guide to use COVID-19 symptoms to appropriately modify health-care strategies and predict clinical outcomes for older patients with omicron infections. FUNDING: Japan Agency for Medical Research and Development.
• Associations of COVID-19 Symptoms with Omicron Subvariants BA.2 and BA.5, Host Status, and Clinical Outcomes: A Registry-Based Observational Study in Sapporo, Japan.

  Sho Nakakubo, Naoki Kishida, Kenichi Okuda, Keisuke Kamada, Masami Iwama, Masaru Suzuki, Isao Yokota, Yoichi M Ito, Yasuyuki Nasuhara, Richard C Boucher, Satoshi Konno

  medRxiv : the preprint server for health sciences 2023/02/07 

  BACKGROUND: Previous SARS-CoV-2 infection and vaccination, coupled to rapid evolution of SARS-CoV-2 variants, have modified COVID-19 clinical manifestations. We characterized clinical symptoms of COVID-19 individuals in omicron BA.2 and BA.5 Japanese pandemic periods to identify omicron and subvariant associations between symptoms, immune status, and clinical outcomes. METHODS: Individuals registered in Sapporo's web-based COVID-19 information system entered 12 pre-selected symptoms, days since symptom onset, vaccination history, SARS-CoV-2 infection history, and background. Symptom frequencies, variables associated with symptoms, and symptoms associated with progression to severe disease were analysed. RESULTS: For all omicron-infected individuals, cough was the most common symptom (62.7%), followed by sore throat (60.7%), nasal discharge (44.3%), and fever (38.8%). Omicron BA.5 infection was associated with a higher symptom burden than BA.2 in vaccinated and unvaccinated individuals. Omicron breakthrough-infected individuals with ≥ 3 vaccinations or previous infection were less likely to exhibit systemic symptoms, but more likely to exhibit upper respiratory symptoms. Infected elderly individuals had lower odds for all symptoms, but, when symptoms were manifest, systemic symptoms were associated with an increased risk, whereas upper respiratory symptoms with a decreased risk, of severe disease. CONCLUSION: Host immunological status, omicron subvariant, and age were associated with a spectrum of COVID-19 symptoms and outcomes. BA.5 produced a greater symptom burden than BA.2. Vaccination and prior infection mitigated systemic symptoms and improved outcomes, but increased upper respiratory tract symptom burden. Systemic, but not upper respiratory, symptoms in the elderly heralded severe disease.
• C-reactive protein level predicts need for medical intervention in pregnant women with SARS-CoV2 infection: A retrospective study.

  Ryutaro Yamamoto, Hiroshi Asano, Takeshi Umazume, Masato Takaoka, Kiwamu Noshiro, Yoshihiro Saito, Kinuko Nakagawa, Kentaro Chiba, Sho Nakakubo, Yasuyuki Nasuhara, Satoshi Konno, Hidemichi Watari

  The journal of obstetrics and gynaecology research 48 (4) 938 - 945 2022/04 

  AIM: To make effective use of the limited available hospital space during the Coronavirus disease 2019 (COVID-19) pandemic, we conducted this study to investigate the laboratory indices that identify pregnant women with SARS-CoV2 infection who require medical intervention. METHODS: We carried out a retrospective analysis of pregnant women positive for COVID-19 who were admitted to Hokkaido University Hospital from September 2020 to June 2021. Medical interventions included oxygen supplementation, systemic corticosteroids, or supplemental liquids to treat infection-related symptoms. RESULTS: Forty-two infected pregnant patients were admitted to the hospital, half of whom required medical intervention (n = 21). Fever, C-reactive protein (CRP), and platelet count are all associated with need for medical intervention. Of the 32 patients with a fever of ≥37.5°C on days 0-3 after onset of syndromes, 22 (69%) continued to have a fever on days 4-6, of which 19 (86.4%) required medical intervention. CRP level on days 4-6 predicted the presence or absence of medical intervention (area under the receiver operating characteristic curve = 0.913), with a sensitivity of 81% and specificity of 100% at a CRP cutoff of 1.28 mg/dL. CONCLUSIONS: The need for medical intervention in pregnant patients can be predicted with high accuracy using a CRP cutoff of 1.28 mg/dL on days 4-6 after onset of syndromes. The presence of fever also may be an easy marker for selecting subjects who need or will need therapeutic intervention. These could be an effective triage method to determine appropriate indications for the hospitalization of pregnant women in future outbreaks.
• Characteristics of COVID-19 patients admitted into two hospitals in sapporo, Japan: Analyses and insights from two outbreak waves.

  Takeshi Hattori, Atsushi Saito, Hirofumi Chiba, Koji Kuronuma, Masaru Amishima, Daisuke Morinaga, Yasuo Shichinohe, Yasuyuki Nasuhara, Satoshi Konno

  Respiratory investigation 59 (2) 180 - 186 2021/03 [Refereed]
   

  BACKGROUND: Coronavirus disease (COVID-19) emerged in January 2020 in Sapporo city, and the outbreak has shown two peaks. METHODS: A total of 260 COVID-19 patients were enrolled and categorized into three groups according to the pandemic pattern, jobs and situation, and disease severity. We compared clinical characteristics according to these categories. RESULTS: We found two pandemic peaks, and the proportion of patients and health providers who were infected in other hospitals had increased in the latter two periods (period 2: 49.6%, period 3: 32.7%). Particularly, the proportion of infected health providers was 27% in period 2, and they tended to be younger females with a mild condition. Severity of the disease (requirement of oxygen and/or mechanical ventilation) was associated with advanced age, and all the patients who died during admission were over 60 years old. CONCLUSIONS: We reported the temporal dynamics and characteristics of the COVID-19 pandemic in Sapporo city, Japan. This survey from the viewpoint of the hospital provides a new insight into and a better guide for the further management of the COVID-19 pandemic.
• Implementation Status of Liver Function Tests for Monitoring Benzbromarone-Induced Hepatotoxicity: An Epidemiological Survey Using the Japanese Claims Database.

  Shungo Imai, Yasuyuki Nasuhara, Kenji Momo, Hiromitsu Oki, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

  Biological & pharmaceutical bulletin 44 (10) 1499 - 1505 2021 [Refereed]
   

  A major adverse effect of benzbromarone is hepatotoxicity. Therefore, periodic liver function tests are required at least for the first 6 months of benzbromarone administration. However, it is not clear whether the relevant blood tests are implemented appropriately. Here, we performed a cross-sectional survey of the implementation status of liver function tests in patients who were newly prescribed benzbromarone, using the Japanese large claims database. Male patients who were newly prescribed benzbromarone from January 2010 to December 2016 were included. We targeted patients who continued benzbromarone during the observation period (up to 180 d from the start of administration). The primary endpoint was the proportion of patients in whom periodic liver function tests were implemented. A periodic liver function test was defined as one or more liver function tests performed during both 1-90 and 91-180 d of initial benzbromarone administration. We labeled the tests as a "periodic test" or "non-periodic test" based on whether periodic liver function tests were performed or not, respectively. Furthermore, factors influencing non-periodic test were analyzed. Periodic testing was implemented only in 28.7% of patients. Additionally, factors such as number of hospital beds ≤19 (compared to 100-199 beds) and duration of the first prescription of benzbromarone were associated with non-periodic testing. Our study revealed that periodic liver function tests are not performed sufficiently in Japan. Thus, clinicians prescribing benzbromarone should be educated about the test. Our blood-test-based approach should be applied to other drugs and countries in future research.
• Proposal of COVID-19 Clinical Risk Score for the management of suspected COVID-19 cases: a case control study.

  Sho Nakakubo, Masaru Suzuki, Keisuke Kamada, Yu Yamashita, Junichi Nakamura, Hiroshi Horii, Kazuki Sato, Munehiro Matsumoto, Yuki Abe, Kosuke Tsuji, Nobuhisa Ishiguro, Yasuyuki Nasuhara, Satoshi Konno

  BMC infectious diseases 20 (1) 858 - 858 2020/11/18 [Refereed]
   

  BACKGROUND: No clinical scoring system has yet been established to estimate the likelihood of coronavirus disease (COVID-19) and determine the suitability of diagnostic testing in suspected COVID-19 patients. METHODS: This was a single-center, retrospective, observational study of patients with suspected COVID-19 and confirmed COVID-19. Patient background, clinical course, laboratory and computed tomography (CT) findings, and the presence of alternative diagnoses were evaluated. Clinical risk scores were developed based on clinical differences between patients with and without COVID-19. RESULTS: Among 110 patients suspected of having COVID-19, 60.9% underwent polymerase chain reaction (PCR) testing based on the judgment of physicians. Two patients were found to have COVID-19. The clinical characteristics of 108 non-COVID-19 patients were compared with those of 23 confirmed COVID-19 patients. Patients with COVID-19 were more likely to have a history of high-risk exposures and an abnormal sense of taste and smell. The COVID-19 group had significantly higher rates of subnormal white blood cell counts, lower eosinophil counts, and lower procalcitonin levels than the non-COVID-19 group. When blood test results, CT findings, and the presence of alternative diagnoses were scored on an 11-point scale (i.e., "COVID-19 Clinical Risk Score"), the COVID-19 group scored significantly higher than the non-COVID-19 group, more than four points in the COVID-19 group. All non-COVID patients who did not undergo PCR had a score of 4 or less. CONCLUSIONS: The COVID-19 Clinical Risk Score may enable the risk classification of patients suspected of having COVID-19 and can help in decision-making in clinical practice, including appropriateness of diagnostic testing. Further studies and prospective validation with an increased sample size are required.
• Older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples.

  Takeshi Hattori, Masaru Amishima, Daisuke Morinaga, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Yasuo Shichinohe, Shinichi Fujisawa, Mutsumi Nishida, Yasuyuki Nasuhara, Takanori Teshima, Satoshi Konno

  The Journal of infection 82 (1) 159 - 198 2020/06/21 [Refereed][Not invited]
  
• Analysis of the Implementation of Blood Tests Specified in the Package Insert After Prescription of Thiamazole.

  Yasuyuki Nasuhara, Ken Sakushima, Hiromitsu Oki, Takehiro Yamada, Ken Iseki, Reona Umeki, Akira Endoh

  Journal of patient safety 16 (1) 24 - 29 2020/03 [Refereed]
   

  OBJECTIVES: The antithyroid drug thiamazole has long been known to cause the serious adverse effect of agranulocytosis, and performing regular blood tests is listed among the warnings on the package insert. We conducted a retrospective survey of how often doctors conducted blood tests in accordance with the package insert when thiamazole was prescribed at our hospital. METHODS: The subjects were patients to whom thiamazole was newly prescribed at our hospital between April 2004 and March 2012. During the target period, thiamazole was newly prescribed to 438 patients. RESULTS: We found that blood tests after prescription of thiamazole as listed in the warning section on the package insert are not performed sufficiently. The rate at which white blood cell counts were obtained decreased over time. The rate at which differential leukocyte counts were obtained was approximately 80% of white blood cell counts at all observational time points. In contrast, the percentage of subjects whose white blood cell counts were measured increased according to a time-trend analysis. CONCLUSIONS: This study revealed that blood tests after prescription of thiamazole as listed in the warning section on the package insert are not performed sufficiently at our hospital. The rate at which differential leukocyte counts were obtained was approximately 80% of white blood cell counts at all observational periods. Physician education should be more rigorously performed than presently done, and automatic generation of warnings that urge blood tests and patient education regarding the importance of blood tests is also important.
• Rapidly progressive organizing pneumonia associated with COVID-19.

  Hiroshi Horii, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Junichi Nakamura, Yasuyuki Nasuhara, Satoshi Konno

  Respiratory medicine case reports 31 101295 - 101295 2020 [Refereed]
   

  We report a case of clinically diagnosed secondary organizing pneumonia (SOP) associated with coronavirus disease 2019 (COVID-19). A 70-year-old woman who had been diagnosed with COVID-19 was admitted to Hokkaido University Hospital. Although her fever, cough, dyspnea, and serum C-reactive protein levels improved, she developed rapidly progressive respiratory failure and computed tomography revealed the development of bilateral lung consolidation. Her dyspnea was relieved, and her oxygenation levels and radiological findings improved after commencing corticosteroid treatment. Blood biomarkers for interstitial lung disease, Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), showed different responses during the clinical course of her disease. Evaluation of serial changes in levels of KL-6 and SP-D may help diagnose and monitor COVID-19-associated organizing pneumonia (OP). Clinicians should be aware that SOP can develop in response to COVID-19 and that these patients may benefit from the use of steroids.
• Unique Mortality Profile in Japanese Patients with COPD: An Analysis from the Hokkaido COPD Cohort Study.

  Hironi Makita, Masaru Suzuki, Satoshi Konno, Kaoruko Shimizu, Yasuyuki Nasuhara, Katsura Nagai, Yasushi Akiyama, Satoshi Fuke, Hiroshi Saito, Takeshi Igarashi, Kimihiro Takeyabu, Masaharu Nishimura

  International journal of chronic obstructive pulmonary disease 15 2081 - 2090 2020 [Refereed]
   

  Purpose: Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries. We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate. Patients and Methods: We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%). The majority of patients were male, and the average age at baseline was 69 years old. About 95% of all patients had accurate mortality data. The risk factors for mortality were also analyzed. Results: During the 10 years, 112 patients (40%) died. Their median survival time was 6.1 years (interquartile range: 4.7-7.9 years), and age at death was 79 ± 6 years old (mean ± SD). Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%). In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (<64 years old). Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality. Conclusion: The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region.
• Venipuncture Nerve Injuries in the Upper Extremity From More Than 1 Million Procedures.

  Yukinori Tsukuda, Tadanao Funakoshi, Yasuyuki Nasuhara, Yusuke Nagano, Chikara Shimizu, Norimasa Iwasaki

  Journal of patient safety 15 (4) 299 - 301 2019/12 [Refereed]
   

  OBJECTIVES: The purpose of this study was to investigate the nerve injury rate for 1 million venipunctures and the efficacy of attempts to avoid severe nerve injury. METHODS: We collected data for outpatients from whom a venipuncture blood sample was obtained in our hospital from 2005 to 2014. Every venipuncture procedure for outpatients was performed by a trained nurse or clinical technologist at the center for blood sampling in our hospital. In addition, a series of lectures by a specialist is held in our hospital at various times. All complaints related to venipuncture blood sampling were reported to our division of hospital safety management and were followed up using the guidelines for injuries related to the venipuncture. RESULTS: The number of venipuncture-related complications was 293 (0.027%, 1/3700) of 1,082,053 during the 10 years. A total of 40 of the 1,082,053 venipunctures were referred to the department of orthopedic surgery, and 16 (0.0015%, 1/67,000) were diagnosed with obvious nerve injuries. The average duration of the treatment was 46.4 days (range, 1-126 days); 69% of the patients recovered within 5 weeks, and all patients recovered within 18 weeks. CONCLUSIONS: Although it is impossible to completely prevent venipuncture-related complications, appropriate venipuncture skills and risk management decrease the incidence of chronic or permanent nerve injury risk after venipuncture.
• Annual change in FEV₁ in elderly 10-year survivors with established chronic obstructive pulmonary disease.

  Suzuki M, Makita H, Konno S, Shimizu K, Nasuhara Y, Nagai K, Akiyama Y, Fuke S, Saito H, Igarashi T, Takeyabu K, Nishimura M

  Scientific reports 9 (1) 2073 - 2073 2019/02 [Refereed][Not invited]
   

  Long-term decline in lung function is generally considered to be progressive in individuals with established chronic obstructive pulmonary disease (COPD), despite the presence of intersubject variation. We hypothesized that the annualized rate of decline in forced expiratory volume in 1 second (FEV1) would not be constant among different time periods in the natural history of established COPD. We compared the annual change rates in FEV1 during the first 5 years and the last 5 years, estimated separately using a linear mixed-effects model in 10-year survivors (n = 110). The subjects were classified into three FEV1 decline groups, based on the 25th and 75th percentile values in each time period. The rates of FEV1 changes, calculated from the first 5 years and the last 5 years, did not correlate with each other among 10-year survivors; the subjects of each FEV1 decline group during the first 5 years did not consistently remain in the same FEV1 decline group during the last 5 years. Smoking status and exacerbation frequency were not associated with decline in FEV1. In conclusion, the disease activity, which is often expressed as annualized change in FEV1, might be changeable either way over years in patients with established COPD.
• A Semiquantitative Computed Tomographic Grading System for Evaluating Therapeutic Response in Pulmonary Alveolar Proteinosis.

  Sayoko Tokura, Masanori Akira, Tomohisa Okuma, Ryushi Tazawa, Toru Arai, Chikatoshi Sugimoto, Akiko Matsumuro, Masaki Hirose, Toshinori Takada, Koh Nakata, Haruyuki Ishii, Yasunori Kasahara, Masayuki Hojo, Shinya Ohkouchi, Yoshiko Tsuchihashi, Masanori Yokoba, Ryosuke Eda, Hideaki Nakayama, Takahito Nei, Konosuke Morimoto, Yasuyuki Nasuhara, Masahito Ebina, Toshio Ichiwata, Koichiro Tatsumi, Etsuro Yamaguchi, Yoshikazu Inoue

  Annals of the American Thoracic Society 14 (9) 1403 - 1411 2017/09 [Refereed]
   

  RATIONALE: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. OBJECTIVES: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. METHODS: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. RESULTS: CT grade score and CT extent score had significant correlation with diffusing capacity of the lung for carbon monoxide percent predicted (%DlCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than ΔCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DlCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. In multivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2. CONCLUSIONS: Although a number of CT variables were collected, the currently proposed grading system that correlates well with PaO2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.
• Characteristics of Medical Adverse Events/Near Misses Associated With Laparoscopic/Thoracoscopic Surgery: A Retrospective Study Based on the Japanese National Database of Medical Adverse Events.

  Abe T, Murai S, Nasuhara Y, Shinohara N

  Journal of patient safety 15 (4) 343 - 351 1549-8417 2017/09 [Refereed][Not invited]
   

  OBJECTIVES: The aim of this study was to clarify the characteristics of adverse events/near misses during laparoscopic/thoracoscopic surgery. METHODS: Using relevant key words for minimally invasive surgeries, 540 records were identified in the database of the Japan Council for Quality Health Care. After data review and the classification of adverse events, 746 events associated with laparoscopic (laparo group) and/or thoracoscopic (thoraco group) surgery were identified. We calculated the frequency of each event, compared the frequency regarding recurrent events, and evaluated the types of event that had resulted in deaths between the 2 groups. RESULTS: There were 582 events in the laparo group, 159 in the thoraco group, and 5 in those undergoing combined surgery. Overall, injury of other organs (11.4%, 85/746), retention of a foreign body (9.1%, 68/746), breakage/failure of medical equipment or devices (6.2%, 46/746), massive bleeding (5.9%, 44/746), misperception of anatomy (5.6%, 42/746), and vascular injury (4.8%, 36/746) were frequently reported. There were marked differences in the frequency of injury of other organs (laparo group: 13.4%, 78/582; thoraco group: 4.4%, 7/159), massive bleeding (laparo group: 3.4%, 20/582; thoraco group: 14.5%, 23/159), and vascular injury (laparo group: 2.6%, 15/582; thoraco group: 12.6%, 20/159) between the 2 groups. Among the 56 patient-death reports, 132 adverse events were identified. In the thoraco group, bleeding events were frequently observed, whereas in the laparo group, various categories of events were noted. CONCLUSIONS: We observed recurrent incidents and differences in the frequency between the 2 groups. Surgeons should keep in mind these characteristics. Retention of a foreign body and the breakage/malfunctioning of instruments might be reduced by the introduction of specialized checklists.
• 医療安全管理者が求める安全性の確立していない医薬品の使用について

  南須原 康行

  医薬ジャーナル 53 2485 - 2490 2017 [Refereed][Invited]
  
• Erratum to: Physicians' responses to computerized drug interaction alerts with password overrides.

  Yasuyuki Nasuhara, Ken Sakushima, Akira Endoh, Reona Umeki, Hiromitsu Oki, Takehiro Yamada, Ken Iseki, Makoto Ishikawa

  BMC medical informatics and decision making 16 (1) 108 - 108 1472-6947 2016/08/10 [Refereed][Not invited]
   

  Background: Although evidence has suggested that computerized drug-drug interaction alert systems may reduce the occurrence of drug-drug interactions, the numerous reminders and alerts generated by such systems could represent an excessive burden for clinicians, resulting in a high override rate of not only unimportant, but also important alerts. Methods: We analyzed physicians' responses to alerts of relative contraindications and contraindications for coadministration in a computerized drug-drug interaction alert system at Hokkaido University Hospital. In this system, the physician must enter a password to override an alert and continue an order. All of the drug-drug interaction alerts generated between December 2011 and November 2012 at Hokkaido University Hospital were included in this study. Results: The system generated a total of 170 alerts of relative contraindications and contraindication for coadministration; 59 (34.7 %) of the corresponding orders were cancelled after the alert was accepted, and 111 (65.3 %) were overridden. The most frequent contraindication alert was for the combination of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates. No incidents involving drug-drug interactions were reported among patients who were prescribed contraindicated drug pairs after an override. Conclusions: Although computerized drug-drug interaction alert systems that require password overrides appear useful for promoting medication safety, having to enter passwords to override alerts may represent an excessive burden for the prescribing physician. Therefore, both patient safety and physicians' workloads should be taken into consideration in future designs of computerized drug-drug interaction alert systems.
• 【特発性間質性肺炎の最前線】分子サイズと肺胞 血液間動態が血清KL-6値に与える影響

  重村 雅彦, 今野 哲, 南須原 康行, 西村 正治

  呼吸器内科 (有)科学評論社 30 (2) 118 - 123 1884-2887 2016/08 [Refereed]
  
• Three-day regimen of oseltamivir for postexposure prophylaxis of influenza in wards

  Nobuhisa Ishiguro, Oyamada Reiko, Nasuhara Yasuyuki, Yamada Takehiro, Miyamoto Takenori, Imai Shungo, Akizawa Koji, Fukumoto Tatsuya, Iwasaki Sumio, Iijima H, Ono K

  Journal of Hospital Infection Elsevier 94 (2) 150 - 153 0195-6701 2016 [Refereed][Not invited]
   

  Inpatients who had been in close contact with patients with influenza were given oseltamivir [75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children] for three days as postexposure prophylaxis (PEP). The index patients with influenza were prescribed a neuraminidase inhibitor and were discharged immediately or transferred to isolation rooms. The protective efficacy of oseltamivir for three days was 93% overall [95% confidence interval (CI) 53-99%; P = 0.023] and 94% for influenza A (95% CI 61-99%; P = 0.017), which is comparable to that of seven- to 10-day regimens of oseltamivir as PEP.
• Physicians' responses to computerized drug interaction alerts with password overrides.

  Yasuyuki Nasuhara, Ken Sakushima, Akira Endoh, Reona Umeki, Hiromitsu Oki, Takehiro Yamada, Ken Iseki, Makoto Ishikawa

  BMC medical informatics and decision making 15 74 - 74 2015/08/28 [Refereed]
   

  BACKGROUND: Although evidence has suggested that computerized drug-drug interaction alert systems may reduce the occurrence of drug-drug interactions, the numerous reminders and alerts generated by such systems could represent an excessive burden for clinicians, resulting in a high override rate of not only unimportant, but also important alerts. METHODS: We analyzed physicians' responses to alerts of relative contraindications and contraindications for coadministration in a computerized drug-drug interaction alert system at Hokkaido University Hospital. In this system, the physician must enter a password to override an alert and continue an order. All of the drug-drug interaction alerts generated between December 2011 and November 2012 at Hokkaido University Hospital were included in this study. RESULTS: The system generated a total of 170 alerts of relative contraindications and contraindication for coadministration; 59 (34.7 %) of the corresponding orders were cancelled after the alert was accepted, and 111 (65.3 %) were overridden. The most frequent contraindication alert was for the combination of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates. No incidents involving drug-drug interactions were reported among patients who were prescribed contraindicated drug pairs after an override. CONCLUSIONS: Although computerized drug-drug interaction alert systems that require password overrides appear useful for promoting medication safety, having to enter passwords to override alerts may represent an excessive burden for the prescribing physician. Therefore, both patient safety and physicians' workloads should be taken into consideration in future designs of computerized drug-drug interaction alert systems.
• Time trend of injection drug errors before and after implementation of bar-code verification system.

  Ken Sakushima, Reona Umeki, Akira Endoh, Yoichi M Ito, Yasuyuki Nasuhara

  Technology and health care : official journal of the European Society for Engineering and Medicine 23 (3) 267 - 74 2015 [Refereed]
   

  BACKGROUND: Bar-code technology, used for verification of patients and their medication, could prevent medication errors in clinical practice. OBJECTIVE: Retrospective analysis of electronically stored medical error reports was conducted in a university hospital. METHODS: The number of reported medication errors of injected drugs, including wrong drug administration and administration to the wrong patient, was compared before and after implementation of the bar-code verification system for inpatient care. RESULTS: A total of 2867 error reports associated with injection drugs were extracted. Wrong patient errors decreased significantly after implementation of the bar-code verification system (17.4/year vs. 4.5/year, p< 0.05), although wrong drug errors did not decrease sufficiently (24.2/year vs. 20.3/year). The source of medication errors due to wrong drugs was drug preparation in hospital wards. CONCLUSION: Bar-code medication administration is effective for prevention of wrong patient errors. However, ordinary bar-code verification systems are limited in their ability to prevent incorrect drug preparation in hospital wards.
• Analysis of the implementation of blood tests specified in the drug package insert after prescription of thiamazole

  NASUHARA Yasuyuki

  Journal of Patient Safety Epub 2015 [Refereed][Not invited]
  
• Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy.

  Ryushi Tazawa, Yoshikazu Inoue, Toru Arai, Toshinori Takada, Yasunori Kasahara, Masayuki Hojo, Shinya Ohkouchi, Yoshiko Tsuchihashi, Masanori Yokoba, Ryosuke Eda, Hideaki Nakayama, Haruyuki Ishii, Takahito Nei, Konosuke Morimoto, Yasuyuki Nasuhara, Masahito Ebina, Masanori Akira, Toshio Ichiwata, Koichiro Tatsumi, Etsuro Yamaguchi, Koh Nakata

  Chest 145 (4) 729 - 737 2014/04 [Refereed]
   

  BACKGROUND: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized. METHODS: To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy. RESULTS: During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P<.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P<.0005). CONCLUSIONS: These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence. TRIAL REGISTRY: ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.
• Serum KL-6 concentrations are associated with molecular sizes and efflux behavior of KL-6/MUC1 in healthy subjects.

  Shigemura M, Konno S, Nasuhara Y, Shijubo N, Shimizu C, Nishimura M

  Clinica chimica acta; international journal of clinical chemistry 424 148 - 152 0009-8981 2013/09 [Refereed][Not invited]
  
• Occupational and environmental impact on the clinical course of autoimmune pulmonary alveolar proteinosis

  Yoshikazu Inoue, Koh Nakata, Toru Arai, Etsuro Yamaguchi, Toshio Ichiwata, Masahito Ebina, Ryushi Tazawa, Haruyuki Ishii, Yasuhiro Setoguchi, Masanori Kitaichi, Masanori Akira, Koichiro Tatsumi, Yasuyuki Nasuhara, Kazutoshi Cho, Yoshiko Tsuchihashi, Kanji Uchida, Toshinori Takada, Hideaki Nakayama, Keisuke Tomii, Chikatoshi Sugimoto, Yasuo Kohashi, Shinya Ohkouchi, Yasunori Kasahara, Kohnosuke Morimoto, Naoko Sakamoto

  EUROPEAN RESPIRATORY JOURNAL 40 0903-1936 2012/09 [Refereed][Not invited]
  
• Impact of asthmatic control status on serum cystatin C concentrations.

  Shigemura M, Konno S, Nasuhara Y, Shimizu C, Matsuno K, Nishimura M

  Clinical chemistry and laboratory medicine : CCLM / FESCC 8 50 1367 - 1371 1434-6621 2012/08 [Refereed][Not invited]
  
• Effects of molecular structural variants on serum Krebs von den Lungen-6 levels in sarcoidosis.

  Shigemura M, Nasuhara Y, Konno S, Shimizu C, Matsuno K, Yamguchi E, Nishimura M

  Journal of translational medicine BioMed Central 10 111 - 111 1479-5876 2012/07 [Refereed][Not invited]
   

  Background: Serum Krebs von den Lungen-6 (KL-6), which is classified as human mucin-1 (MUC1), is used as a marker of sarcoidosis and other interstitial lung diseases. However, there remain some limitations due to a lack of information on the factors contributing to increased levels of serum KL-6. This study was designed to investigate the factors contributing to increased levels of serum KL-6 by molecular analysis. Methods: Western blot analysis using anti-KL-6 antibody was performed simultaneously on the bronchoalveolar lavage fluid (BALF) and serum obtained from 128 subjects with sarcoidosis. Results: KL-6/MUC1 in BALF showed three bands and five band patterns. These band patterns were associated with the MUC1 genotype and the KL-6 levels. KL-6/MUC1 band patterns in serum were dependent on molecular size class in BALF. Significantly increased levels of serum KL-6, serum/BALF KL-6 ratio and serum soluble interleukin 2 receptor were observed in the subjects with influx of high molecular size KL-6/MUC1 from the alveoli to blood circulation. The multivariate linear regression analysis involving potentially relevant variables such as age, gender, smoking status, lung parenchymal involvement based on radiographical stage and molecular size of KL-6/MUC1 in serum showed that the molecular size of KL-6/MUC1 in serum was significant independent determinant of serum KL-6 levels. Conclusions: The molecular structural variants of KL-6/MUC1 and its leakage behavior affect serum levels of KL-6 in sarcoidosis. This information may assist in the interpretation of serum KL-6 levels in sarcoidosis.
• Reduced GM-CSF autoantibody in improved lung of autoimmune pulmonary alveolar proteinosis

  K. Ohashi, A. Sato, T. Takada, T. Arai, Y. Kasahara, M. Hojo, T. Nei, H. Nakayama, N. Motoi, S. Urano, R. Eda, M. Yokoba, Y. Tsuchihashi, Y. Nasuhara, H. Ishii, M. Ebina, E. Yamaguchi, Y. Inoue, K. Nakata, R. Tazawa

  European Respiratory Journal 39 (3) 777 - 780 1399-3003 2012/03/01 [Refereed][Not invited]
  
• Endobronchial ultrasonography with a guide sheath in the diagnosis of benign peripheral diseases.

  Shinagawa N, Nakano K, Asahina H, Kikuchi E, Ito T, Matsuno Y, Oizumi S, Nasuhara Y, Nishimura M

  The Annals of thoracic surgery 93 (3) 951 - 957 0003-4975 2012/03 [Refereed][Not invited]
  
• Direct evidence that GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis.

  Kazumasa Ohashi, Atsuyasu Sato, Toshinori Takada, Toru Arai, Takahito Nei, Yasunori Kasahara, Natsuki Motoi, Masayuki Hojo, Shinya Urano, Haruyuki Ishii, Masanori Yokoba, Ryosuke Eda, Hideaki Nakayama, Yasuyuki Nasuhara, Yoshiko Tsuchihashi, Chinatsu Kaneko, Hiroko Kanazawa, Masahito Ebina, Etsuro Yamaguchi, Jacqueline Kirchner, Yoshikazu Inoue, Koh Nakata, Ryushi Tazawa

  Respiratory medicine 106 (2) 284 - 93 2012/02 [Refereed]
   

  BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear. OBJECTIVES: To figure out changes in surfactant clearance during GM-CSF inhalation therapy. METHODS: We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5-21 mg, duration 12-24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference ≥13 mmHg (n = 10) and low responders with that < 13 mmHg (n = 9). RESULTS: Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment. CONCLUSIONS: GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis.
• Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease.

  Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, Shimizu K, Betsuyaku T, Ito YM, Fuke S, Igarashi T, Akiyama Y, Ogura S, Hokkaido COPD Cohort, Study Investigators

  American journal of respiratory and critical care medicine 1 185 (1) 44 - 52 1073-449X 2012/01 [Refereed][Not invited]
   

  RATIONALE: Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes. OBJECTIVES: To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity. METHODS: A total of 279 eligible patients with COPD (stages I-IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient. MEASUREMENTS AND MAIN RESULTS: Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32±24 (SD) ml/yr (n=261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63±2, -31±1, and -2±1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils. CONCLUSIONS: Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.
• [A case of multifocal micronodular pneumocyte hyperplasia without clinical findings of tuberous sclerosis].

  Natsuko Taniguchi, Satoshi Konno, Yasuyuki Nasuhara, Yoshihiro Matsuno, Teruaki Oka, Masaharu Nishimura

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 49 (5) 355 - 9 1343-3490 2011/05 [Refereed]
   

  A 30-year-old woman was referred because of multiple ground-glass opacities (GGOs) on chest CT examination. Lung biopsy was performed. Histologically, multifocal well-demarcated nodular lesions comprising proliferation of type II pneumocytes with mild fibrous thickening of the alveolar septa were observed in the lung tissue. We made a histopathologic diagnosis of multifocal micronodular pneumocyte hyperplasia (MMPH). Neither the clinical findings nor the family history of the patient suggested tuberous sclerosis (TSC). MMPH is a pulmonary manifestation of tuberous sclerosis, together with lymphangioleiomyomatosis (LAM). MMPH should be considered as a differential diagnosis of multiple GGOs in the lung even when findings of TSC and LAM are not recognized.
• Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.

  Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ishii H, Yokoba M, Tanaka N, Yamaguchi E, Eda R, Tsuchihashi Y, Morimoto K, Akira M, Terada M, Otsuka J, Ebina M, Kaneko C, Nukiwa T, Krischer JP, Akazawa K, Nakata K

  American journal of respiratory and critical care medicine 12 181 (12) 1345 - 1354 1073-449X 2010/06 [Refereed][Not invited]
   

  RATIONALE: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. OBJECTIVES: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. METHODS: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk). MEASUREMENTS AND MAIN RESULTS: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. CONCLUSIONS: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).
• [Intravascular large B-cell lymphoma with massive pulmonary lesions].

  Asumi Higashiyama, Satoshi Hashino, Masahiro Onozawa, Mutsumi Takahata, Kohei Okada, Kaoru Kahata, Natsuko Taniguchi, Yasuyuki Nasuhara, Kanako Kubota, Nozomu Fujimoto, Yoshihiro Matsuno, Masahiro Nishimura, Masahiro Asaka

  [Rinsho ketsueki] The Japanese journal of clinical hematology 51 (5) 353 - 6 0485-1439 2010/05 [Refereed]
   

  A 61-year-old man was admitted to our hospital with dyspnea on effort. Neither computed tomography scan nor chest X-ray film detected any specific findings that could explain hypoxemia. Since (67)Ga scintigraphy showed abnormal uptake in the bilateral lungs, transbronchial lung biopsy (TBLB) was performed. The TBLB specimen was diagnosed as intravascular large B-cell lymphoma (IVLBCL). There was no involvement of any other organ considered typical of IVLBCL. In cases showing clinical findings such as hypoxia despite mild pulmonary radiographic changes, a definitive diagnosis should be made using methods such as TBLB with consideration given to the possibility of IVLBCL.
• Levels of transferrin in bronchoalveolar lavage fluid in sarcoidosis.

  Shigemura M, Nasuhara Y, Konno S, Hattori T, Shimizu C, Matsuno K, Nishimura M

  Lung 2 188 (2) 151 - 157 0341-2040 2010/04 [Refereed][Not invited]
   

  There has been only one report showing high levels of transferrin (Tf) in bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis. The aim of this study is to assess the levels of Tf in both BALF and serum and to examine the relationship between the levels of Tf and other disease markers in sarcoidosis. Subjects were 64 sarcoidosis and 10 healthy controls. Tf in BALF and serum was measured by nephelometric assay. Median Tf levels in BALF from sarcoidosis was 0.70 mg/dl (range, 0.00-3.97), which was significantly higher when compared with controls (0.36 mg/dl; range, 0.00-1.02) (p = 0.005). In contrast, median Tf levels in serum from sarcoidosis was 258 mg/dl (range, 171-383), which was significantly lower when compared with controls (322 mg/dl; range, 234-356) (p = 0.003). Tf levels in BALF were significantly correlated with both the percentage of lymphocytes (r = 0.617, p = 0.001) and serum angiotensin-converting enzyme activity (r = 0.363, p = 0.003) and serum soluble interleukin-2 receptor (r = 0.450, p = 0.001) in sarcoidosis. Levels of Tf in BALF from patients with sarcoidosis were not influenced by smoking status. The levels of Tf in sarcoidosis are high in BALF, but low in serum. Increased levels of Tf in BALF may reflect the disease activity.
• Aging enhances susceptibility to cigarette smoke-induced inflammation through bronchiolar chemokines.

  Chinatsu Moriyama, Tomoko Betsuyaku, Yoko Ito, Ichiro Hamamura, Junko Hata, Hiroshi Takahashi, Yasuyuki Nasuhara, Masaharu Nishimura

  American journal of respiratory cell and molecular biology 42 (3) 304 - 11 2010/03 [Refereed]
   

  Cigarette smoking and aging are major risk factors for chronic obstructive pulmonary disease. An unsolved question is whether elderly lungs are particularly vulnerable to cigarette smoke (CS) exposure. In this study, we used a mouse model to test the hypothesis that aging increases the susceptibility to CS-induced pulmonary inflammation. We subjected 9-week-old and 69-week-old C57BL/6J mice to CS (whole-body exposure, 90 min/d), and evaluated neutrophil infiltration in the lungs, the levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluid, and mRNA expression in bronchiolar epithelium retrieved by laser capture microdissection. The 69-week-old mice showed a greater number of neutrophils and higher levels of bronchiolar KC and MIP-2 expression than 9-week-old mice after 9 days of CS exposure. Furthermore, single CS exposure induced the rapid up-regulation of KC and MIP-2 in bronchiolar epithelium in both 9-week-old and 69-week-old mice, and the much higher levels in 69-week-old mice were associated with greater nuclear translocation of NF-kappaB. In contrast, no age-related differences were observed in the bronchiolar expression of NF-E2-related factor 2-regulated antioxidant and detoxification genes, heme oxygenase-1, reduced nicotinamide adenine dinucleotide phosphate quinone reductase 1, and glutamate-cysteine ligase, modifier unit, or antioxidant activity in bronchoalveolar lavage fluid, regardless of CS exposure. In summary, aging increases susceptibility to CS-induced inflammation in a mouse model, and robust mRNA up-regulation and nuclear translocation of NF-kappaB in bronchiolar epithelium may be involved.
• [Flow-volume curve as an aid to diagnosis in double aortic arch masquerading as asthma in a young adult].

  Takayuki Yoshida, Satoshi Konno, Ayumu Takahashi, Yasuyuki Nasuhara, Tomoko Betsuyaku, Masaharu Nishimura

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 48 (3) 229 - 34 1343-3490 2010/03 [Refereed]
   

  We describe a young adult with double aortic arch who for several years had experienced stridor during exercise. He had been given a diagnosis of exercise-induced asthma, also known as hyperventilation syndrome. Antiasthmatic drugs, including inhaled corticosteroids and a short-acting bronchodilator, in addition to antidepressants, did not improve his symptoms. He had a history of allergic rhinitis and a familial history of asthma, but no signs of asthma as assessed by expectorated sputum and airway responsiveness (Dmin). However, flow-volume curves demonstrated a pattern consistent with upper airway constriction. Computed tomography confirmed severe tracheal narrowing caused by a double aortic arch. Compressive tracheal narrowing was also evaluated by fiber-optic tracheobronchoscopy. A treadmill exercise study induced respiratory distress with audible stridor that resolved itself without intervention. He underwent surgical division of the left aortic arch, which relieved the stridor during exercise. The flow-volume curve improved but constriction was still indicated even at 1.5 years after surgery. Double aortic arch should be considered in the differential diagnosis of drug-resistant stridor. This case re-emphasizes the value of flow-volume curves for diagnosing upper-airway obstruction.
• Endobronchial actinomycosis associated with a foreign body--successful short-term treatment with antibiotics--.

  Maki K, Shinagawa N, Nasuhara Y, Oizumi S, Domen H, Haga H, Nishimura M

  Internal medicine (Tokyo, Japan) The Japanese Society of Internal Medicine 49 (13) 1293 - 1296 0918-2918 2010 [Refereed][Not invited]
   

  Primary endobronchial actinomycosis is a very rare condition. We report herein the case of a healthy 66-year-old woman who presented with right lower lobe endobronchial actinomycosis associated with aspiration of a foreign body, which was presumed to be a fish bone swallowed 28 months previously. The patient achieved complete clinical and radiological recovery after removal of the foreign body and 1-month antibiotic therapy of oral amoxycillin. Our experience in the management of this patient should help clinicians to realize the importance of bronchoscopic investigation and the management of this rare but treatable condition.
  
• [Usefulness of fluorodeoxyglucose-positron emission tomography in a case of pleural sarcoidosis].

  Takeshi Hattori, Satoshi Konno, Takashi Inomata, Yasuyuki Nasuhara, Tomoko Betsuyaku, Masaharu Nishimura

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 47 (7) 658 - 62 1343-3490 2009/07 [Refereed]
   

  BACKGROUND: Pleural sarcoidosis is not a rare disease, and some patients with sarcoidosis experience chest pain, although the cause is often unknown. Various studies have indicated that fluorodeoxyglucose-positron emission tomography (FDG-PET) is useful for diagnosing and monitoring sarcoidosis. CASE: A 62-year-old man noted left-side dominant chest and back pain, although chest computed tomography (CT) revealed no abnormalities. Two months later, chest and back pain rapidly increased in severity and blurred vision appeared. In addition to uveitis, renal dysfunction was observed and chest CT on admission revealed enlargement of bilateral hilar/mediastinal lymph nodes and diffuse small nodular opacities and subpleural nodules, mainly in the segment of the left upper lobe (S1+2). FDG-PET revealed intense FDG uptake in bilateral peripheral lung parenchyma, spread widely along the subpleura and right inguinal lymph nodes with high uptake in the hilar and mediastinal lymph nodes. Sarcoidosis was diagnosed by transbronchial lung biopsy and renal biopsy. Oral corticosteroid treatment was performed due to persistent chest and back pain and rapid progression of renal dysfunction. Chest and back pain immediately disappeared and renal function improved. Follow-up FDG-PET performed 2 months after corticosteroid treatment revealed no areas of intense FDG uptake.
• MS18-#4 喘息患者における血清シスタチンC値に関する検討(気管支喘息-診断と管理4,第59回日本アレルギー学会秋季学術大会)

  重村 雅彦, 今野 哲, 南須原 康行, 西村 正治

  アレルギー 一般社団法人 日本アレルギー学会 58 (8) 1254 - 1254 2009
• [Efficacy of leukotriene receptor antagonists in asthma treatment and analysis of background factors evaluated by a questionnaire survey among physicians].

  Yoshinobu Fukui, Nobuyuki Hizawa, Daisuke Takahashi, Yukiko Maeda, Motoko Kobayashi, Yasuyuki Nasuhara, Masaharu Nishimura

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 46 (12) 972 - 80 1343-3490 2008/12 [Refereed]
   

  The efficacy of leukotriene receptor antagonists (LTRAs) in the treatment of asthma and the involvement of various patient background factors were investigated. A questionnaire was used to survey the physicians of 1,600 asthma patients regarding the use of LTRAs, whether treatment was being continued or had been discontinued, and reasons for continuation or discontinuation. The results showed that 797 patients had used an LTRA, with 468 having used pranlukast (P), 294 having used montelukast (M) and 25 having used zafirlukast. For the remaining 10 patients, either the drug name was unknown or multiple LTRAs had been used. The P Group was slightly younger in age (median: P, 55 years, M, 57 years) and had a higher frequency of mild, intermittent disease (P: 20.3%; M:11.2%). The P Group also had a higher percentage of patients who continued taking an LTRA because the drug was "clearly effective" (P: 34.6%; M: 17.3%), and a lower percentage of patients who discontinued the drug because the drug was "ineffective" (P: 2.6%; M:19.0%). Logistic regression analysis showed the following as independent factors contributing to efficacy of the LTRA in the treatment of the asthma (R2 = 0.19): P as the drug used (p < 0.01); allergic rhinitis not present as a complication (p < 0.01); and mild severity of asthma (p = 0.02). Further, the present findings indicate that LTRAs are highly effective for patients who have mild asthma without complication by allergic rhinitis. Further investigation is necessary to determine differences in efficacy among different LTRAs.
• the Hokkaido COPD Cohort Study Group Functional SNPs of the CCL5 gene and non-emphysematous phenotype in patients with COPD.

  Hizawa, N, Makita H, Nasuhara Y, Hasegawa M, Nagai K, Ito Y, Betsuyaku T, Konno S, Nishimura M

  Eur Respir J. 32 (2) 372-378  2008/01 [Refereed][Not invited]
  
• beta(2)-Adrenergic receptor genetic Polymorphisms and short-term bronchodilator responses in patients with COPD

  Hizawa, Nobuyuki, Makita, Hironi, Nasuhara, Yasuyuki, Betsuyaku, Tomoko, Roh, Yoko, Nagai, Katsura, Hasegawa, Masant, Nishimura, Masaham

  CHEST AMER COLL CHEST PHYSICIANS 132 (5) 1485 - 1492 0012-3692 2007/11 [Refereed][Not invited]
  
• Lipopolysaccaride-induced neutrophilic inflammation in the lungs differs with age

  Yoko Ito, Tomoko Betsuyaku, Yasuyuki Nasuhara, Masaharu Nishimura

  EXPERIMENTAL LUNG RESEARCH 33 (7) 375 - 384 0190-2148 2007 [Refereed][Not invited]
   

  In aged humans and animals, lung injuries are generally more serious and prolonged. From a kinetic perspective, the authors thus assessed whether lung expression of proinflammatory cytokines were altered with age following intratracheal lipopolysaccharide (LPS) challenge in mice. Tumor necrosis factor-alpha, interleukin-1 beta, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-2, and keratinocyte-derived chemokine were significantly higher in 65-week-old mice along with sustained neutrophilia when compared to 11-week-old mice at 72 hours, but not at earlier time points. The authors concluded that the degree of LPS-induced neutrohilic inflammation and the expression of these cytokines differ with age at later phases of acute lung injury.
• [Cibenzoline succinate induced pneumonitis].

  Hasegawa M, Nasuhara Y, Maki N, Miura T, Betsuyaku T, Hizawa N, Nishimura M, Onozuka H, Tsutsui H

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 7 95 (7) 1362 - 1364 0021-5384 2006/07 [Refereed][Not invited]
   

  症例は70歳男性. 発作性心房細動に対し, コハク酸シベンゾリン (シベノール^®) の服用を開始したところ, 15日目ごろより労作時呼吸困難を自覚し, 25日目に胸部異常陰影を指摘された. 抗生剤投与にて改善がみられないため, 我々はコハク酸シベンゾリンによる薬剤性肺炎も疑い, 同剤を中止した上でステロイド治療を施行した. 肺炎の改善を認めたが発作性心房細動が再発したため, 慎重な観察の下同剤を再開したところ肺炎の再増悪を認めた. 以上よりコハク酸シベンゾリンによる薬剤性肺炎と診断した.
• Long term smoking with age builds up excessive oxidative stress in bronchoalveolar lavage fluid

  K. Nagai, T. Betsuyaku, T. Kondo, Y. Nasuhara, M. Nishimura

  Thorax 61 (6) 496 - 502 0040-6376 2006/06 

  Background: Epithelial lining fluid plays a critical role in protecting the lung from oxidative stress, in which the oxidised status may change by ageing, smoking history, and pulmonary emphysema. Methods: Bronchoalveolar lavage (BAL) was performed on 109 young and older subjects with various smoking histories. The protein carbonyls, total and oxidised glutathione were examined in BAL fluid. Results: By Western blot analysis, the major carbonylated protein in the BAL fluid was sized at 68 kDa, corresponding to albumin. The amount of carbonylated albumin per mg total albumin in BAL fluid was four times higher in older current smokers and three times higher in older former smokers than in age matched non-smokers (p< 0.0001, p = 0.0003, respectively), but not in young smokers. Total glutathione in BAL fluid was significantly increased both in young (p = 0.006) and older current smokers (p = 0.0003) compared with age matched non-smokers. In contrast, the ratio of oxidised to total glutathione was significantly raised (72%) only in older current smokers compared with the other groups. There was no significant difference in these parameters between older smokers with and without mild emphysema. Conclusions: Oxidised glutathione associated with excessive protein carbonylation accumulates in the lung of older smokers with long term smoking histories even in the absence of lung diseases, but they are not significantly enhanced in smokers with mild emphysema.
• Decrease of vascular endothelial growth factor in macrophages from long-term smokers

  K Nagal, T Betsuyaku, Y Ito, Y Nasuhara, M Nishimura

  EUROPEAN RESPIRATORY JOURNAL 25 (4) 626 - 633 0903-1936 2005/04 [Refereed][Not invited]
   

  Vascular endothelial growth factor (VEGF), a survival factor for endothelial cells and a promoter of angiogenesis, is reportedly expressed in alveolar macrophages (AMs). To investigate whether long-term smoking with age affects VEGF expression in AMs, bronchoalveolar lavage (BAL) was performed on 18 young and 23 older volunteers with various smoking histories. The expressions of VEGF and its functional receptor, fms-like tyrosine kinase (Fit)-1, were quantified in AMs by real-time RT-PCR and, further, the level of VEGF in BAL fluid was determined by ELISA. VEGF mRNA in AMs demonstrated a 1.8-fold reduction in current smokers compared with nonsmokers in older subjects and, furthermore, a 1.5-fold downregulation in those with emphysema, although there was no difference between current smokers and nonsmokers, among the young subjects. The downregulation in total VEGF mRNA was supported by the substantial reduction of VEGF121 and VEGF165 isoforms. However, in contrast, Flt-1 mill did not differ within the older groups, whereas it was upregulated in young current smokers compared with age-matched nonsmokers. VEGF in BAL fluid is significantly decreased in current smokers compared with nonsmokers, regardless of their age. In conclusion, these data imply that the biological availability of vascular endothelial growth factor in alveolar macrophages is impaired in older current smokers with long-term smoking histories.
• 114 喘息におけるロイコトリエン受容体拮抗薬の有効性とその背景の検討 : アンケートの結果

  福居 嘉信, 檜澤 伸之, 高橋 大輔, 前田 由起子, 小林 基子, 南須原 康行, 西村 正治

  アレルギー 一般社団法人 日本アレルギー学会 54 (3) 349 - 349 2005
• 4 COPDの病態における細気管支上皮の抗酸化機構, 炎症関連遺伝子発現(13 慢性気道炎症における気道上皮細胞の役割, 第55回日本アレルギー学会秋季学術大会)

  別役 智子, 福家 聡, 南須原 康行, 西村 正治

  アレルギー 一般社団法人 日本アレルギー学会 54 (8) 920 - 920 2005
• Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid

  Tomoko Betsuyaku, Y. Kuroki, K. Nagai, Y. Nasuhara, M. Nishimura

  European Respiratory Journal 24 (6) 964 - 970 0903-1936 2004/12 

  Surfactant protein (SP)-A and SP-D are collagen-like glycoproteins that are synthesized in the distal pulmonary epithelium. This study examined the effects of ageing and long-term smoking on SP-A and SP-D in the lungs. The possible links to the development of pulmonary emphysema were also investigated. Sequential lavage was performed in young and middle-aged or elderly nonsmokers and asymptomatic current smokers with various smoking histories. Middle-aged or elderly smokers were further categorised according to the presence of emphysema by high-resolution computed tomography. Levels of SP-A and SP-D in bronchial lavage (BL) fluid and in bronchoalveolar lavage (BAL) fluid were quantified by ELISA. Significant decreases in SP-A were seen with age in nonsmokers in BL fluid, but not in BAL fluid. Middle-aged or elderly smokers with emphysema had lower levels of SP-A in both BL and BAL fluids when compared with young subjects, and in BL fluid when compared with middle-aged or elderly smokers without emphysema. SP-D did not change with age alone, however, it was decreased in middle-aged or elderly smokers when compared with similarly aged nonsmokers. In conclusion, surfactant protein-A may decrease with age alone or due to the cumulative effects of long-term smoking and development of emphysema, while surfactant protein-D decreases due to long-term smoking. © ERS Journals Ltd 2004.
• Chemokines in bronchiolar epithelium in the development of chronic obstructive pulmonary disease

  S Fuke, T Betsuyaku, Y Nasuhara, T Morikawa, H Katoh, M Nishimura

  AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 31 (4) 405 - 412 1044-1549 2004/10 [Refereed][Not invited]
   

  The inflammatory chemokines interleukin-8, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1, are reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although bronchiolar epithelial cells and macrophages are known to be the cellular sources, the relative contribution of each cell type remains to be elucidated. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were interleukin-8, macrophage inflammatory protein-lot, and monocyte chemoattractant protein-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never-smokers or smokers without either airflow limitation or emphysema. No difference was observed in macrophages. Complementary DNA (cDNA) array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory chemokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase-polymerase chain reaction and cDNA microarrays, to investigate functional profiles of individual structural and inflammatory cells in human lungs.
• Effect of low-dose theophylline on airway inflammation in COPD

  Motoko Kobayashi, Yasuyuki Nasuhara, Tomoko Betsuyaku, Eiji Shibuya, Yoshinori Tanino, Mishie Tanino, Kei Takamura, Katsura Nagai, Takeshi Hosokawa, Masaharu Nishimura

  Respirology 9 (2) 249 - 254 1323-7799 2004/06 

  Objective: Recent studies have shown that theophylline may exert anti-inflammatory effects on neutrophils. We undertook to assess the effect of theophylline on airway inflammation in COPD. Methodology: We performed a 4-week randomized double-blind, placebo-controlled study in 11 theophylline-naive patients with mild to moderate COPD. After a 1-week run-in period, six subjects were administered 400 mg/day theophylline (Theodur Nikken Chemicals Co. Ltd, Tokyo, Japan) for 4 weeks, while five subjects were administered a placebo. Induced sputum was obtained before and after the run-in period and then after 2 and 4 weeks of treatment. Cell differential count and levels of interleukin-8, matrix metalloproteinase-9, neutrophil elastase (NE), myeloperoxidase (MPO), α1-antitrypsin (αs1-AT), leukotriene B 4 and tissue inhibitor of metalloproteinases-1 (TIMP-1) were assessed. Results: No variable was significantly different during the run-in period or with placebo treatment. In contrast, theophylline treatment significantly decreased NE and MPO levels at 4 weeks, although the cell differential count did not change appreciably as a result of treatment. Conclusion: These results suggest that 4 weeks of theophylline treatment attenuates neutrophil-associated inflammation in the airways of mild to moderate COPD patients. However, the clinical benefits remain to be determined.
• Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line

  K Takamura, Y Nasuhara, M Kobayashi, T Betsuyaku, Y Tanino, Kinoshita, I, E Yamaguchi, S Matsukura, RP Schleimer, M Nishimura

  AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 286 (4) L777 - L785 1040-0605 2004/04 [Refereed][Not invited]
   

  Retinoic acid (RA) is known to accelerate wound healing and induce cell differentiation. All-trans RA (ATRA) exerts its effect by binding retinoic acid receptors, which are members of the nuclear receptor family. We investigated whether RA can alter expression of eotaxin, a potent eosinophil chemoattractant that is regulated by the transcription factors signal transducer and activator of transcription 6 (STAT6) and NF-kappaB. We examined the effects of RA on eotaxin expression in a human bronchial epithelial cell line BEAS-2B. ATRA and its stereodimer 9-cis retinoic acid (9-cis RA) inhibited IL-4-induced release of eotaxin at 10(-6) M by 78.0 and 52.0%, respectively (P < 0.05). ATRA and 9-cis RA also significantly inhibited IL-4-induced eotaxin mRNA expression at 10(-6) M by 52.3 and 53.5%, respectively (P < 0.05). In contrast, neither ATRA nor 9-cis RA had any effects on TNF-alpha-induced eotaxin production. In transfection studies using eotaxin promoter luciferase plasmids, the inhibitory effect of ATRA on IL-4-induced eotaxin production was confirmed at the transcriptional level. Interestingly, ATRA had no effects on IL-4-induced tyrosine phosphorylation, nuclear translocation, or DNA binding activity of STAT6. Activating protein-1 was not involved in ATRA-mediated transrepression of eotaxin with IL-4 stimulation. The mechanism of the inhibitory effect of ATRA on IL-4-induced eotaxin production in human bronchial epithelial cells has not been elucidated but does not appear to be due to an effect on STAT6 activation. These findings raise the possibility that RA may reduce eosinophilic airway inflammation, one of the prominent pathological features of allergic diseases such as bronchial asthma.
• [A case of paclitaxel-induced pneumonitis].

  Taniguchi N, Shinagawa N, Kinoshita I, Nasuhara Y, Yamazaki K, Yamaguchi E, Akita H, Nishimura M

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 2 42 158 - 163 1345-9538 2004/02 [Refereed][Not invited]
  
• 38 ムスカリン受容体M1遺伝子多型と喘息発症の関連

  前田 由起子, 檜澤 伸之, 地主 英世, 小林 基子, 高橋 大輔, 福居 嘉信, 別役 智子, 南須原 康行, 西村 正治

  アレルギー 一般社団法人 日本アレルギー学会 53 (8) 890 - 890 2004
• Studies on airway hyperresponsiveness by the astograph® method in asthmatics and young adult non-asthmatic asymptomatics

  Yoshinobu Fukui, Etsuro Yamaguchi, Nobuyuki Hizawa, Yukiko Maeda, Daisuke Takahashi, Satoshi Konno, Motoko Kobayashi, Takeshi Hosokawa, Eisei Jinushi, Kei Takamura, Yasuyuki Nasuhara, Masaharu Nishimura

  Japanese Journal of Allergology 53 (6) 565 - 574 0021-4884 2004 [Refereed][Not invited]
   

  We investigated airway hyperresponsiveness (AHR) by the continuous inhalation method using an Astograph® in 105 asthmatics and 141 non-asthmatic asymptomatics. The range of Dmin (1 U = one minute inhalation of 1 mg/ml of methacholine) of asthmatics was 0.001 to 28.70 U, and that of adjusted Dmin of non-asthmatic asymptomatics was 0.28 to 190 U thus, an apparent overlap was recognized in the distributions of Dmin. Ninety-five percent of asthmatics had a Dmin lower than 7 U, and 95% of non-asthmatic asymptomatics had a Dmin higher than 0.9 U. Presuming that almost all asthmatics had AHR, it was inferred that nearly half of non-asthmatic asymptomatics had AHR, too. Comparison with previous reports suggests that AHR in healthy people may be increasing generally. When Dmin is determined to be > 7 U by the Astograph® method, it is likely that the patient does not have asthma. When a patient has a Dmin < 0.9 U, it is highly probable that the patient has asthma.
• Extracellular matrix metalloproteinase inducer is increased in smokers' bronchoalveolar lavage fluid

  T Betsuyaku, M Tanino, K Nagai, Y Nasuhara, M Nishimura, RM Senior

  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 168 (2) 222 - 227 1073-449X 2003/07 [Refereed][Not invited]
   

  Extracellular matrix metalloproteinase inducer (EMMPRIN), also called basigin, is present in the lung during development, but its expression in normal adult lung is minimal. Increases of EMMPRIN have been found in various forms of experimental lung injury. To determine whether EMMPRIN might be involved in alveolar injury/ repair associated with smoking, we developed an ELISA for EMMPRIN and applied it to bronchoalveolar lavage fluids from never-smokers (n = 7), former smokers (n = 16), and current smokers (n = 58). The smoker groups included subjects with emphysema, as determined by high-resolution chest computed tomography. EMMPRIN levels were significantly elevated in current and former smokers (315 +/- 20 and 175 +/- 15 pg/ml SEM, respectively, compared with 31 +/- 7 pg/ml in never-smokers), but the EMMPRIN levels of smokers with emphysema were not different from smokers without emphysema. Immunohistochemistry of smokers' lung tissue showed EMMPRIN in bronchiolar epithelium and alveolar macrophages, but EMMPRIN mRNA in alveolar macrophages was not different between current and never-smokers. Matrix metalloproteinase-1 was also detectable in the bronchoalveolar lavage fluid from some smokers but not in never-smokers. These findings indicate that smoking is associated with increased intrapulmonary EMMPRIN. Whether EMMPRIN is involved in smoking-induced lung pathology remains to be determined.
• 84 アストグラフ法による気道過敏性の指標における基準範囲の検討

  福居 嘉信, 今野 哲, 小林 基子, 地主 英世, 高村 圭, 南須原 康行, 檜澤 伸之, 山口 悦郎, 西村 正治

  アレルギー 一般社団法人 日本アレルギー学会 51 (9) 927 - 927 2002
• 4 喘息とβ-受容体、ムスカリン受容体の遺伝子多型(2 アレルギー性疾患と遺伝)

  檜澤 伸之, 山口 悦郎, 地主 英世, 今野 哲, 南須原 康行, 棟方 充, 川上 義和

  アレルギー 一般社団法人 日本アレルギー学会 49 (9) 801 - 801 2000
• Inhibition of ozone-induced lung neutrophilia and nuclear factor-kappa B binding activity by vitamin A in rat

  T Hisada, IM Adcock, Y Nasuhara, M Salmon, TJ Huang, PJ Barnes, KF Chung

  EUROPEAN JOURNAL OF PHARMACOLOGY 377 (1) 63 - 68 0014-2999 1999/07 [Not refereed][Not invited]
   

  Vitamin A binds to retinoic acid receptors, which in turn may interact with other transcription factors. We determined its effect (2500 and 5000 IU/kg) on nuclear factor-kappa B binding activity in the lung, airway inflammation and bronchial hyperresponsiveness in rats exposed to ozone. Ozone (3 ppm, 3 h) caused neutrophil influx into bronchoalveolar lavage fluid (16.2 +/- 0.8 x 10(5) cells/ml, p < 0.01) and bronchial hyperresponsiveness (-logPC(200)ACh = 2.54 +/- 0.19, p < 0.05, compared to control animals, respectively). Vitamin A inhibited this neutrophilia dose-dependently together with the increased DNA-binding activity of nuclear factor-kappa B in lung extracts. Vitamin A did not affect bronchial hyperresponsiveness at both doses. Vitamin A inhibits ozone-induced neutrophilic inflammation through a reduction in nuclear factor-kappa B DNA binding activity. (C) 1999 Elsevier Science B.V. All rights reserved.
• Role of cysteinyl-leukotrienes in eotaxin-induced bronchial hyperresponsiveness and eosinophil migration in IL-5 transgenic mice

  T Hisada, M Salmon, Y Nasuhara, KF Chung

  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 159 (3) A404 - A404 1073-449X 1999/03 [Not refereed][Not invited]
  
• A Case of Mycosis Fungoides with Pulmonary Involvement: Effect of Etoposide and Prednisolone.

  Nasuhara Yasuyuki, Kobayashi Shuichi, Munakata Mitsuru, Kawakami Yoshikazu, Fujita Miri

  The Japanese journal of thoracic diseases The Japanese Respiratory Society 33 (9) 1013 - 1018 0301-1542 1995 

  Persistent coughing and bloody sputum developed in a 75-year-old man with mycosis fungoides. Chest X-ray films on admission showed combined patterns of alveolar and interstitial shadows in both lung fields. Histological examination of the transbronchial lung biopsy specimen revealed patchy infiltration of mycosis fungoides cells in alveolar septa. VEPA chemotherapy was ineffective against skin lesions and caused bacterial pneumonia, but combined treatment with etoposide (200mg, once a week) and prednisolone (30mg, 3 days per week) resulted in remission. The patient has been taking oral etoposide and prednisolone regularly, and has been free of skin and pulmonary lesions for two years.
  Combined therapy with low-dose etoposide and prednisolone may be worth trying in cases of advanced mycosis fungoides with pulmonary involvement.

MISC

• 7対1看護導入がインシデント報告件数に与えた影響について 新人看護職数の増加に着目して

  南須原 康行, 佐久嶋 研, 奥原 芳子, 渋谷 かをり, 伊藤 陽一, 石川 誠, 宝金 清博  日本医療マネジメント学会雑誌  14-  (1)  25  -30  2013/05  [Not refereed][Not invited]
   

  北海道大学病院における2003年度から2009年度までの7年間にわたるインシデントレポートの中から、看護職によって報告されたものを抽出し、報告者の経験年数、レポート件数、場面などについて分析を行った。7年間で看護職から報告されたインシデントレポート総数は12,798件であった。7対1看護の導入により2007年度に145名の看護職の増員があり、総看護職の増員が22.0%であったのに対し、インシデントレポート件数は33.0%の増加であった。2007年度は総看護職数における1年目看護職数の割合が高く、1年目看護職による報告件数の占める割合が他の年度と比較して高かった。一方、1年目看護職1人あたりの平均年間報告件数の経年変化をみると、2007年度はそれ以前に比べて増加していなかった。看護職の増員は、看護職1人あたりのインシデントレポート件数の減少には繋がらなかった。看護職1年目ではインシデント全体に占める処方・与薬の割合が、2・3年目、4年目以上と比較して有意に大きかった。その内訳では、末梢静脈点滴なかでも投与速度に関するものの割合が、1年目および2・3年目は4年目以上に比べて有意に大きかった。看護職の新人教育においては、新人が関与する可能性の高いインシデントに重点をおいた教育が必要であろう。(著者抄録)
• 肺胞蛋白症のGM‐CSF吸入治療の予後と肺活量

  田澤立之, 新井徹, 笠原靖紀, 放生雅章, 大河内眞也, 江田良輔, 横場正典, 土橋佳子, 中山秀章, 石井晴之, 森本浩之輔, 南須原康行, 高田俊範, 海老名雅仁, 山口悦郎, 井上義一, 中田光  日本呼吸器学会誌  2-  (増刊)  223  -223  2013/03/10  [Not refereed][Not invited]
  
• Initiatives of a collaborative audit of medical records with the division of hospital safety management and the medical record center

  HATSUYAMA Takashi, KATSUYA Go, SASAKI Ayaka, YOKOYAMA Runa, SAITO Erika, SHIBUYA Kaori, OKUHARA Yoshiko, ISHIKAWA Makoto, NASUHARA Yasuyuki, HOUKIN Kiyohiro  診療情報管理 : 日本診療情報管理学会誌 = Health information management  24-  (3)  68  -71  2012/12/25  [Not refereed][Not invited]
  
• 転倒・転落防止及び対応に関する看護師の意識調査

  南須原康行, 佐久嶋研, 奥原芳子, 渋谷かをり, 石川誠, 伊藤陽一, 宝金清博  医療の質・安全学会誌  7-  (Suppl.)  205  -205  2012/10  [Not refereed][Not invited]
  
• Beta2-adrenergic receptor polymorphisms as a determinant of preferential bronchodilator responses to beta 2-agonist and anticholinergic agents in Japanese patients with chronic obstructive pulmonary disease

  Satoshi Konno, Hironi Makita, Masaru Hasegawa, Yasuyuki Nasuhara, Katsura Nagai, Tomoko Betsuyaku, Nobuyuki Hizawa, Masaharu Nishimura  PHARMACOGENETICS AND GENOMICS  21-  (11)  687  -693  2011/11  [Refereed][Not invited]
   

  Background Previous studies have shown that polymorphisms in the beta 2-adrenergic receptor gene (ADRB2) may influence bronchodilator response (BDR) to both beta 2-agonists and anticholinergics, possibly by intracellular cross-talk, but in opposite ways, in the Japanese population. We hypothesized that the preferential response to either class of bronchodilators might be determined by ADRB2 polymorphisms in patients with chronic obstructive pulmonary disease (COPD). Objective To examine the association of ADRB2 polymorphisms and preferential BDR to beta 2-agonists and anticholinergics in patients with COPD. Design and participants The participants had been enrolled in the Hokkaido COPD cohort study. BDR to either class of bronchodilators (salbutamol or oxytropium, 0.4 mg) was measured every 6 months for 2 years. Considering the variation of BDR within and between days, mean values of postbronchodilator increases in forced expiratory volume in 1 s (Delta FEV1) for the two agents measured at two different visits were initially used for the primary analysis (N = 189). To confirm the results of the primary analysis, Delta FEV1 measured at a single visit was also used for secondary analyses. Results Although a significant correlation between BDRs to salbutamol and to oxytropium was observed (P < 0.001, r = 0.36), there were individuals who responded preferentially to one of the two agents. When the participants were classified into two groups based on the bronchodilator causing the better response (salbutamol-dominant group and oxytropium-dominant group), Arg allele was significantly more common in the oxytropium-dominant group than in the salbutamol-dominant group (0.001 < P < 0.05). Conclusion ADRB2 polymorphism may be a determinant of preferential BDR to either beta 2-agonists or anticholinergics in patients with COPD. Pharmacogenetics and Genomics 21:687-693 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
• 当院における成人用転倒・転落アセスメントシートの妥当性についての検討

  南須原 康行, 佐久嶋 研, 伊藤 陽一, 奥原 芳子, 渋谷 かをり, 石川 誠, 寶金 清博  医療の質・安全学会誌  6-  (Suppl.)  176  -176  2011/10  [Not refereed][Not invited]
  
• Comparison of airway remodelling assessed by computed tomography in asthma and COPD

  Kaoruko Shimizu, Masaru Hasegawa, Hironi Makita, Yasuyuki Nasuhara, Satoshi Konno, Masaharu Nishimura  RESPIRATORY MEDICINE  105-  (9)  1275  -1283  2011/09  [Refereed][Not invited]
   

  Background: Few studies have directly compared airway remodelling assessed by computed tomography (CT) between asthma and chronic obstructive pulmonary disease (COPD). The present study was conducted to determine whether there are any differences between the two diseases with similar levels of airflow limitation under clinically stable conditions. Methods: Subjects included older male asthmatic patients (n = 19) showing FEV(1)/FVC <70% with smoking history less than 5-pack/year. Age- and sex-matched COPD patients (n = 28) who demonstrated similar airflow limitation as asthmatic patients and age-matched healthy non-smokers (n = 13) were recruited. Using proprietary software, eight airways were selected in the right lung, and wall area percent (WA%) and airway luminal area (Ai) were measured at the mid-portion of the 3rd to 6th generation of each airway. For comparison, the average of eight measurements per generation was recorded. Results: FEV(1)% predicted and FEV(1)/FVC was similar between asthma and COPD (82.3 +/- 3.3% vs. 77.6 +/- 1.8% and 57.7 +/- 1.6% vs. 57.9 +/- 1.4%). At any generation, WA% was larger and Ai was smaller in asthma, both followed by COPD and then controls. Significant differences were observed between asthma and controls in WA% of the 3rd to 5th generation and Ai of any generation, while no differences were seen between COPD and controls. There were significant differences in Ai of any generation between asthma and COPD.
• Two Atypical Cases Of Hard Metal Lung Disease

  T. Hosokawa, H. Terui, T. Ogi, C. Moriyama, A. Isada, K. Nagai, S. Konno, Y. Nasuhara, M. Nishimura, K. Kubota, Y. Matsuno, A. Morioka, I. Nakano, K. Kimura, K. Okamoto, M. Uo  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  183-  2011  [Refereed][Not invited]
  
• 結節性硬化症病変を伴わないmultifocal micronodular pneumocyte hyperplasia の1例

  日本呼吸器学会雑誌  49-  (5)  355  -359  2011  [Not refereed][Not invited]
  
• A Case of Follicular Bronchiolitis Associated with Asthma, Eosinophilia, and Increased Immunoglobulin E

  Kaoruko Shimizu, Satoshi Konno, Yasuyuki Nasuhara, Mishie Tanino, Yoshihiro Matsuno, Masaharu Nishimura  JOURNAL OF ASTHMA  47-  (10)  1161  -1164  2010/12  [Refereed][Not invited]
   

  A 49-year-old woman, who had been diagnosed with asthma, showed a bilateral diffuse pattern of small centrilobular nodules on CT. Laboratory data revealed peripheral eosinophilia and a marked increase in total serum IgE levels. The nodules detected on CT were initially considered to be associated with bronchiolar infiltration of eosinophils. Pathological findings from thoracoscopy revealed infiltration of eosinophils into the airway lumen and walls, goblet cell hyperplasia, and thickening of the basement membrane in large bronchi, consistent with asthma. However, hyperplastic lymphoid follicles with reactive germinal centers were observed along the bronchioles. The follicles had no evidence of monoclonality suggested by immunohistological analysis, and no remarkable infiltrates of eosinophils, suggesting follicular bronchiolitis (FB). After treatment with prednisolone, the small diffuse nodules improved markedly, and peripheral eosinophilia and total serum IgE levels also decreased. To the best of our knowledge, this is the first documented case report of FB associated with asthma, eosinophilia, and elevated IgE with a definite pathophysiological diagnosis.
• Airflow limitation and airway dimensions assessed per bronchial generation in older asthmatics

  Kaoruko Shimizu, Masaru Hasegawa, Hironi Makita, Yasuyuki Nasuhara, Satoshi Konno, Masaharu Nishimura  RESPIRATORY MEDICINE  104-  (12)  1809  -1816  2010/12  [Refereed][Not invited]
   

  Background Computed tomography (CT) has been used for non invasive quantitative assessment of airway dimensions, potentially showing airway remodeling, in asthma However, most studies have examined either only one airway or only airways in anatomically unidentified cross sections Using software capable of precisely identifying the generation of airways and measuring airway dimensions perpendicular to the long axis of airways, we examined, in older patients with stable asthma, how inter subject variation in airway dimensions correlated among the 3rd to 6th generation of airways, and then examined relationships between airway dimensions of each generation and indices of airflow limitation Methods Subjects aged >= 55 years old comprised 59 asthmatic patients who underwent CT and pulmonary function tests on the same day We measured airway wall area (WA%) and innerluminal area (Ai) from the 3rd to the 6th generation of eight bronchi in the right lung Results Excellent correlations were identified for both WA% and Ai among the generations (r = 0 744-0 930 for WA%) when we took the average of all measured bronchi per generation as a personal representative value Significant correlations of airflow limitation indices with both WA% and Ai/BSA were found at each of the 3rd to 6th generations with similar correlation coefficients (WA% for FEV(1) %predicted, r = -0 410 to -0 556) Conclusions In older patients with stable asthma, airway wall thickening and narrowing might occur in a parallel manner through 3rd to 6th generation airways Airway dimensions at these areas of airways may thus have significant and similar correlations with indices of airflow limitation (C) 2010 Elsevier Ltd All rights reserved
• O14-3 肺CT3次元気道解析を用いた気管支喘息とCOPDにおける気道病変の比較(O14 喘息画像解析,口演,第60回日本アレルギー学会秋季学術大会)

  清水 薫子, 長谷川 大, 牧田 比呂仁, 南須原 康行, 今野 哲, 西村 正治  アレルギー  59-  (9)  1384  -1384  2010/10/30  [Not refereed][Not invited]
  
• 喘息として加療されフローボリューム子九千が発見の契機となった成人重複大動脈弓の1例

  日本呼吸器学会雑誌  48-  (3)  229  -234  2010  [Not refereed][Not invited]
  
• 高度の肺野病変を呈した血管内大細胞型B細胞リンパ腫

  血液臨床  51-  (5)  353  -356  2010  [Not refereed][Not invited]
  
• MPO-ANCA陽性であったが糸球体腎炎や血管炎は確認されず、間質性肺炎に感染症を合併して死亡した症例

  石津 明洋, 岩崎 沙理, 外丸 詩野, 武田 広子, 大塚 紀幸, 富居 一範, 笠原 正典, 清水 健一, 南須原 康行, 西村 正治  北海道医学雑誌  84-  (5)  403  -403  2009/09  [Not refereed][Not invited]
  
• Comparison of the Pharmacodynamics of Biapenem in Bronchial Epithelial Lining Fluid in Healthy Volunteers Given Half-Hour and Three-Hour Intravenous Infusions

  Eiki Kikuchi, Junko Kikuchi, Yasuyuki Nasuhara, Satoshi Oizumi, Akitoshi Ishizaka, Masaharu Nishimura  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY  53-  (7)  2799  -2803  2009/07  [Refereed][Not invited]
   

  The time above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) parameter that correlates with the therapeutic efficacy of beta-lactam antibiotics. A prolonged infusion can provide plasma drug concentrations that remain above the MIC for a long period. The objective of this study was to compare the PK/PD parameters in bronchial epithelial lining fluid (ELF) of biapenem given as 0.5-h and 3-h infusions by using bronchoscopic microsampling (BMS). Six healthy adult volunteers received 0.5-h and 3-h infusions of 0.3 g of biapenem with a washout interval. BMS was performed repeatedly from 0.5 to 24 h after biapenem administration in order to determine the pharmacokinetics in bronchial ELF. The subjects received intravenous biapenem with the same regimens again and then underwent bronchoalveolar lavage (BAL) at the end of infusion in order to determine the concentration of the drug in alveolar ELF. The percentages (means +/- standard deviations) of T>MIC in bronchial ELF at MICs from 0.25 to 4 mu g/ml ranged from zero to 34.6% +/- 5.2% after the 0.5-h infusion and from 5.1% +/- 5.6% to 52.2% +/- 17.0% after the 3-h infusion. The percentage of T>MIC in bronchial ELF after the 3-h infusion tended to be higher than that after the 0.5-h infusion. The concentrations of the drug in alveolar ELF after 0.5-h and 3-h infusions were 3.5 +/- 1.2 mu g/ml and 1.3 +/- 0.3 mu g/ml, respectively. The present results support the use of prolonged infusions of beta-lactam antibiotics and may provide critical information for successful treatment of lower respiratory tract infections based on PK/PD parameters in bronchial ELF.
• Relationship between improved airflow limitation and changes in airway calibre induced by inhaled anticholinergic agents in COPD

  M. Hasegawa, H. Makita, Y. Nasuhara, N. Odajima, K. Nagai, Y. Ito, T. Betsuyaku, M. Nishimura  THORAX  64-  (4)  332  -338  2009/04  [Refereed][Not invited]
   

  Background: Although airflow limitation improved by inhaled anticholinergic drugs varies among individuals with chronic obstructive pulmonary disease (COPD), the relationship between actual bronchodilation and improved pulmonary function and where in the lung such bronchodilation occurs remains unknown. A study was undertaken to determine the relationship between improved pulmonary function and changes in airway calibre at various sites in the airways in response to inhaled anticholinergic agents in patients with COPD using three-dimensional computed tomography (CT). Methods: CT scans were performed at deep inspiration and detailed pulmonary function tests before and 1 week after daily inhalations of tiotropium bromide in 15 patients with clinically stable COPD. The airway luminal area was examined at the third (segmental) to the sixth generations of eight bronchi in the right lung. Results: Bronchodilation was demonstrated by an overall average increase of 39% in the inner luminal area, and the mean (SE) forced expiratory volume in 1 s (FEV(1)) increased from 1.23 (0.11) l to 1.47 (0.13) l. The magnitude of bronchodilation was closely correlated with improved pulmonary function, particularly with that of FEV1 (r = 0.843, p < 0.001). Such correlations were significant at the fourth to the sixth generation but not at the third generation of bronchi, and the slope of the regression lines became steeper from the third to the sixth generation. Conclusions: Inhaled anticholinergic agents induce overall bronchodilation which is in proportion to improvements in FEV1 in patients with COPD. Bronchodilation at the distal rather than the proximal airways is the determinant of functional improvement.
• Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice

  Masaru Suzuki, Tomoko Betsuyaku, Yoko Ito, Katsura Nagai, Nao Odajima, Chinatsu Moriyama, Yasuyuki Nasuhara, Masaharu Nishimura  AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY  296-  (4)  L614  -L623  2009/04  [Not refereed][Not invited]
   

  Suzuki M, Betsuyaku T, Ito Y, Nagai K, Odajima N, Moriyama C, Nasuhara Y, Nishimura M. Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 296: L614-L623, 2009. First published January 23, 2009; doi:10.1152/ajplung.90443.2008.-Curcumin, a yellow pigment obtained from turmeric (Curcumina longa), is a dietary polyphenol that has been reported to possess antiinflammatory and antioxidant properties. The effect of curcumin against the development of pulmonary emphysema in animal models is unknown. The aim of this study was to determine whether curcumin is able to attenuate the development of pulmonary emphysema in mice. Nine-week-old male C57BL/6J mice were treated with intratracheal porcine pancreatic elastase (PPE) or exposed to mainstream cigarette smoke (CS) (60 min/day for 10 consecutive days or 5 days/wk for 12 wk) to induce pulmonary inflammation and emphysema. Curcumin (100 mg/kg) or vehicle was administrated daily by oral gavage 1 h and 24 h before intratracheal PPE treatment and daily thereafter throughout a 21-day period in PPE-exposed mice and 1 h before each CS exposure in CS-exposed mice. As a result, curcumin treatment significantly inhibited PPE-induced increase of neutrophils in bronchoalveolar lavage fluid at 6 h and on day 1 after PPE administration, with an increase in antioxidant gene expression at 6 h and significantly attenuated PPE-induced air space enlargement on day 21. It was also found that curcumin treatment significantly inhibited CS-induced increase of neutrophils and macrophages in bronchoalveolar lavage fluid after 10 consecutive days of CS exposure and significantly attenuated CS-induced air space enlargement after 12 wk of CS exposure. In conclusion, oral curcumin administration attenuated PPE- and CS-induced pulmonary inflammation and emphysema in mice. on March 24, 2009 ajplung. physiology. org Downloaded from
• Aging affects lipopolysaccharide-induced upregulation of heme oxygenase-1 in the lungs and alveolar macrophages

  Yoko Ito, Tomoko Betsuyaku, Chinatsu Moriyama, Yasuyuki Nasuhara, Masaharu Nishimura  BIOGERONTOLOGY  10-  (2)  173  -180  2009/04  [Refereed][Not invited]
   

  Lung injuries are generally more serious and cause high mortality in aged humans and animals. Heme Oxygenase-1 (HO-1) is known to be readily inducible in alveolar macrophages (AMs) and airway epithelial cells to confer cytoprotection against oxidative stress. We thus investigated whether aging impairs the stress-induced upregulation of HO-1. In this study, we first quantified basal levels of HO-1 expression in lungs from male ICR mice of various ages. Second, young (9-11 weeks) and old (65-66 weeks) mice were subjected to intratracheal administration of lipopolysaccharide (LPS) and expression of HO-1 in the lungs was quantified at 2, 24 and 72 h. HO-1 expression in bronchiolar epithelial cells harvested by laser capture microdissection (LCM) was also specifically quantified in the two age groups. Third, we examined HO-1 expression in AMs lavaged from 22-week-old and 86-96-week-old male ICR mice in response to LPS for 24 h in vitro. We found that basal expression of HO-1 in the lungs did not differ with age. LPS-induced HO-1 upregulation was significantly impaired in the lungs of 65-66-week-old mice than in 9-11-week-old mice at 2 and 24 h, although there were no differences in the magnitude of HO-1 upregulation in bronchiolar epithelium at 2 h. LPS-induced upregulation of HO-1 was observed in AMs from 22-week-old mice (1.8-fold), but not in AMs from 86-96-week-old mice in vitro. In summary, we demonstrated age-related defects in HO-1 induction in the whole lungs and in AMs in response to LPS.
• What is revealed by progress in technology of CT imaging in COPD?

  長谷川 大, 南須原 康行  臨床放射線  54-  (1)  17  -25  2009/01
• Catalase Expression in Pulmonary Macrophages of Smokers and Chronic Obstructive Pulmonary Disease (COPD) Patients.

  T. Inomata, T. Betsuyaku, Y. Ito, Y. Nasuhara, M. Nishimura  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  179-  2009  [Refereed][Not invited]
  
• 胸痛を呈し、胸膜病変の診断と病勢評価にFDG-PET (fluorodeoxyglucose-positron emission tomography) が有用であったサルコイドーシスの1例

  日本呼吸器学会雑誌  47-  (7)  658  -662  2009  [Not refereed][Not invited]
  
• Matrix metalloproteinases in blood from patients with LAM

  Nao Odajima, Tomoko Betsuyaku, Yasuyuki Nasuhara, Hiromasa Inoue, Kuniaki Seyama, Masaharu Nishimura  RESPIRATORY MEDICINE  103-  (1)  124  -129  2009/01  [Refereed][Not invited]
   

  Pulmonary lymphangioleiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) and destruction of alveolar structure. Immunohistochemical studies suggest that excess matrix metalloproteinases (MMPs) synthesized by LAM cells function in the proteolytic mechanisms of this disease. We postulated MMP levels in the blood are elevated in LAM patients. Serum samples were collected from 36 LAM patients and 25 controls and gelatinolytic activities were semi-quantified by gelatin zymography. The reliability of serum data for MMP-9 was confirmed by the measurement of MMP-9 concentration in plasma by enzyme-linked immunosorbent assay as well as by gelatin zymography. Serum levels of MMP-9 (0.7 +/- 0.1 AU), but not MMP-2, were significantly elevated in LAM patients compared with controls (0.1 +/- 0 AU). Plasma and serum levels of MMP-9 significantly correlated. These results suggest the involvement of MMP-9 in LAM. (C) 2008 Elsevier Ltd. All rights reserved.
• Down-Regulated NF-E2-Related Factor 2 in Pulmonary Macrophages of Aged Smokers and Patients with Chronic Obstructive Pulmonary Disease

  Masaru Suzuki, Tomoko Betsuyaku, Yoko Ito, Katsura Nagai, Yasuyuki Nasuhara, Kichizo Kaga, Satoshi Kondo, Masaharu Nishimura  AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY  39-  (6)  673  -682  2008/12  [Refereed][Not invited]
   

  Pulmonary macrophages are one of the sources of various antioxidant and detoxification enzymes for which NF-E2-related factor 2 (Nrf2) is a key transcriptional factor. Although Nrf2 deficiency reportedly induces severe emphysema in mice exposed to cigarette smoke (CS), no reports have studied Nrf2 regulation in chronic obstructive pulmonary disease (COPD). In this study, Nrf2 activation in response to CS was evaluated in human alveolar macrophages, and age-related differences in CS-induced Nrf2 regulation in mouse alveolar macrophages were determined. Furthermore, Nrf2 mRNA levels in human macrophages harvested by bronchoalveolar lavage or laser capture microdissection were measured. CS induced nuclear Nrf2 accumulation and up-regulation of Nrf2 target genes without substantial changes in Nrf2 mRNA levels in human alveolar macrophages. In humans, the Nrf2 mRNA level in lavaged macrophages of young subjects (n = 14) was independent of smoking status; however, the Nrf`2 mRNA level was down-regulated in the lavaged macrophages of older current smokers (n = 14) compared with older nonsmokers (n 9) (P < 0.001). Among older subjects, the macrophage Nrf2 mRNA level was inversely correlated with oxidized glutathione and carbonylated albumin levels in bronchoalveolar lavage fluid. In mice, aging suppressed the CS-induced up-regulation of Nrf2 target genes, as well as Nrf2, in alveolar macrophages. Furthermore, the Nrf2 mRNA level was decreased in laser capture microdissection-retrieved macrophages obtained from subjects with COPD (n = 10) compared with control subjects (n = 10) (P = 0.001). In conclusion, CS induces Nrf2 activation in macrophages, and Nrf2 expression is decreased in the macrophages of older current smokers and patients with COPD.
• Diversity of protein carbonylation in allergic airway inflammation

  Katsura Nagai, Tomoko Betsuyaku, Satoshi Konno, Yoko Ito, Yasuyuki Nasuhara, Nobuyuki Hizawa, Takahito Kondo, Masaharu Nishimura  FREE RADICAL RESEARCH  42-  (11-12)  921  -929  2008/11  [Refereed][Not invited]
   

  Oxidative stress is involved in asthma. This study assessed the carbonylation of sputum proteins in 23 uncontrolled adult asthmatic patients and 23 healthy controls. Carbonylated proteins (68 kDa and 53 kDa) were elevated in asthmatics when compared to controls and the 68-kDa carbonylated protein was significantly correlated with sputum eosinophilia. The kinetics of protein carbonylation in bronchoalveolar lavage fluid (BALF) were then examined in a mouse ovalbumin-induced allergic inflammation model. It was found that the carbonylation of various BALF proteins did not uniformly occur after challenge. The appearance of the 53-kDa carbonylated protein was limited within 24 h, while carbonylation of 68-kDa protein peaked at 48 h and was associated with BALF eosinophilia. Thus, it was demonstrated that the 68-kDa and 53-kDa proteins, corresponding to albumin and alpha 1-antitrypsin, respectively, were specifically carbonylated in allergic inflammation in humans and in mice and that eosinophils may play a role in mediating carbonylation of albumin.
• 肺限局型MPO-ANCA関連血管炎と考えられた一剖検例

  外丸 詩野, 武田 広子, 岩崎 沙理, 大塚 紀幸, 富居 一範, 笠原 正典, 清水 健一, 南須原 康行, 西村 正治, 石津 明洋  日本病理学会会誌  97-  (2)  33  -33  2008/09  [Not refereed][Not invited]
  
• Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysernatous phenotype in COPD patients

  N. Hizawa, H. Makita, Y. Nasuhara, M. Hasegawa, K. Nagai, Y. Ito, T. Betsuyaku, S. Konno, M. Nishimura  EUROPEAN RESPIRATORY JOURNAL  32-  (2)  372  -378  2008/08  [Refereed][Not invited]
   

  It was previously reported that the gain-of-function -28 guanine allele of the promoter single nucleotide polymorphism (SNP; cytosine to guanine substitution of nucleotide -28 (-28C > G)) in the CC chemokine ligand 5 gene (CCL5) was associated with susceptibility to late-onset asthma in patients who developed asthma at age >= 40 yrs. The clinical diagnosis of chronic obstructive pulmonary disease (COPD) includes emphysema and small airway disease, and upregulation of CCL5 has been described in the airways of patients with COPD. It was hypothesised that CCL5 has a genetic impact upon the variable expression of emphysema in patients with COPD. Patients with COPD were studied (n=267). All of the patients underwent pulmonary high-resolution computed tomography (CT), and visual scoring (CT score) was performed to determine emphysema severity. Three SNPs of CCL5 were genotyped, including -403G > A, -28C > G and 375T > C. A significant difference was found in CT score according to CCL5 genotype; the -28G allele was inversely associated with CT score. When the analysis was confined to 180 patients with bronchial reversibility of < 15%, even stronger evidence for this association was noted. Functional single nucleotide polymorphisms in the CC chemokine ligand 5 gene were associated with milder emphysema. Together with previous findings, the present study may identify the CC chemokine ligand 5 gene as part of a common pathway in the pathogenesis of late-onset asthma and chronic obstructive pulmonary disease with milder emphysema.
• ビアペネム30分点滴静注と3時間点滴静注における気管支上皮被覆液中薬物動態の解析

  菊地英毅, 山崎浩一, 菊地順子, 石坂彰敏, 南須原康行, 西村正治  日本呼吸器学会雑誌  46-  155  2008/05/10  [Not refereed][Not invited]
  
• Role of basement membrane in EMMPRIN/CD147 induction in rat tracheal epithelial cells

  Takeshi Hosokawa, Tomoko Betsuyaku, Nao Odajima, Masaru Suzuki, Katsumi Mochitate, Yasuyuki Nasuhara, Masaharu Nishimura  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS  368-  (2)  426  -432  2008/04  [Refereed][Not invited]
   

  Extracellular matrix metalloproteinase inducer (EMMPRIN) is a glycosylated transmembrane protein known to induce matrix metalloproteinases (MMPs). Although the expression of EMMPRIN is physiologically limited to fetal lung epithelium, the transcriptional regulation of this protein remains to be elucidated. We hypothesized that the interaction of epithelial cells with the basement membrane regulates EMMPRIN expression. The basement membrane has highly integrated architecture composed of specific extracellular matrix, such as laminins and type IV collagen, and exhibits multiple functions. We previously developed a structured basement membrane mimic, a synthesized basement membrane (sBM) substratum, in which laminin-111, a unique component of embryonic lungs, is incorporated. In the present study we quantified expression of EMMPRIN mRNA of rat tracheal epithelial cells cultured on sBM, laminin-111, type IV collagen, or laminin-332. EMMPRIN was upregulated on sBM and laminin-111, although this was not accompanied by MMP-9 induction. In contrast, type IV collagen and laminin-332 did not induce EMMPRIN. These findings suggest potential roles for basement membrane in the transcriptional regulation of tracheal epithelial EMMPRIN. (c) 2008 Elsevier Inc. All rights reserved.
• Dual oxidase 1 and 2 expression in airway epithelium of smokers and patients with mild/moderate chronic obstructive pulmonary disease

  Katsura Nagai, Tomoko Betsuyaku, Masaru Suzuki, Yasuyuki Nasuhara, Kichizo Kaga, Satoshi Kondo, Masaharu Nishimura  ANTIOXIDANTS & REDOX SIGNALING  10-  (4)  705  -714  2008/04  [Refereed][Not invited]
   

  Dual oxidase (Duox) 1 and Duox2 are important sources of hydrogen peroxide production and play a role in host defense in airways. Little is known about their regulation in association with smoking or chronic obstructive pulmonary disease (COPD). We investigated the epithelial expression of Duox1 and Duox2 in the airways of smokers, and the relationship between this expression and COPD at early stage. First, using bronchoscopy, we harvested tracheal and bronchial epithelium from individuals who have never smoked and current smokers. Duox1 expression in brushed tracheal and bronchial epithelium was significantly downregulated, whereas Duox2 was upregulated, in current smokers as compared to individuals who have never smoked. Second, laser capture microdissection and microscope-assisted manual dissection were performed in surgically resected lung tissues to collect bronchiolar epithelium and alveolar septa. Subjects with mild/moderate COPD, who were all former smokers, exhibited downregulation of bronchiolar Duox1 and Duox2 when compared to individuals who have never smoked, whereas a difference between former smokers, with and without COPD, was observed only for Duox1. Alveolar Duox1 and Duox2 expression was low and did not differ among the groups. These results imply that the airway expression of Duox1 and Duox2 is diversely associated with smoking and COPD.
• 呼吸器内科医による成人喘息診断の実態―アンケート調査の結果―

  日本呼吸器学会雑誌  46-  (8)  601  -607  2008  [Not refereed][Not invited]
  
• Decreased airway expression of vascular endothelial growth factor in cigarette smoke-induced emphysema in mice and COPD patients

  Masaru Suzuki, Tomoko Betsuyaku, Katsura Nagai, Satoshi Fuke, Yasuyuki Nasuhara, Kichizo Kaga, Satoshi Kondo, Ichiro Hamamura, Junko Hata, Hiroshi Takahashi, Masaharu Nishimura  INHALATION TOXICOLOGY  20-  (3)  349  -359  2008  [Refereed][Not invited]
   

  Vascular endothelial growth factor (VEGF) signaling is crucial for lung structure maintenance. Although VEGF deficiency plays a role in the pathogenesis of emphysema in animals, little is known about VEGF expression levels and functions, as well as VEGF receptors, in airway epithelial cells, which are in direct contact with the environment. In this study, C57BL/6J mice were exposed to cigarette smoke (CS) for short (similar to 10 days) and long (4-24 wk) time periods, and bronchiolar expressions of VEGF and its receptors VEGFR-1 and VEGFR-2 were examined. The relationships between the expressions of VEGF, VEGFR-1, and VEGFR-2 and smoking histories and/or chronic obstructive pulmonary disease (COPD) were examined in humans. The mRNA levels were quantified in bronchiolar epithelium harvested by laser capture microdissection in both mouse and human lung tissues or in human bronchial epithelium harvested by bronchoscopic brushing. The VEGF protein level was assessed by immunohistochemistry or enzyme-linked immunosorbent assay. Repeated CS exposure downregulated bronchiolar expressions of VEGF and both VEGF receptors at various time points prior to the development of emphysema. In humans, bronchiolar VEGF was significantly decreased in smokers with COPD compared to lifelong nonsmokers, as well as to smokers without COPD; however, there was no difference in bronchiolar VEGF levels between lifelong nonsmokers and smokers without COPD. On the other hand, bronchiolar VEGFR-2 was downregulated in smokers with and without COPD compared to lifelong nonsmokers. These findings suggest the association of downregulation of bronchiolar VEGF and its receptors with cigarette smoking and COPD.
• 慢性閉塞性肺疾患と中高年発症喫煙者喘息における血清総ＩｇＥ値、末梢血好酸球数およびアトピー素因の比較

  清水 健一, 檜澤 伸之, 牧田 比呂仁, 今野 哲, 南須原 康行, 別役 智子, 西村 正治  日本医師会雑誌  137-  (2)  326  -331  2008  [Not refereed][Not invited]
   

  呼吸器専門医によって臨床的に診断された慢性閉塞性肺疾患(COPD)患者274例と喘息患者98例を対象に、血清総IgE値、末梢血好酸球数、更にはありふれた吸入抗原に対する特異的IgE抗体の有無で判定したアトピー性素因を比較し、COPD患者と中高年発症の喫煙喘息患者との間に相違点が認められるかを検討した。その結果、中高年発症の喫煙喘息患者が血清総IgE値、末梢血好酸球数、アトピー性素因を有する割合はCOPD患者よりも有意に高値であり、これらのアレルギー性の指標を用いることで、高い特異度で喘息病態の存在を疑うことができる可能性が示唆された。
• The realities of clinical asthma diagnosis from questionnaire results

  Nihon Kokyuki Gakkai Zasshi  46-  (8)  601  -607  2008  [Not refereed][Not invited]
  
• Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease

  Hironi Makita, Yasuyuki Nasuhara, Katsura Nagai, Yoko Ito, Masaru Hasegawa, Tomoko Betsuyaku, Yuya Onodera, Nobuyuki Hizawa, Masaharu Nishimura  THORAX  62-  (11)  932  -937  2007/11  [Refereed][Not invited]
   

  Background: Airflow limitation in chronic obstructive pulmonary disease ( COPD) is caused by a mixture of small airway disease and emphysema, the relative contributions of which may vary among patients. Phenotypes of COPD classified purely based on severity of emphysema are not well defined and may be different from the classic phenotypes of "pink puffers'' and "blue bloaters''. Methods: To characterise clinical phenotypes based on severity of emphysema, 274 subjects with COPD were recruited, excluding those with physician-diagnosed bronchial asthma. For all subjects a detailed interview of disease history and symptoms, quality of life (QOL) measurement, blood sampling, pulmonary function tests before and after inhalation of salbutamol (0.4 mg) and high- resolution CT scanning were performed. Results: Severity of emphysema visually evaluated varied widely even among subjects with the same stage of disease. No significant differences were noted among three groups of subjects classified by severity of emphysema in age, smoking history, chronic bronchitis symptoms, blood eosinophil count, serum IgE level or bronchodilator response. However, subjects with severe emphysema had significantly lower body mass index (BMI) and poorer QOL scores, evaluated using St George's Respiratory Questionnaire (SGRQ), than those with no/mild emphysema (mean ( SD) BMI 21.2 (0.5) vs 23.5 (0.3) kg/m(2), respectively; SGRQ total score 40 (3) vs 28 (2), respectively; p < 0.001 for both). These characteristics held true even if subjects with the same degree of airflow limitation were chosen. Conclusions: The severity of emphysema varies widely even in patients with the same stage of COPD, and chronic bronchitis symptoms are equally distributed irrespective of emphysema severity. Patients with the phenotype in which emphysema predominates have lower BMI and poorer health-related QOL.
• Loss of caveolin-1 in bronchiolization in lung fibrosis

  Nao Odajima, Tomoko Betsuyaku, Yasuyuki Nasuhara, Masaharu Nishimura  JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY  55-  (9)  899  -909  2007/09  [Not refereed][Not invited]
   

  Bronchiolization is a key process in fibrosing lung in which the proliferative status of bronchiolar epithelium changes, leading to abnormal epithelial morphology. Within the context that caveolin-1 acts to suppress epithelial proliferation, we postulated that stimulating epithelial injury would lead to caveolin-1 downregulation and encourage proliferation. The present study evaluates the expression of caveolin-1, especially in bronchiolization, in CS7BL/6J mice with bleomycin-induced lung fibrosis and in various types of re-epithelialization in human interstitial pneumonias (IPs). Immunohistochemically, levels of caveolin-1 decreased in the bronchiolar epithelium of mice treated with bleomycin. Levels of caveolin-1 mRNA in the whole lung were decreased at 7 and 14 days. Caveolin-1 mRNA was also decreased in laser-capture microdissection- retrieved bronchiolar epithelial cells at 7 days. Among patients with 12 IPs, including four usual IPs (UIPs) and eight nonspecific IPs (NSIPs), whole lung caveolin-1 was significantly decreased compared with 12 controls at both mRNA and protein levels. By scoring immunointensity, caveolin-1 was significantly reduced in bronchiolization and squamous metaplasia as well as in bronchiolar epithelium in 23 IPs (12 UIPs and 11 NSIPs) compared with bronchiolar epithelium from seven controls. These data suggested that loss of caveolin-1 is associated with abnormal re-epithelialization in lung fibrosis.
• Increase in soluble CD138 in bronchoalveolar lavage fluid of multicentric Castleman's disease

  Masaru Hasegawa, Tomoko Betsuyaku, Nobuya Yoshida, Yasuyuki Nasuhara, Ichiro Kinoshita, Satoshi Ohta, Tomoo Itoh, Pyong Woo Park, Masaharu Nishimura  RESPIROLOGY  12-  (1)  140  -143  2007/01  [Refereed][Not invited]
   

  Multicentric Castleman's disease (MCD) is a rare and often incurable lymphoproliferative disorder. It is typically a systemic illness, but occasionally manifests primarily as a pulmonary parenchymal disease with massive infiltration of CD138 (syndecan-1)-positive plasma cells. This is the first report to demonstrate a marked elevation of soluble CD138, despite the absence of plasma cells, in BAL fluid in an MCD patient with pulmonary involvement. This finding suggests that the quantitative measurement of soluble CD138 in BAL fluid may reflect plasma cell infiltration and disease activity in the lungs of patients with MCD.
• A case of idiopathic nonspecific interstitial pneumonia and autoimmune hemolytic anemia after complete cure of polymyalgia rheumatica

  NAKADATE Megumi, NASUHARA Yasuyuki, HAMADA Kunio, NISHIMURA Masaharu  日本呼吸器学会雑誌 = The journal of the Japanese Respiratory Society  44-  (11)  864  -868  2006/11/10
• Airflow limitation and airway dimensions in chronic obstructive pulmonary disease

  M Hasegawa, Y Nasuhara, Y Onodera, H Makita, K Nagai, S Fuke, Y Ito, T Betsuyaku, M Nishimura  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  173-  (12)  1309  -1315  2006/06  [Refereed][Not invited]
   

  Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation caused by emphysema and/or airway narrowing. Computed tomography has been widely used to assess emphysema severity, but less attention has been paid to the assessment of airway disease using computed tomography. Objectives: To obtain longitudinal images and accurately analyze short axis images of airways with an inner diameter >= 2 mm located anywhere in the lung with new software for measuring airway dimensions using curved multiplanar reconstruction. Methods: In 52 patients with clinically stable COPD (stage I, 14; stage II, 22; stage III, 14; stage IV, 2), we used the software to analyze the relationship of the airflow limitation index (FEV1, % predicted) with the airway dimensions from the third to the sixth generations of the apical bronchus (B1) of the right upper lobe and the anterior basal bronchus (88) of the right lower lobe. Measurements and Main Results: Airway luminal area (Ai) and wall area percent (WA%) were significantly correlated with FEV1 (% predicted). More importantly, the correlation coefficients (r) improved as the airways became smaller in size from the third (segmental) to sixth generations in both bronchi (Ai: r = 0.26, 0.37, 0.58, and 0.64 for 81; r = 0.60, 0.65, 0.63, and 0.73 for BB). Conclusions: We are the first to use three-dimensional computed tomography to demonstrate that airflow limitation in COPD is more closely related to the dimensions of the distal (small) airways than proximal (large) airways.
• 【抗菌薬サイクリングvsミキシング 耐性菌対策としての抗菌薬使用への介入】 ICUにおける抗菌薬サイクリング

  松田 直之, 秋沢 宏次, 南須原 康行, 石黒 信久, 奥 直子, 早川 峰司, 澤村 淳, 石川 岳彦, 亀上 隆, 西村 正治, 丸藤 哲  Progress in Medicine  25-  (9)  2329  -2336  2005/09  [Not refereed][Not invited]
  
• 目でみる症例 特発性器質化肺炎(COP/BOOP)

  小田島 奈央, 南須原 康行, 西村 正治  内科  96-  (1)  147  -151  2005/07
• Organizing pneumonia associated with Q fever

  ONOE Kazuyuki, NASUHARA Yasuyuki, KASAHARA Ikumi, HIZAWA Nobuyuki, NISHIMURA Masaharu, UENO Hiroshi, MURAMATSU Yasukazu, MORITA Chiharu, TAMURA Yutaka  Nihon Naika Gakkai Kaishi  94-  (5)  961  -963  2005  [Not refereed][Not invited]
   

  症例は69歳女性.特発性器質化肺炎としてステロイド治療を開始し,自他覚所見は速やかに改善した.しかし,経過中行った検索にてCoxiella burnetiiに対する血清抗体価上昇,血液PCR陽性であったため, Q熱が器質化肺炎の原因と考えられた. Q熱については,診断法が一般的でなく市中肺炎の原因としても見逃されていることが多いとされており,特発性器質化肺炎と診断されている症例の中に, Q熱によって引き起こされている症例が少なからず存在する可能性がある.
• 「気管支肺胞洗浄所見の変化を追跡したgefitinibによる間質性肺炎の1例」

  『日呼吸会誌』  43-  466  -470  2005  [Not refereed][Not invited]
  
• 「咳喘息に対する吸入ステロイド単独療法とプロカテロール併用療法の比較」

  『呼吸』  24-  65  -70  2005  [Not refereed][Not invited]
  
• Nagai K，Betsuyaku T，Ito Y，Nasuhara Y，Nishimura M．： “Decrease of vascular endothelial growth factor in macrophages from long-team smokers” ，Eur Respir J，25：626-633 (2005)*

  2005  [Refereed][Not invited]
  
• Expression of pulmonary VEGF family declines with age and is further down-regulated in lipopolysaccharide (LPS)-induced lung injury

  Y Ito, T Betsuyaku, K Nagai, Y Nasuhara, M Nishimura  EXPERIMENTAL GERONTOLOGY  40-  (4)  315  -323  2005  [Refereed][Not invited]
   

  Vascular endothelial growth factor (VEGF) is a survival factor in endothelial cells and a promoter of angiogenesis that reportedly plays a pivotal role protecting against injury. In aged humans and animals, lung injuries are generally more serious and cause higher mortality. We thus hypothesized that the expression of VEGF and its related molecules in the lung declines with age. In this study, we first examined the expression of VEGF family (VEGF-A, -B, -C and -D), VEGF-A isoforms (VEGF120, 164, 188), and VEGF-specific receptors (VEGFR-1: Flt-1: VEGFR-2: Flk-1 and VEGFR-3: Flt-4) by quantitative RT-PCR in lungs front young and old mice. Expression of all these except for VEGF-D was significantly lower in old mice than in young mice. We then subjected young and old mice to lipopolysaccaride (LPS)-induced lung injury. Old animals demonstrated poor survival and prolonged lung inflammation when compared with young counterparts. At 24 and 72 h after intratracheal LPS administration, expression of the examined factors was down-regulated in the lungs irrespective of age. In conclusion. pulmonary expression of the VEGF family and their receptors declines with age, and is further down-regulated in LPS-induced lung injury, although the mechanism of age- and/or injury-related clown-regulation of VEGF remains unknown. (c) 2005 Elsevier Inc. All rights reserved.
• A case of paclitaxel-induced pneumonitis

  Natsuko Taniguchi, Naofumi Shinagawa, Ichiro Kinoshita, Yasuyuki Nasuhara, Koichi Yamazaki, Etsuro Yamaguchi, Hirotoshi Akita, Masaharu Nishimura  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society  42-  (2)  158  -163  2004  

  A 79-year-old woman with small-cell lung cancer was treated weekly with paclitaxel after previous treatment with carboplatin and etoposide. Within the first course of paclitaxel, chest radiography and CT revealed thickening of the bronchovascular bundle and interlobular septa, and infiltrates in both lung fields. A marked increase in the number of lymphocytes was found on bronchoalveolar lavage (BAL). Microorganisms such as Cytomegalovirus, Mycobacteria, and Pneumocystis carinii were absent from the BAL fluid. Interstitial infiltration was partially improved simply by stopping paclitaxel administration, without the need for any additional therapy. Drug-induced pneumonitis caused by paclitaxel was diagnosed on the basis of the clinical course and findings, although a drug lymphocyte stimulation test yielded negative results for paclitaxel. Interstitial infiltrates on imaging, symptoms and arterial blood gas results improved with administration of oral prednisolone. The possibility of pneumonitis induced by paclitaxel should be considered even in cases without interstitial lung disease.
• 「パクリタキセル投与との関連が示唆された薬剤性肺炎の1例」

  『日呼吸会誌』  42-  158  -163  2004  [Not refereed][Not invited]
  
• 「気管支喘息患者と若年成人無症候者におけるアストグラフ法による気道過敏性の検討」

  『アレルギー』  53-  565  -574  2004  [Not refereed][Not invited]
  
• Kobayashi M，Nasuhara Y，Betsuyaku T，Shibuya E，Tanino Y，Tanino M，Takamura K，Nagai K，Hosokawa T，Nishimura M．：“Effect of low-dose theophylline on airway inflammation in COPD”，Respirology，9：249-254 (2004)*

  2004  [Refereed][Not invited]
  
• Takamura K，Nasuhara Y，Kobayashi M，Betsuyaku T，Tanino Y，Kinoshita I，Yamaguchi E，Matsukura S，Schleimer RP，Nishimura M．：“Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line”，Am J Physiol Lung Cell Mol ・・・

  2004  [Refereed][Not invited]
   

  Takamura K，Nasuhara Y，Kobayashi M，Betsuyaku T，Tanino Y，Kinoshita I，Yamaguchi E，Matsukura S，Schleimer RP，Nishimura M．：“Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line”，Am J Physiol Lung Cell Mol Physiol，286：777-785 (2004)*
• Fuke S，Betsuyaku T，Nasuhara Y，Morikawa T，Katoh H，Nishimura M．：“Chemokines in Bronchiolar Epithelium in the Development of Chronic Obstructive Pulmonary Disease”，Am J Respir Cell Mol Biol，31：405-412 (2004)*

  2004  [Refereed][Not invited]
  
• Catley MC，Cambridge LM，Nasuhara Y，Itoh K，Chivers JE，Beaton A，Holden NS，Bergmann MW，Barnes PJ，Newton R．：“Inhibitors of Protein Kinase C (PKC) Prevent Activated Transcription；Role of events down stream of NF-κB DNA binding”，J Biol Chem，279：18457-18466 (2・・・

  2004  [Refereed][Not invited]
   

  Catley MC，Cambridge LM，Nasuhara Y，Itoh K，Chivers JE，Beaton A，Holden NS，Bergmann MW，Barnes PJ，Newton R．：“Inhibitors of Protein Kinase C (PKC) Prevent Activated Transcription；Role of events down stream of NF-κB DNA binding”，J Biol Chem，279：18457-18466 (2004)*
• Betsuyaku T，Kuroki Y，Nagai K，Nasuhara Y，Nishimura M．：“Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid”，Eur Respir J，24：964-970 (2004)*

  2004  [Refereed][Not invited]
  
• 「喘息におけるβ刺激薬」

  『International Review of Asthma』  6-  30  -36  2004  [Not refereed][Not invited]
  
• 6. RS_3PE症候群に肺扁平上皮癌を合併した1例(第29回日本肺癌学会北海道支部会)(支部活動)

  菅 正之, 山崎 浩一, 木下 一郎, 濱田 邦夫, 南須原 康行, 西村 正治, 天崎 吉晴, 秋田 弘俊  肺癌  43-  (7)  1047  -1047  2003/12/30
• A Case of Idiopathic Pulmonary Upper Lobe Fibrosis Complicated by Invasive Pulmonary Aspergillosis

  FUKE Satoshi, BETSUYAKU Tomoko, OIZUMI Satoshi, NASUHARA Yasuyuki, SAITO Hiroshi, YAMAGUCHI Etsuro, NISHIMURA Masaharu  日本呼吸器学会雑誌 = The journal of the Japanese Respiratory Society  41-  (3)  196  -201  2003/03/10
• Betsuyaku T, Tanino M, Nagai K, Nasuhara Y, Nishimura M, Senior RM. Related Articles, Links Extracellular matrix metalloproteinase inducer is increased in smokers' bronchoalveolar lavage fluid. Am J Respir Crit Care Med. 2003 Jul 15;168(2):222-7.*

  2003  [Refereed][Not invited]
  
• Elevated serum KL-6 concentrations in patients with diabetes mellitus

  T Takahashi, K Takamura, S Sakaue, J Ishii, H Yokouchi, Y Nasuhara  JOURNAL OF DIABETES AND ITS COMPLICATIONS  16-  (5)  352  -358  2002/09  [Not refereed][Not invited]
   

  To clarify the influence of blood glucose level or diabetes mellitus on serum KL-6, a mucin-like glycoprotein, concentrations, they were measured against 176 diabetic subjects, including receiving insulin (INS) group (n = 54), oral antidiabetics (OAD) group (n = 78), and diet and exercise (D&E) group (n = 44). Serum KL-6 concentrations in the diabetic subjects were significantly greater than those in the normal healthy control subjects (643.0 +/- 32.7 U/ml, 206.5 +/- 6.1 U/ml, P<.0001, respectively), and those in the INS and OAD groups were significantly greater than those in the D&E group (708.2 +/- 66.9, 691.7 +/- 51.9, and 476.6 +/- 34.9 U/ml, P<.05, P<.05, respectively). Serum KL-6 concentrations did not correlate with urine KL-6 concentrations (n=73, r=-044, P=.74). Immunohistochemical staining of the diabetic kidneys with a monoclonal antibody to KL-6 antigen showed positive immunoreactivity on Henle's loop, renal tubules, and epithelial cells in Bowman's space of sclerosing glomerulus. In conclusion, diabetes mellitus or complications of diabetes mellitus resulted in serum KL-6 elevation regardless of serum glucose level, but serum KL-6 concentrations were not influenced despite control of diabetes mellitus. (C) 2002 Elsevier Science Inc. All rights reserved.
• Q&A COPDと気管支喘息との病態の相違について教えてください (特集 プライマリケアのための慢性閉塞性肺疾患(COPD)の管理)

  南須原 康行, 西村 正治  治療  84-  (9)  2310  -2312  2002/09
• Takahashi, T., Ohtsuka, Y., Munakata, Y., Nasuhara, Y., Kamachi-Satoh, A., Homma, Y., Kawakami Y.:"Occurence of Farmer's Lung Disease is relevant to meteorological conditions: A 20-year follow-up field survey analysis", Am J Ind Med, 41:506-513(2002)*

  2002  [Refereed][Not invited]
  
• Kamachi, A., Nasuhara, Y., Nishimura, M., Takahashi, T., Homma, Y., Ohtsuka, Y., Munakata, M.: "Dissociation between airway responsiveness to methacholine and responsiveness to antigen", Eur Respir J, 19:76-83 (2002)*

  2002  [Refereed][Not invited]
  
• Enhancement of goblet cell hyperplasia and airway hyperresponsiveness by salbutamol in a rat model of atopic asthma

  A Kamachi, M Munakata, Y Nasuhara, M Nishimura, Y Ohtsuka, M Amishima, T Takahashi, Y Homma, Y Kawakami  THORAX  56-  (1)  19  -24  2001/01  [Not refereed][Not invited]
   

  Background-Goblet cell hyperplasia (GCH) is a prominent feature in animal models of atopic asthma produced by immunisation and following multiple challenges with antigens. The aim of this study was to examine the effect of a beta (2) agonist on the development of GCH induced by the immune response. Methods-Brown Norway rats were immunised and challenged with an aerosol of ovalbumin for four weeks. Salbutamol (0.5 mg/kg/day) or vehicle was continuously delivered for the four weeks using a subcutaneously implanted osmotic minipump. The density of goblet cells, other morphological changes, and airway responsiveness to methacholine were evaluated 24 hours after the final challenge. Results-Treatment with salbutamol induced a more than twofold increase in the mean (SE) number of goblet cells (53.7 (7.3) vs 114.5 (11.8) cells/10(3) epithelial cells, p<0.01) while it did not significantly influence airway wall thickening and eosinophilic infiltration. Airway responsiveness to methacholine expressed as the logarithmic value of the concentration of methacholine required to generate a 50% increase in airway pressure (logPC(150)Mch) was also enhanced by the <beta>(2) agonist (-0.56 (0.21) vs -0.95 (0.05), p<0.05). Additional experiments revealed that the same dose of the <beta>(2) agonist alone did not cause GCH in non-immunised rats and that the enhancement of GCH by salbutamol was completely abolished by simultaneous treatment with methylprednisolone (0.5 mg/kg/day). Conclusions-These data suggest that salbutamol enhances goblet cell hyperplasia and airway hyperresponsiveness in this rat model of atopic asthma.
• Effect of an oral β2-adrenoceptor agonist in a patient with idiopathic interstitial pneumonia

  T. Takahashi, Y. Nasuhara, K. Takamura, Y. Kawakami  Allergology International  50-  (1)  109  -111  2001  [Refereed][Not invited]
   

  A 63-year-old man was referred to our hospital because of a dry cough. His chest roentgenogram revealed ground-glass opacities and honeycomb formations bilaterally in the lower lung fields. Pulmonary function tests showed a depleted lung volume and decreased arterial oxygen tension. He was clinically diagnosed as having idiopathic interstitial pneumonia (IIP). A β2-adrenoceptor agonist was administrated because the patient's symptoms improved after its inhalation. Following treatment with an oral β2-adrenoceptor agonist, the dry cough disappeared, lung function tests remained unchanged and an improvement in arterial oxygen tension was observed. Although β2-adrenoceptor agonist therapy does not improve disease activity or progression in patients with IIP, its use may mitigate symptoms associated with the disease.
• Kamachi,A., Munakata,M., Nasuhara,Y., Nishimura,M., Ohtsuka,Y., Kawakami,Y.:"Enhancement of gblet cell hyperplasia and airway hypereponsiveness by salbutamol in a rat model of atopic asthma", Thorax,56:19-24(2001)*

  2001  [Refereed][Not invited]
  
• p38 MAP kinase and MKK-1 co-operate in the generation of GM-CSF from LPS-stimulated human monocytes by an NF-kappa B-independent mechanism

  KK Meja, PM Seldon, Y Nasuhara, K Ito, PJ Barnes, MA Lindsay, MA Giembycz  BRITISH JOURNAL OF PHARMACOLOGY  131-  (6)  1143  -1153  2000/11  [Refereed][Not invited]
   

  1 The extent to which the p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK)-1-signalling pathways regulate the expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) from LPS-stimulated human monocytes has been investigated and compared to the well studied cytokine tumour necrosis factor-alpha (TNF alpha). 2 Lipopolysaccharide (LPS) evoked a concentration-dependent generation of GM-CSF from human monocytes. Temporally, this effect was preceded by an increase in GM-CSF mRNA transcripts and abolished by actinomycin D and cycloheximide. 3 LPS-induced GM-CSF release and mRNA expression were associated with a rapid and time-dependent activation of p38 MAP kinase, ERK-1 and ERK-2. 4 The respective MKK-1 and p38 MAP kinase inhibitors, PD 098059 and SE 203580, maximally suppressed LPS-induced GM-CSF generation by >90%, indicating that both of these signalling cascades co-operate in the generation of this cytokine. 5 Electrophoretic mobility shift assays demonstrated that LPS increased nuclear factor kappaB (NF-kappaB):DNA binding. SN50, an inhibitor of NF-kappaB translocation, abolished LPS-induced NF-kappaB:DNA binding and the elaboration of TNF alpha, a cytokine known to be regulated by NF-kappaB in monocytes. In contrast, SN50 failed to affect the release of GM-CSF from the same monocyte cultures. 6 Collectively, these results suggest that the generation of GM-CSF by LPS-stimulated human monocytes is regulated in a co-operative fashion by p38 MAP kinase- and MKK-1-dependent signalling pathways independently of the activation of NF-kappaB.
• Extracellular signal-regulated kinase 1/2 control Ca2+-independent force development in histamine-stimulated bovine tracheal smooth muscle

  A Koch, Y Nasuhara, PJ Barnes, MA Lindsay, MA Giembycz  BRITISH JOURNAL OF PHARMACOLOGY  131-  (5)  981  -989  2000/11  [Refereed][Not invited]
   

  1 The role of extracellular signal-regulated kinase (ERK)-1 and ERK-2 in controlling histamine-induced tone in bovine trachealis was investigated. PD 098059, an inhibitor of mitogen-activated protein kinase kinase (MKK)-1, had no effect on the histamine concentration-response relationship that described contraction. However, in the presence of EGTA, PD 098059 produced a parallel 5 fold rightwards shift of the histamine concentration-response curve without reducing the maximum response. The Pz-adrenoceptor agonist, procaterol, also displaced the histamine-concentration response curve to the right but the effect was much greater than that evoked by PD 098059, noncompetitive and seen in the absence and presence of EGTA. 2 A low basal level of pERK-1 and pERK-2 was always detected in untreated trachealis, which was significantly higher in EGTA-treated tissues and inhibited by PD 098059 and procaterol. Histamine markedly enhanced the phosphorylation of ERK-1 and ERK-2 by a mechanism that was also enhanced by EGTA and significantly attenuated by procaterol and PD 098059. 3 Neither cholera toxin nor Sp-8-Br-cAMPS mimicked the ability of procaterol to dephosphorylate ERK. Similarly, neither pertussis toxin (PTX) nor Rp-8-Br-cAMPS, an inhibitor of cyclic AMP-dependent protein kinase (PKA), affected basal pERK levels or antagonized the inhibitory effect of procaterol. 4 These data implicate the MKK-1/ERK signalling cascade in Ca2+-independent, histamine-induced contraction of bovine trachealis. In addition, the ability of procaterol to dephosphorylate ERK in an Rp-8-Br-cAMPS- and PTX-insensitive manner suggests that this may contribute to the anti-spasmogenic activity of beta (2)-adrenoceptor agonists by activating a novel PKA-independent pathway.
• Hisada,T., Salmon,M., Nasuhara,Y., Chung,KF. "Involvement of haemooxygenase-1 in ozone-induced airway inflammation and hyperresponsiveness",Eur J Pharmacol, 399:229-234(2000)*

  2000  [Refereed][Not invited]
  
• Cysteinyl-leukotrienes partly mediate eotaxin-induced bronchial hyperresponsiveness and eosinophilia in IL-5 transgenic mice

  T Hisada, M Salmon, Y Nasuhara, KF Chung  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  160-  (2)  571  -575  1999/08  [Refereed][Not invited]
   

  Eotaxin, a selective chemoattractant for eosinophils, induces lung eosinophilia and bronchial hyperresponsiveness (BHR) when administered intratracheally to interleukin-5 (IL-5) transgenic mice. We determined whether these effects of eotaxin were mediated through the production of cysteinyl-leukotrienes. IL-5 transgenic mice were administered eotaxin (5 mu g) intratracheally after pretreatment with either diluent or a selective 5-lipoxygenase inhibitor SB210661 or a cysteinyl-leukotriene receptor antagonist, pranlukast. Twenty-four hours later, bronchial responsiveness to acetylcholine was measured and the degree of eosinophil influx was determined in bronchoalveolar lavage fluid (BALF) or in lung tissue. Both pranlukast and 5B210661 significantly attenuated BHR induced by eotaxin with logPC(50), which is the concentration of acetylcholine needed to increase baseline insufflation pressure by 50%, from -0.43 +/- 0.16 to 0.39 +/- 0.10 and from -0.22 +/- 0.10 to 0.53 +/- 0.10, respectively (p < 0.05). There was also a significant attenuation of the eosinophil counts in BALF and in airways. BALF levels of leukotriene C-4 (LTC4) showed a significant increase after eotaxin from 23.9 +/- 6.7 to 165.0 +/- 35.0 pg/ml (p < 0.05) but were partially suppressed by both SB210661 (71.2 +/- 21.0) and pranlukast (62.7 +/- 11.5). Concentrations of LTB4 were not significantly changed. We conclude that eotaxin-induced effects in the airways of IL-5 transgenic mice are partly mediated by the activation of 5-lipoxygenase enzyme leading to the generation of cysteinyl-leukotrienes.
• Ligand-induced differentiation of glucocorticoid receptor (GR) trans-repression and transactivation: preferential targetting of NF-kappa B and lack of I-kappa B involvement

  IM Adcock, Y Nasuhara, DA Stevens, PJ Barnes  BRITISH JOURNAL OF PHARMACOLOGY  127-  (4)  1003  -1011  1999/06  [Refereed][Not invited]
   

  1 Glucocorticoids are highly effective in controlling chronic inflammatory diseases, such as asthma and rheumatoid arthritis, but the exact molecular mechanism of their anti-inflammatory action remains uncertain. They act by binding to a cytosolic receptor (GR) resulting in activation or repression of gene expression. This may occur via direct binding of the GR to DNA (transactivation) or by inhibition of the activity of transcription factors such as AP-1 and NF-kappa B (transrepression). 2 The topically active steroids fluticasone propionate (EC50 = 1.8 x 10(-11) M) and budesonide (EC50 = 5.0 x 10(-11) M) were more potent in inhibiting GM-CSF release from A549 cells than tipredane (EC50 = 8.3 x 10(-10) M), butixicort (EC50 = 3.7 x 10(-8) M) and dexamethasone (EC50 = 2.2 x 10(-9) M). The anti-glucocorticoid RU486 also inhibited GM-CSF release in these cells (IC50 = 1.8 x 10(-10) M). 3 The concentration-dependent ability of fluticasone propionate (EC50 = 9.8 x 10(-10) M), budesonide ;(EC50 = 1.1 x 10(-9) M) and dexamethasone (EC50 = 3.6 x 10(-8) M) to induce transcription of the beta(2)-receptor was found to correlate with GR DNA binding and occurred at 10-100 fold higher concentrations than the inhibition of GM-CSF release. No induction of the endogenous inhibitors of NF-kappa B, I kappa B alpha or I-kappa B beta, was seen at 24 h and the ability of IL-1 beta to degrade and subsequently induce I kappa B alpha was not altered by glucocorticoids. 4 The ability of fluticasone propionate (IC50 = 0.5 x 10(-11) M), budesonide (IC50 = 2.7 x 10(-11) M), dexamethasone (IC50 = 0.5 x 10(-9) M) and RU486 (IC50 = 2.7 x 10(-11) M) to inhibit a 3 x kappa B was associated with inhibition of GM-CSF release. 5 These data suggest that the anti-inflammatory properties of a range of glucocorticoids relate to their ability to transrepress rather than transactivate genes.
• Hisada,T., Adcock,I.M., Nasuhara,Y., Salmon,M., Huang,T.J., Chung,K.F.: "Inhibition of ozone-induced lung neutrophilia and nuclear factor-kappa B binding activity by vitamin A in rat", Eur.J.Pharmacol., 377:63-68 (1999)*

  1999  [Refereed][Not invited]
  
• Nasuhara,Y., Adcock,I.M., Catley,M., Barnes,P.J., Newton,R.: "Differential IkB kinase activation and IkBa degradation by interleukin-1b and tumor necrosis factor-a in human U937 monocytic cells", J.Biol.Chem., 274:571-575 (1999)*

  1999  [Not refereed][Not invited]
  

Association Memberships

• 日本結核・非結核性抗酸菌症学会   JAPAN SOCIETY FOR HEALTH CARE MANAGEMENT   医療の質・安全学会   日本内科学会   日本呼吸器学会   日本感染症学会   American College of Physicians   

Works

• 第61回日本アレルギー学会秋季学術大会

  2011
• 第51回日本呼吸器学会学術講演会4

  2011
• 第51回日本呼吸器学会学術講演会3

  2011
• 第51回日本呼吸器学会学術講演会2

  2011
• 第51回日本呼吸器学会学術講演会1

  2011
• 第60回日本アレルギー学会秋季学術大会

  2010
• 第257回日本内科学会北海道地方会

  2010
• 第255回日本内科学会北海道地方会

  2010
• 第50回日本呼吸器学会学術講演会3

  2010
• 第50回日本呼吸器学会学術講演会1 English mini symposium

  2010
• 第107回日本内科学会総会

  2010
• 第50回日本呼吸器学会学術講演会2 教育講演10

  2010
• 第50回日本呼吸器学会学術講演会4

  2010
• 第99回日本呼吸器学会北海道地方会

  2010
• 第254回日本内科学会北海道地方会

  2010
• 第2回呼吸機能イメージング2

  2010
• 第2回呼吸機能イメージング研究会1

  2010
• 第252回日本内科学会北海道地方会発表

  2009
• 第251回日本内科学会北海道地方会発表

  2009
• 第49回日本呼吸器学会学術講演会発表 5

  2009
• 第49回日本呼吸器学会学術講演会発表 4

  2009
• 第49回日本呼吸器学会学術講演会発表 3

  2009
• 第49回日本呼吸器学会学術講演会発表 2

  2009
• 第49回日本呼吸器学会学術講演会発表 1

  2009
• 第250回日本内科学会北海道地方会発表 2

  2009
• 第250回日本内科学会北海道地方会発表 1

  2009
• 第97回日本呼吸器学会北海道地方会発表 2

  2009
• 第97回日本呼吸器学会北海道地方会発表 1

  2009

Research Projects

• 人工知能技術を利用した医用画像診断支援システムの倫理リスクマネジメント手法の研究

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2020/04 -2021/03 

  Author : 平田 雄一, 平田 健司, 南須原 康行, 白土 博樹

   

  本研究は、将来的に重要性が増すと予想される人工知能技術を利用した医用画像診断支援システムの倫理リスクを具体化するための新しいリスクマネジメント手法の構築を試み、人工知能技術を利用した医用画像診断支援システムの倫理リスクの低減策の検討を詳細に深く行えるようにすることを目的とした。 具体的には、本研究では、医学物理学の放射線治療分野や放射線安全管理分野において、既に活用されている複雑なシステムを、システムの要素(コンポーネント)間の入力と出力により決定される制御関係の安全性に着目して解析する安全解析手法であるSTAMP(System Theoretic Accident Model and Processes)を、人工知能技術を利用した医用画像診断支援システムの倫理リスクのリスクマネジメントに応用した。 2020年度は、新しい倫理リスク・マネジメント・モデルを、医用画像に関する倫理リスク事項のネットワークを高速に処理するために本研究で購入した高速データ処理が可能な高性能ワークステーション上に実装されたSTAMPのモデリングツールであるSTAMP Workbenchを基盤とした新しい倫理リスク・モデリング・システムにより構築した。 その結果、本研究で構築した、STAMP Workbenchを基盤とした、人工知能技術を利用した医用画像診断支援システムの新しい倫理リスクマネジメント手法は、放射線治療における事故防止のための強力なツールとなりえることが明らかになった。 そして、日本放射線腫瘍学会第33回学術大会において、本研究の分担者全員と共同して上記研究結果を発表した。
• Continuous training system for developing highly competent endoscopic surgeons

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2017/04 -2020/03 

  Author : Abe Takashige

   

  We develop a wet-lab training model for learning laparoscopic surgical skills and evaluating learners’ competency level outside the operating room, using swine organs. 45 participants (experts [≧50 laparoscopic surgeries]: n=13, intermediates [11-49]: n=8, novices [0-10]: n=33) completed 3 tasks (Task 1: tissue dissection around aorta, Task 2: tissue dissection and divide renal artery, Task 3: renal parenchymal closure). Each performance was video-recorded and later evaluated by two experts, according to Global Operative Assessment of Laparoscopic Skills. We observed good construct validity in all 3 tasks. The subjective mental workload was also assessed (NASA Task Load Index [NASA-TLX]), and higher NASA-TLX scores were observed in novices. We also evaluated the validity of the laparoscopic radical nephrectomy module of the LapVision virtual reality simulator. 33 subjects performed training, and we observed good construct validities for the nephrectomy module.
• Building the high-reliability surgical team by use of previous medical incidents reports

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2014/04 -2017/03 

  Author : Abe Takashige

   

  Using the relevant key words with minimum invasive surgeries, 540 records were identified in the database of the Japan Council for Quality Health Care. After data review and the classification of adverse events, 746 events associated with laparoscopic (laparo-group) and/or thoracoscopic (thoraco-group) surgery were identified. There were 582 events in the laparo-group, 159 in the thoraco-group, and 5 in those undergoing a combined surgery. Overall, injury of other organs, retention of a foreign body, breakage/failure of medical equipment or devices, massive bleeding, misperception of anatomy, and vascular injurywere frequently reported. There were marked differences in the frequency of injury of other organs, massive bleeding, and vascular injury.
• Associations of TF and F7 with pathogenesis of asthma and COPD

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2011 -2013 

  Author : KONNO Satoshi, ISADA Akira, NASUHARA Yasuyuki

   

  Levels of tissue factor(TF) and factor7 in BALF were signnificantly increased after OVA challenge in two murine models of asthma (acute and chronic models). Intraperitoneal administration of TF-factor7 inhibitor significantly decreased the number of eosinophils in BALF, OVA-IgE levels in serum and bronchial hyperresponsiveness in these moedels, suggesting the potential of TF-factor7 as a novel therapeutic target for asthma treatment. In genetic studies, we conducted case (asthma)-control studies for several genes related with coagulation cascade, including TF,F2R,CC16 and CAT and significant associations of several SNPs in these genes and asthma were identified.
• Dehydroxymethylepoxyquinomicin(DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodeling in murine models of asthma

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2009 -2011 

  Author : NISHIMURA Masaharu, TODO Satoru, NASUHARA Yasuyuki, KONNO Satoshi

   

  DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in murine asthma model. It also inhibited parameters of airway remodeling including mucus production, peribronchial fibrosis and the expression ofα-smooth muscle actin. These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodeling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.
• Understanding the pathogenesis of severe airway diseases by large cohort studies

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2009 -2011 

  Author : NISHIMURA Masaharu, KONNO Satoshi, NASUHARA Yasuyuki, MAKITA Hironi

   

  The rate of annual change in post-bronchodilator FEV1 is highly variable over a period of 5 years among patients with COPD who receive appropriate therapy. Emphysema severity, which varies substantially even for the same spirometric stage, is independently associated with a rapid annual decline in FEV1. The presence of sustainers, who can maintain pulmonary function, warrants specific attention together with rapid decliners in clinical practice.
• The effect of aging and smoking on the phagocytosis of apoptotic cells in alveolar macrophages

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2008 -2010 

  Author : NASUHARA Yasuyuki, ITO Yoko, BETSUYAKU Tomoko

   

  Our aims of this study are to examine expressions of various receptors for recognition and/or clearance of apoptotic cells on macrophages and assess the relationship with aging and/or smoking. The expression of phosphatidylserine receptor (PSR) and scavenger receptor A (SR-A) in alveolar macrophages was downregulated in smokers when compared to lifelong non-smokers only in the older subjects, but not in younger subjects. The expression of PSR is elevated on U937-derived macrophage like cells if these are incubated in CSE. The cigarette smoke extract-induced upregulation of PSR was inhibited by the vascular endothelial growth factor (VEGF) receptor blockade, SU5614, in U937-derived macrophage-like cells. These results showed that VEGF was indirectly associated with the ability to phagocytose apoptotic cells through the expression of PSR.
• New challenges to chronic airway diseases-pathogenesis, diagnosis and treatment-

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2007 -2008 

  Author : NISHIMURA Masaharu, HIZAWA Nobuyuki, BETSUYAKU Tomoko, NASUHARA Asuyuki

   

  難治性の気道疾患という観点から慢性閉塞性肺疾患(Chronic obstructive pulmonary disease : COPD)と気管支喘息をとらえ、その克服をめざしたものである。近年、酸化ストレスが、COPD、気管支喘息の病態に様々な形で関与すると考えられており、具体的には1)治療標的の特定を目指す病態の解明、2)低侵襲的気道病態の評価法の開発(新規酸化ストレスバイオマーカー・3次元的気道画像解析)、3)抗酸化剤治療介入へ向けての基礎的研究、4)北海道COPDコホート研究という4つのプロジェクトからなる。
• 3次元CTによる気腫・気道病変の評価と慢性閉塞性肺疾患病態解析への応用

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2005 -2006 

  Author : 西村 正治, 南須原 康行, 小野寺 裕也

   

  今年度は、3次元画像解析を用いて、以下の3つの検討を行い結果を得た。1)以前から検討してきた右上葉肺尖枝B1と下葉前下行枝B8の2本の気管支に加えて、各部位より複数の枝(上葉3本、中葉2本、下葉3本)を測定し、COPD患者における気道病変の均一性の検討を行った。測定評価については、昨年度と同様に3次から6次分枝にかけて中枢から末梢にかけて気道の壁面積比(WA%)を検討した。多くの気管支を調べた結果、末梢の6次では中枢の3次に比べてlobeによるばらつきが少なく、我々が今まで検討していたB1,8の2本が特に末梢の6次に関しては他の気管支の6次の病変を十分に反映しているものと考えられた。2)-950HUを閾値にして気腫病変を立体的に定量評価し、さらに気腫病変を上肺、中肺、下肺と分割することにより、COPDにおける局所における気腫病変と気流制限および気道病変の関係について検討を行った。気流制限の程度は、上肺の気腫とは全く相関は見られなかったが、下肺の気腫とは強い相関が見られた。一方、上肺の気腫は同じく上肺の気道病変とは相関が見られなかったが、下肺の気腫と下肺の末梢気道病変に相関が見られ、下肺の気腫病変の進展と末梢気道病変の進行は、パラレルに進むことが考えられた。3)COPDにおける、気管支拡張薬(チオトロピウム)の気道への影響を3次元画像解析にて検討した。吸入による気流制限の改善の程度は、全体として気道内腔面積の改善の程度と相関し、その関係は3次、4次よりも5次、6次といったより末梢の気道内腔面積の改善と強い相関が見られた。
• Role of basigin/EMMPRIN in lung epithelial cell injuries and repair and the mechanism of MMP induction

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2005 -2006 

  Author : BETSUYAKU Tomoko, NASUHARA Yasuyuki

   

  Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycosylated transmembrane protein that induces matrix metalloproteinases (MMPs), is minimally expressed in the normal adult lung. We previously reported that it is upregulated in murine bleomycin-induced lung injury. In this study, we determined the expression of EMMPRIN and its association with MMPs-2,-7, and-9 in interstitial pneumonias (IPs). We performed immunohistochemistry for EMMPRIN and MMPs on lung tissue from 22 subjects with various IPs. We did bronchoalveolar lavage (BAL) on 9 of these subjects and 13 others with IPs to measure the soluble EMMPRIN in BAL fluid. For comparison, immunohistochemistry or BAL was done on 14 subjects without IPs. The staining intensity for each protein was scored from 0 to 3 in various epithelial cell types. Soluble EMMPRIN in BAL fluid was measured by an enzyme-linked immunosorbent assay. EMMPRIN was prominent in abnormal epithelial cells. It was more prominent in hyperplastic type II cells compared to epithelium in alveolar bronchiolization. It was also elevated in BAL fluid from the subjects with IPs. MMPs were expressed in cells expressing EMMPRIN, although the profile of MMPs varied among the different abnormal epithelial cell types with MMP-2 and MMP-7 in hyperplastic type II cells and MMP-7 and MMP-9 in cells showing squamous metaplasia and cells comprising bronchiolization. These results suggest a role of EMMPRIN in reepithelialization in IPs.
• Integrated research for pathogenesis and epidemiology of chronic obstructive pulmonary disease

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2005 -2006 

  Author : NISHIMURA Masaharu, HIZAWA Nobuyuki, BETSUYAKU Tomoko, NASUHARA Yasuyuki, ONODERA Yuya

   

  Epidemiological evidence suggests that cigarette smoking and aging are the two major risk factors for the development of chronic obstructive pulmonary disease (COPD). The molecular mechanism is poorly understood, in which the pathophysiology of COPD is involved. Respiratory tract is the major interface to the environment and the lung epithelium and alveolar macrophages are the first line of defense against cigarette smoke. We found that cumulative effects of aging and long-term smoking differently affected the accumulation of glutathione disulfide, an oxidized form of glutathione associated with excessive carbonyl proteins in BAL fluid, which might lead to the impaired antioxidant barrier system in the extracellular milieu in alveolar space. The lungs are anatomically complex organs. We first applied laser capture microdissection (LCM) techniques to analyze cell-specific gene expression in the smoking lungs. This study provides the molecular information of bronchiolar epithelium, macrophages, and alveolar septae in the pathogenesis of COPD. The combination of LCM with nucleotide arrays offers exciting discovery of the molecular responses of different lung cells to smoke exposure. We especially focus on the groups of genes controlling the defense mechanism, regulating the inflammation, and contributing to the maintenance of lung structure, which is related to cell apoptosis and repair. The cell-specific gene expression profile in COPD patients as well as in smoking mice could open the possibilities for the development of new therapeutic strategies, considering targeted site and the delivery of drugs.
• Internal factors in inflammatory respiratory diseases

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2002 -2004 

  Author : NASUHARA Yasuyuki, HIZAWA Nobuyuki, BETSUYAKU Tomoko, NISHIMURA Masaharu

   

  We performed the study to examine whether the 109C/T FcεRIβ promoter polymorphism influences the genetic effects of the functional polymorphism (4G/5G) at the PAI-1 promoter region on asthma susceptibility using a case-control analysis. Individuals homozygous for both the FcεRIβ-109T allele and the PAI-1 5G allele had a reduced susceptibility to asthma ; the odds ratio associated with the PAI-1 5G/5G genotype was 1.14 (p=0.72) in carriers of the FcεRIβ-109C allele, 0.29 (p=0.00023) in carriers of the FcεRIβ-109T/T genotype compared to individuals carrying the FcεRIβ-109T/T genotype and the PAI-1 4G allele. The regression model also showed an interaction between FcεRIβ and PAI-1 genotypes on asthma (p for interaction=0.0017). The present findings suggest a synergistic interaction between FcεRIβ and PAI-1 genes in asthma susceptibility. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were IL-8, MIP-1α, and MCP-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never smokers or smokers without either airflow limitation or emphysema. cDNA array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory cytokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase-polymerase chain reaction and cDNA microarrays, to investigate functional profiles of indivisual structural and inflammatory cells in human lungs.
• 難治性気管支喘息の病因解明と抗マクロファージ遊走阻止因子抗体による治療の試み

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2000 -2001 

  Author : 西村 正治, 南須原 康行, 西平 順

   

  ・抗MIF抗体のアトピー型気管支喘息モデルに対する効果 昨年度は,BNラットを卵白アルブミンで感作したアトピー型気管支喘息モデルにおいて,1)吸入誘発後の肺胞洗浄液中のMIF濃度は,未処置群に比して有意に上昇していた,2)坑MIF抗体は卵白アルブミンによる特異的気道収縮を著明に抑制した.3)抗MIF抗体は肺胞洗浄液中の総細胞数はを有意に減少した,その分画の検討において,この減少は主に好酸球と好中球の減少によることが判明した,4)感作ラットでは卵白アルブミンに対する特異的IgGが上昇するが,抗MIF抗体はその上昇には影響を与えなかった,との結果を得た.これらの結果より,抗MIF抗体はアトピー型喘息モデルにおいて,特異的IgEの産生には影響を与えないが,特異的気道収縮および気道炎症を抑制することが示唆された. 今年度はさらに, 1)抗MIF抗体は,メサコリンに対する気道反応つまり非特異的気道収縮を抑制した. 2)吸入後の肺組織を用いて,定量的real time PCR法により,好酸球の走化因子であるエオタキシンの発現を検討した結果,抗MIF抗体はエオタキシンの発現を抑制した. との結果を得た.現在,好中球の走化因子であるCINCについて肺胞洗浄液を用いて,抗MIF抗体の効果を検討中である.さらに,今後は肺組織標本を用いて,MIF発現部位,時間的推移などについて更なる検討を加える予定である.
• Identification of Genes for High IgE responsiveness in Chromosomes 5q31 and 11q13

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 1998 -2000 

  Author : YAMAGUCHI Etsuro, NASUHARA Yasuyuki, ITOH Akihide

   

  (1) We found a C to T change, novel single nucleotide polymorphism at position -109 in the promoter region of high affinity receptor for Fc portion of IgE.There was no significant difference in the distribution of this polymorphism between patients with asthma and healthy controls. However, asthmatic patients homozygous for allele T had significantly higher total serum IgE levels (p=0.0015) than those with other genotypes (TC or CC). When ages at asthma onset were taken into account, the effects polymorphism on serum total IgE became more evident (p=0.0004). (2) We have also found a novel polymorphism (+33C/T) in the untranslated region of the IL-4 gene. The allele frequencies of T in asthmatic patients and healthy controls were 0.675 and 0.671, respectively, and there was no significant difference between the two groups. Meanwhile, individuals with genotype CT or CC in all study subjects or asthmatic patients had significantly higher serum total IgE levels, even when corrected for sex and ages compared with those with genotype CC. (3) We analyzed the interaction of two aforementioned single nucleotide polymorphisms (SNP) on serum total IgE levels. The effects of the two SNP in asthmatic patients seemed to be dependent on genotypes of each SNP. (4) We found no significant differences in the frequencies of two aforementioned SNP between patients with atopic dermatitis and healthy controls, thus indicating that these gene polymorphisms did not contribute to the development of the disease. Also, the two SNP did not correlate with serum total IgE levels in patients with atopic dermatitis. Therefore, we concluded that gene polymorphisms or environmental factors other than genes for high affinity IgE Fc receptor or IL-4 had greater impact on the interindividual differences in increased levels of serum total IgE in patients with atopic dermatitis. (5) We have found SNPs without amino acid changes at positions 287 and 1353 downstream from a translation initiation site of the muscarinic receptor M1 gene. A case-control study on the polymorphisms revealed that the frequency of genotype CC in patients with asthma was significantly higher than healthy controls, thus suggesting that M1 receptor gene may affect the occurrence of asthma independently of atopy.
• 特発性間質性肺炎の進展予防