Nasuhara Yasuyuki

Hokkaido University Hospital Division of Hospital Safety ManagementProfessor
Last Updated :2025/06/13

■Researcher basic information

Researchmap personal page

Research Keyword

  • patient safety
  • 呼吸器内科学

Research Field

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

Educational Organization

■Career

Career

  • Apr. 2025 - Present
    Hokkaido University, Hokkaido University Hospital, Division of Safety Management, Prosessor, Director l
  • Apr. 2019 - Mar. 2025
    Hokkaido University, Hokkaido University Hospital, Division of Safety Management, Director, Vice Director of Hokkaido University Hospital
  • Jul. 2017 - Mar. 2019
    Hokkaido University, Hokkaido University Hospital, Division of Safety Management, Prosessor
  • Apr. 2008 - Jun. 2017
    Hokkaido University, Hokkaido University Hospital, Division of Safety Management, Associate Professor
  • 2005
    - 北海道大学病院 講師
  • 2005
    - Lecturer

Educational Background

  • Mar. 1988 - Present, Hokkaido University, School of Medicine

Position History

  • 北海道大学病院副病院長, 2019年4月1日 - 2022年3月31日
  • 北海道大学病院副病院長, 2022年4月1日 - 2025年3月31日

■Research activity information

Awards

  • 2005, ベルツ賞               
    Japan

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, 30 Jun. 2023, [International Magazine]
    English, Scientific journal, 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, 07 Feb. 2023, [International Magazine]
    English, 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, Apr. 2022, [International Magazine]
    English, Scientific journal, 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, Mar. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, [Peer-reviewed], [Domestic magazines]
    English, Scientific journal, 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, 18 Nov. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, 21 Jun. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal
  • 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, Mar. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, Dec. 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, Feb. 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, Sep. 2017, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, Sep. 2017, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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.
  • 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, 10 Aug. 2016, [Peer-reviewed], [International Magazine]
    English, Scientific journal
  • 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, 94, 2, 150, 153, Elsevier, 2016, [Peer-reviewed]
    English, Scientific journal, 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, 28 Aug. 2015, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, [Peer-reviewed]
    English, Scientific journal
  • 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, Apr. 2014, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, Sep. 2013, [Peer-reviewed]
    English, Scientific journal
  • 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, Sep. 2012, [Peer-reviewed]
    English
  • 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, 50, 1367, 1371, 8, Aug. 2012, [Peer-reviewed]
  • 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, 10, 111, 111, BioMed Central, Jul. 2012, [Peer-reviewed]
    English, Scientific journal, 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, European Respiratory Society, 01 Mar. 2012, [Peer-reviewed]
    English
  • 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, Mar. 2012, [Peer-reviewed]
    English, Scientific journal
  • 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, Feb. 2012, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, 185, 1, 44, 52, 1, Jan. 2012, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, May 2011, [Peer-reviewed], [Domestic magazines]
    Japanese, Scientific journal, 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, 181, 12, 1345, 1354, 12, Jun. 2010, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, May 2010, [Peer-reviewed], [Domestic magazines]
    Japanese, Scientific journal, 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, 188, 2, 151, 157, 2, Apr. 2010, [Peer-reviewed]
    English, 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, Mar. 2010, [Peer-reviewed], [International Magazine]
    English, Scientific journal, 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, Mar. 2010, [Peer-reviewed], [Domestic magazines]
    Japanese, Scientific journal, 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), 49, 13, 1293, 1296, The Japanese Society of Internal Medicine, 2010, [Peer-reviewed]
    English, 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, Jul. 2009, [Peer-reviewed], [Domestic magazines]
    Japanese, Scientific journal, 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.
  • [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, Dec. 2008, [Peer-reviewed], [Domestic magazines]
    Japanese, Scientific journal, 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, Jan. 2008, [Peer-reviewed]
    English, Scientific journal
  • 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, 132, 5, 1485, 1492, AMER COLL CHEST PHYSICIANS, Nov. 2007, [Peer-reviewed], [International Magazine]
    English, Scientific journal, BACKGROUND: COPD is characterized by a persistent airflow limitation that is not fully reversible; thus, the reversibility of airflow limitations in response to a bronchodilator is an important component of COPD. Several studies have established that two common nonsynonymous polymorphisms in the beta2-adrenergic receptor gene (ADRB2), Arg16Gly and Gln27Glu, have important effects in modulating responses to beta2-agonists; however, the effects of these polymorphisms on responses to beta2-agonists in patients with COPD is unknown. OBJECTIVE: To examine whether different genotypes at these two polymorphisms are related to differential responses to inhaled beta2-agonists in patients with COPD. DESIGN AND PARTICIPANTS: A total of 246 patients with COPD who were participants in a longitudinal study of COPD (ie, the Hokkaido COPD cohort study) were studied. We compared short-term bronchodilator responses (BDRs) to salbutamol according to ADRB2 genotypes at codons 16 and 27. RESULTS: The presence of the Arg16 allele was associated with lower BDRs to beta2-agonist inhalation. The mean (+/-SD) log (postbronchodilator FEV1-prebronchodilator FEV1) values of Gly16 homozygotes (n=65), Arg16Gly16 heterozygotes (n=106), and Arg16 homozygotes (n=75) were 2.19+/-0.43, 2.09+/-0.42, and 2.01+/-0.42, respectively (p<0.05). The genetic effects of the Arg16Gly polymorphism were independent of the severity of airflow limitation, age, and smoking status. The most common Arg16-Gln27 haplotype was also significantly associated with decreased BDRs to salbutamol (p<0.01). CONCLUSION: The genetic effects of ADRB2 gene polymorphisms may explain some of the variability in response to therapeutic doses of a short-acting beta2-agonists in patients with COPD.
  • 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, 2007, [Peer-reviewed]
    English, Scientific journal
  • [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, 95, 7, 1362, 1364, 7, Jul. 2006, [Peer-reviewed]
    Japanese, 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, Jun. 2006
    English, Scientific journal
  • Role of macrophage migration inhibitory factor in ovalbumin-induced airway inflammation in rats
    M. Kobayashi, Y. Nasuhara, A. Kamachi, Y. Tanino, T. Betsuyaku, E. Yamaguchi, J. Nishihira, M. Nishimura
    European Respiratory Journal, 27, 4, 726, 734, Apr. 2006
    English, Scientific journal
  • 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, Apr. 2005, [Peer-reviewed]
    English, Scientific journal
  • 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, Dec. 2004
    English, Scientific journal
  • 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, Oct. 2004, [Peer-reviewed]
    English, Scientific journal
  • 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, Jun. 2004
    English, Scientific journal
  • 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, Apr. 2004, [Peer-reviewed]
    English, Scientific journal
  • [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, 42, 158, 163, 2, Feb. 2004, [Peer-reviewed]
  • 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, 2004, [Peer-reviewed]
    Japanese, Scientific journal
  • 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, Jul. 2003, [Peer-reviewed]
    English, Scientific journal
  • Dissociation between airway responsiveness to methacholine and responsiveness to antigen
    A. Kamachi, Y. Nasuhara, M. Nishimura, T. Takahashi, Y. Homma, Y. Ohtsuka, M. Munakata
    European Respiratory Journal, 19, 1, 76, 83, 2002
    English, Scientific journal
  • 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, Jul. 1999
    English, Scientific journal
  • 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, Mar. 1999
    English
  • Intravascular lymphomatosis diagnosed by transbronchial lung biopsy
    K. Takamura, Y. Nasuhara, T. Mishina, T. Matsuda, M. Nishimura, Y. Kawakami, M. Fujita, C. Mikuni, K. Yamashiro
    European Respiratory Journal, 10, 4, 955, 957, European Respiratory Society, 1997
    English, Scientific journal
  • Meanings of the clinical parameters of airway hyperresponsiveness
    M. Munakata, Y. Nasuhara, A. Sato, T. Takahashi, R. Sato, Y. Homma, Y. Kawakami
    Japanese Journal of Thoracic Diseases, 34, 42, 47, 1996
    Japanese, International conference proceedings

Other Activities and Achievements

Affiliated academic society

  • 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               

Research Themes

  • 医療機関内の医療事故の機能的な報告体制の構築のための研究               
    厚生労働行政推進調査事業費補助金 地域医療基盤開発推進研究事業
    Apr. 2023 - Mar. 2025
    木村壮介, 宮田哲郎, 後信, 南須原康行, 秋元菜穂子
    厚生労働省, 医療事故の機能的な報告体制の構築, 一般社団法人 日本医療安全調査機構, Coinvestigator, 22IA1004
  • 院内の医療安全管理体制を定量的に評価する指標の確立と実装を行う研究               
    厚生労働行政推進調査事業補助金 地域医療基盤開発推進研究事業
    Apr. 2022 - Mar. 2024
    長尾能雅, 大川淳, 遠山信幸, 南須原康行, 兼児敏浩, 浦松雅史, 平松真理子, 梅村朋, 植村政和
    厚生労働省, これまでの研究成果を基に医療安全評価指標を確立し、試験的な導入を経て本格的な社会実装に向けた検証を行う, 名古屋大学医学部附属病院, Coinvestigator, 22IA002
  • 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
    科学研究費助成事業
    01 Apr. 2020 - 31 Mar. 2021
    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。
    日本学術振興会, 基盤研究(C), 北海道大学, 20K12708
  • Continuous training system for developing highly competent endoscopic surgeons
    Grants-in-Aid for Scientific Research
    01 Apr. 2017 - 31 Mar. 2020
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 17K08897
  • 医療安全管理体制の可視化と人材育成のための研究               
    厚生労働科学研究補助金 地域医療基盤開発推進研究事業
    Apr. 2018 - Mar. 2020
    長尾能雅, 遠山信幸, 南須原康行, 兼児敏浩, 新井有美, 浦松雅史, 田辺公一, 深見達弥, 植村政和, 梅村朋
    厚生労働省, 名古屋大学医学部附属病院, Coinvestigator
  • Building the high-reliability surgical team by use of previous medical incidents reports
    Grants-in-Aid for Scientific Research
    01 Apr. 2014 - 31 Mar. 2017
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 26460853
  • Associations of TF and F7 with pathogenesis of asthma and COPD
    Grants-in-Aid for Scientific Research
    2011 - 2013
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 23591110
  • Dehydroxymethylepoxyquinomicin(DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodeling in murine models of asthma
    Grants-in-Aid for Scientific Research
    2009 - 2011
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 21659206
  • Understanding the pathogenesis of severe airway diseases by large cohort studies
    Grants-in-Aid for Scientific Research
    2009 - 2011
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 21390253
  • The effect of aging and smoking on the phagocytosis of apoptotic cells in alveolar macrophages
    Grants-in-Aid for Scientific Research
    2008 - 2010
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 20590890
  • New challenges to chronic airway diseases-pathogenesis, diagnosis and treatment-
    Grants-in-Aid for Scientific Research
    2007 - 2008
    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。
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 19390221
  • 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
    科学研究費助成事業
    2005 - 2006
    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。
    日本学術振興会, 萌芽研究, 北海道大学, 17659242
  • Role of basigin/EMMPRIN in lung epithelial cell injuries and repair and the mechanism of MMP induction
    Grants-in-Aid for Scientific Research
    2005 - 2006
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), HOKKAIDO UNIVERSITY, 17590772
  • Integrated research for pathogenesis and epidemiology of chronic obstructive pulmonary disease
    Grants-in-Aid for Scientific Research
    2005 - 2006
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), HOKKAIDO UNIVERSITY, 17390239
  • Internal factors in inflammatory respiratory diseases
    Grants-in-Aid for Scientific Research
    2002 - 2004
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), HOKKAIDO UNIVERSITY, 14370193
  • 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
    科学研究費助成事業
    2000 - 2001
    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.
    日本学術振興会, 萌芽的研究, 北海道大学, 12877091
  • Identification of Genes for High IgE responsiveness in Chromosomes 5q31 and 11q13
    Grants-in-Aid for Scientific Research
    1998 - 2000
    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.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (A)., HOKKAIDO UNIVERSITY, 10307013
  • 特発性間質性肺炎の進展予防               
    Competitive research funding