Updated on 2024/04/08

写真a

 
TANAKA Taku
 
Organization
Nagoya University Hospital Emergency and Medical Intensive Care Unit Assistant Professor
Title
Assistant Professor

Degree 2

  1. 学士(医学) ( 2007.3   岐阜大学 ) 

  2. PhD ( 2021.1   Nagoya University ) 

Research Interests 1

  1. 急性肝不全

Research Areas 3

  1. Life Science / Gastroenterology

  2. Life Science / Emergency medicine

  3. Life Science / Emergency medicine

Current Research Project and SDGs 1

  1. acute liver failure

Research History 4

  1. Nagoya University   Assistant professor of hospital

    2021.4

  2. Nagoya University   Graduate School of Medicine Emergensy and medical Intensive Care Unit   Assistant professor of hospital

    2020.4

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    Country:Japan

  3. Nagoya University   Gastroenterology and Hepatology

    2016.7 - 2020.3

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    Country:Japan

  4. Gifu University   Researcher

    2007.6 - 2008.3

Education 2

  1. Nagoya University

    2016.4 - 2020.3

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    Country: Japan

  2. Gifu University   Faculty of Medicine

    2001.4 - 2007.3

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    Country: Japan

Professional Memberships 12

  1. 日本肝臓学会   肝臓専門医

  2. 日本消化器内視鏡学会   消化器内視鏡専門医

  3. 日本消化器病学会   消化器病専門医

  4. 日本集中治療医学会   会員

  5. 日本内科学会   総合内科専門医

  6. 日本救急医学会   救急科専門医

  7. 日本急性血液浄化学会   会員

  8. 日本肝癌分子標的治療研究会   会員

  9. 日本透析学会   会員

  10. 日本血栓止血学会   会員

  11. 日本呼吸療法医学会   会員

  12. Japanese Society for Abdominal Emergency Medicine

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Papers 11

  1. External validation of the HACOR score and ROX index for predicting treatment failure in patients with coronavirus disease 2019 pneumonia managed on high-flow nasal cannula therapy: a multicenter retrospective observational study in Japan.

    Okano H, Yamamoto R, Iwasaki Y, Irimada D, Konno D, Tanaka T, Oishi T, Nawa H, Yano A, Taniguchi H, Otawara M, Matsuoka A, Yamauchi M

    Journal of intensive care   Vol. 12 ( 1 ) page: 7   2024.2

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    Language:English   Publisher:Journal of Intensive Care  

    Background: The HACOR score for predicting treatment failure includes vital signs and acid–base balance factors, whereas the ROX index only considers the respiratory rate, oxygen saturation, and fraction of inspired oxygen (FiO2). We aimed to externally validate the HACOR score and ROX index for predicting treatment failure in patients with coronavirus disease 2019 (COVID-19) on high-flow nasal cannula (HFNC) therapy in Japan. Methods: This retrospective, observational, multicenter study included patients, aged ≥ 18 years, diagnosed with COVID-19 and treated with HFNC therapy between January 16, 2020, and March 31, 2022. The HACOR score and ROX index were calculated at 2, 6, 12, 24, and 48 h after stating HFNC therapy. The primary outcome was treatment failure (requirement for intubation or occurrence of death within 7 days). We calculated the area under the receiver operating characteristic curve (AUROC) and assessed the diagnostic performance of these indicators. The 2-h time-point prediction was considered the primary analysis and that of other time-points as the secondary analysis. We also assessed 2-h time-point sensitivity and specificity using previously reported cutoff values (HACOR score > 5, ROX index < 2.85). Results: We analyzed 300 patients from 9 institutions (median age, 60 years; median SpO2/FiO2 ratio at the start of HFNC therapy, 121). Within 7 days of HFNC therapy, treatment failure occurred in 127 (42%) patients. The HACOR score and ROX index at the 2-h time-point exhibited AUROC discrimination values of 0.63 and 0.57 (P = 0.24), respectively. These values varied with temporal changes—0.58 and 0.62 at 6 h, 0.70 and 0.68 at 12 h, 0.68 and 0.69 at 24 h, and 0.75 and 0.75 at 48 h, respectively. The 2-h time-point sensitivity and specificity were 18% and 91% for the HACOR score, respectively, and 3% and 100% for the ROX index, respectively. Visual calibration assessment revealed well calibrated HACOR score, but not ROX index. Conclusions: In COVID-19 patients receiving HFNC therapy in Japan, the predictive performance of the HACOR score and ROX index at the 2-h time-point may be inadequate. Furthermore, clinicians should be mindful of time-point scores owing to the variation of the models’ predictive performance with the time-point. Trial registration UMIN (registration number: UMIN000050024, January 13, 2023)

    DOI: 10.1186/s40560-024-00720-8

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  2. Association between loss of hypercoagulable phenotype, clinical features and complement pathway consumption in COVID-19. International journal

    Daisuke Kasugai, Taku Tanaka, Takako Suzuki, Yoshinori Ito, Kazuki Nishida, Masayuki Ozaki, Takeo Kutsuna, Toshiki Yokoyama, Hitoshi Kaneko, Ryo Ogata, Ryohei Matsui, Takahiro Goshima, Hiroshi Hamada, Azusa Ishii, Yusuke Kodama, Naruhiro Jingushi, Ken Ishikura, Ryo Kamidani, Masashi Tada, Hideshi Okada, Takanori Yamamoto, Yukari Goto

    Frontiers in immunology   Vol. 15   page: 1337070 - 1337070   2024

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    Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Coronavirus disease 2019 (COVID-19) features a hypercoagulable state, but therapeutic anticoagulation effectiveness varies with disease severity. We aimed to evaluate the dynamics of the coagulation profile and its association with COVID-19 severity, outcomes, and biomarker trajectories. METHODS: This multicenter, prospective, observational study included patients with COVID-19 requiring respiratory support. Rotational thromboelastometry findings were evaluated for coagulation and fibrinolysis status. Hypercoagulable status was defined as supranormal range of maximum clot elasticity in an external pathway. Longitudinal laboratory parameters were collected to characterize the coagulation phenotype. RESULTS: Of 166 patients, 90 (54%) were severely ill at inclusion (invasive mechanical ventilation, 84; extracorporeal membrane oxygenation, 6). Higher maximum elasticity (P=0.02) and lower maximum lysis in the external pathway (P=0.03) were observed in severely ill patients compared with the corresponding values in patients on non-invasive oxygen supplementation. Hypercoagulability components correlated with platelet and fibrinogen levels. Hypercoagulable phenotype was associated with favorable outcomes in severely ill patients, while normocoagulable phenotype was not (median time to recovery, 15 days vs. 27 days, P=0.002), but no significant association was observed in moderately ill patients. In patients with severe COVID-19, lower initial C3, minimum C3, CH50, and greater changes in CH50 were associated with the normocoagulable phenotype. Changes in complement components correlated with dynamics of coagulation markers, hematocrit, and alveolar injury markers. CONCLUSIONS: While hypercoagulable states become more evident with increasing severity of respiratory disease in patients with COVID-19, normocoagulable phenotype is associated with triggered by alternative pathway activation and poor outcomes.

    DOI: 10.3389/fimmu.2024.1337070

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  3. Proteomic Analysis Reveals Changes in Tight Junctions in the Small Intestinal Epithelium of Mice Fed a High-Fat Diet Reviewed

    Muto, H.; Honda, T.; Tanaka, T.; Yokoyama, S.; Yamamoto, K.; Ito, T.; Imai, N.; Ishizu, Y.; Maeda, K.; Ishikawa, T.; Adachi, S.; Sato, C.; Tsuji, N.M.; Ishigami, M.; Fujishiro, M.; Kawashima, H

    Nutrients     2023.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: https://doi.org/10.3390/nu15061473

  4. ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19 Reviewed International coauthorship International journal

    ISARIC Clinical Characterization Group; Garcia-Gallo E, Merson L, Kennon K, Kelly S, Citarella BW, Fryer DV, Shrapnel S, Lee J, Duque S, Fuentes YV, Balan V, Smith S, Wei J, Gonçalves BP, Russell CD, Sigfrid L, Dagens A, Olliaro PL, Baruch J, Kartsonaki C, Dunning J, Rojek A, Rashan A, Beane A, Murthy S, Reyes LF.

    Scientefic Data   Vol. 9 ( 1 ) page: 454   2022.7

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    Language:English   Publishing type:Research paper (scientific journal)  

  5. Global and regional long-term survival following resection for HCC in the recent decade: A meta-analysis of 110 studies Reviewed

    Rosyli F. Reveron-Thornton,Margaret L. P. Teng,Eunice Yewon Lee,Andrew Tran,Sean Vajanaphanich,Eunice X. Tan,Sanjna N. Nerurkar,Rui Xin Ng,Readon Teh,Debi Prasad Tripathy,Takanori Ito,Taku Tanaka,Nozomi Miyake,Biyao Zou,Connie Wong,Hidenori Toyoda,Carlos O. Esquivel,C. Andrew Bonham,Mindie H. Nguyen,Daniel Q. Huang

    Hepatology Communications     2022.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/hep4.1923.

    Other Link: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep4.1923

  6. The protective effect of tight-fitting powered air-purifying respirators during chest compressions Reviewed

    AMERICAN JOURNAL OF EMERGENCY MEDICINE   Vol. 49   page: 172 - 177   2021.11

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  7. Conditioned medium from stem cells derived from human exfoliated deciduous teeth ameliorates NASH via the Gut-Liver axis. Reviewed International journal

    Hisanori Muto, Takanori Ito, Taku Tanaka, Shinya Yokoyama, Kenta Yamamoto, Norihiro Imai, Yoji Ishizu, Keiko Maeda, Takashi Honda, Tetsuya Ishikawa, Asuka Kato, Taichi Ohshiro, Fumiya Kano, Akihito Yamamoto, Kiyoshi Sakai, Hideharu Hibi, Masatoshi Ishigami, Mitsuhiro Fujishiro

    Scientific reports   Vol. 11 ( 1 ) page: 18778 - 18778   2021.9

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    Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

    DOI: 10.1038/s41598-021-98254-8

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  8. The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040. Reviewed International journal

    Takanori Ito, Masatoshi Ishigami, Biyao Zou, Taku Tanaka, Hirokazu Takahashi, Masayuki Kurosaki, Mayumi Maeda, Khin Naing Thin, Kenichi Tanaka, Yuka Takahashi, Yoshito Itoh, Kentaro Oniki, Yuya Seko, Junji Saruwatari, Miwa Kawanaka, Masanori Atsukawa, Hideyuki Hyogo, Masafumi Ono, Eiichi Ogawa, Scott D Barnett, Christopher D Stave, Ramsey C Cheung, Mitsuhiro Fujishiro, Yuichiro Eguchi, Hidenori Toyoda, Mindie H Nguyen

    Hepatology international   Vol. 15 ( 2 ) page: 366 - 379   2021.4

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    BACKGROUND: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD. METHODS: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients. RESULTS: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD. CONCLUSION: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.

    DOI: 10.1007/s12072-021-10143-4

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  9. Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty. Reviewed

    Naoki Ozawa, Kazuki Sato, Ayumi Sugimura, Shigeyoshi Maki, Taku Tanaka, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Masatoshi Ishigami, Mitsuhiro Fujishiro, Tetsuya Ishikawa, Shoko Ando

    Japan journal of nursing science : JJNS   Vol. 18 ( 3 ) page: e12415   2021.3

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    AIM: Patients with nonalcoholic fatty liver disease (NAFLD) have a low quality of life (QOL) and illness uncertainty. This study examined the structure of QOL and associated factors, including illness uncertainty, among individuals with NAFLD. METHODS: A cross-sectional survey was conducted using a self-administered questionnaire for outpatients with NAFLD. QOL was measured using the Short Form-8. Dietary habits, physical activity level, illness uncertainty, health locus of control, and knowledge of NAFLD were assessed. Path analysis was used to study the associated factors of QOL and their structure, including uncertainty of disease. RESULTS: Path analysis of 168 NAFLD patients indicated that a high Physical Component Summary score on the Short Form-8-representing physical QOL-was predicted by a body mass index <25 kg/m2 and high educational level. A high Mental Component Summary score-representing mental QOL-was predicted by being male, good dietary habits, low illness uncertainty, and presence of consultants. The model showed satisfactory goodness-of-fit without being rejected by the chi-square test (goodness-of-fit index = .947, adjusted goodness-of-fit index = .917, comparative fit index = .967, root mean square error of approximation = 0.023). CONCLUSIONS: Nurses need to work closely with NAFLD patients as consultants, providing adequate information about the causes, treatments, and dietary habits, and focusing on the individual's perception of health. This could reduce illness uncertainty and contribute to the improvement of QOL.

    DOI: 10.1111/jjns.12415

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  10. Efficacy and Safety of Sorafenib in Unresectable Hepatocellular Carcinoma with Bile Duct Invasion. Invited Reviewed International journal

    Taku Tanaka, Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro

    Oncology   Vol. 98 ( 9 ) page: 621 - 629   2020

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    INTRODUCTION: Because the frequency of bile duct invasion in hepatocellular carcinoma (HCC) patients is very rare, there is limited clinical evidence to demonstrate the outcomes of systemic therapy in HCC with bile duct invasion. OBJECTIVE: Our aim was to clarify the efficacy and safety of sorafenib treatment in patients with unresectable advanced HCC with bile duct invasion. METHODS: One hundred and seventy-five patients with advanced HCC were enrolled in this study. We retrospectively compared the outcomes of sorafenib between patients without bile duct invasion [B (-) group, n = 165] and those with bile duct invasion [B (+) group, n = 10]. RESULTS: There were no significant differences in the confirmed objective response rate (ORR) and the confirmed disease control (DC) rate between the B (-) and the B (+) groups (13.9 vs. 20.0%, p = 0.637 for ORR; 47.2 vs. 70.0%, p = 0.202 for DC rate, respectively). There were no significant differences in median overall survival (OS) and time to progression (TTP) between the B (-) group and the B (+) group (14.8 vs. 14.1 months, p = 0.780 for OS; 3.4 vs. 5.7 months, p = 0.277 for TTP, respectively). Post-treatment factors associated with good OS were changes in albumin-bilirubin score (0-6 weeks) of <0.25, and antitumor response at 6 weeks of DC. Though 5 of 10 patients (50%) in the B (+) group had bile duct complications, such as obstructive jaundice and biliary bleeding, these 5 patients were able to recover from biliary troubles by careful and vigorous management with biliary endoscopic intervention, and were able to continue sorafenib therapy safely. CONCLUSIONS: Our present results suggest that sorafenib might have potential therapeutic efficacy and safety in advanced HCC patients with bile duct invasion. In case of biliary tract troubles before and during sorafenib treatment, early biliary management may be important to continue sorafenib therapy safely. Further studies are needed to confirm the outcomes of sorafenib in advanced HCC patients with bile duct invasion.

    DOI: 10.1159/000507051

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  11. Blunt cardiac injury due to trauma associated with snowboarding: a case report. Reviewed International journal

    Yamaji F, Okada H, Nakajima Y, Suzuki K, Yoshida T, Mizuno Y, Okamoto H, Kitagawa Y, Tanaka T, Nakano S, Nachi S, Doi T, Kumada K, Yoshida S, Ishida N, Shimabukuro K, Ushikoshi H, Toyoda I, Doi K, Ogura S

    Journal of medical case reports   Vol. 11 ( 1 ) page: 80 - 80   2017.3

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    BACKGROUND: Cardiac trauma is associated with a much higher mortality rate than injuries to other organ systems, even though cardiac trauma is identified in less than 10% of all trauma admissions. Here we report blunt trauma of the left atrium due to snowboarding trauma. CASE PRESENTATION: A 45-year-old Asian man collided with a tree while he was snowboarding and drinking. He lost consciousness temporarily. An air ambulance was requested and he was transported to an advanced critical care center. On arrival, a pericardial effusion was detected by a focused assessment with sonography for trauma. His presenting electrocardiogram revealed normal sinus rhythm and complete right bundle branch block. Laboratory findings included a white blood cell count of 13.5 × 103/μl, serum creatine kinase level of 459 IU/l, and creatine kinase-myocardial band level of 185 IU/l. Enhanced computed tomography showed a large pericardial effusion and bleeding from his left adrenal gland. There were no pelvic fractures. A diagnosis of cardiac tamponade due to blunt cardiac injury and left adrenal injury due to blunt trauma was made. Subsequently, emergency thoracic surgery and transcatheter arterial embolization of his left adrenal artery were performed simultaneously. A laceration of the left atrial appendage in the lateral wall of his left ventricle was detected intraoperatively and repaired. His postoperative course progressed favorably, although a pericardial effusion was still detected on chest computed tomography on hospital day 35. His electrocardiogram showed normal sinus rhythm and the complete right bundle branch block pattern changed to a narrow QRS wave pattern. He was discharged on hospital day 40. CONCLUSIONS: The present case report illustrates two points: (1) severe injuries resulted from snowboarding, and (2) complete right bundle branch block was caused by blunt cardiac injury. The present report showed blunt trauma of the left atrium with complete right bundle branch block as an electrocardiogram change due to snowboarding trauma. To detect cardiac trauma in snowboarding accidents, an examination of an electrocardiogram is required in all patients who might have a bruised chest.

    DOI: 10.1186/s13256-017-1242-2

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Books 1

  1. 消化器内科専攻医マニュアル

    田中 卓( Role: Contributor ,  急性肝不全に対する血液浄化方法)

    CBR  2022.1  ( ISBN:9784908083730

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    Total pages:615   Responsible for pages:181-186   Language:Japanese Book type:Textbook, survey, introduction

MISC 1

  1. Relative bradycardia as a clinical feature in patients with coronavirus disease 2019 (COVID-19): A report of two cases.

    Hiroaki Hiraiwa, Yukari Goto, Genki Nakamura, Yuma Yasuda, Yoshinori Sakai, Daisuke Kasugai, Shinsuke Jinno, Taku Tanaka, Hiroaki Ogawa, Michiko Higashi, Takanori Yamamoto, Naruhiro Jingushi, Masayuki Ozaki, Atsushi Numaguchi, Toru Kondo, Ryota Morimoto, Takahiro Okumura, Naoyuki Matsuda, Toyoaki Murohara

    Journal of cardiology cases   Vol. 22 ( 6 ) page: 260 - 264   2020.12

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    We treated two patients with COVID-19 pneumonia requiring mechanical ventilation. Case 1 was a 73-year-old Japanese man. Computed tomography (CT) revealed ground-glass opacities in both lungs. He had severe respiratory failure with a partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen ratio (P/F ratio) of 203. Electrocardiogram showed a heart rate (HR) of 56 beats/min, slight ST depression in leads II, III, and aVF, and mild saddle-back type ST elevation in leads V1 and V2. High-sensitivity cardiac troponin T (cTnT) level was slightly elevated. Despite a high fever and hypoxemia, his HR remained within 50-70 beats/min. Case 2 was a 52-year-old Japanese woman. CT revealed ground-glass opacities in the lower left lung. Electrocardiogram showed a HR of only 81 beats/min, despite a body temperature of 39.2 °C, slight ST depression in leads V4, V5, V6, and a prominent U wave in multiple leads. She had an elevated cTnT and a P/F ratio of 165. Despite a high fever and hypoxemia, her HR remained within 50-70 beats/min. Both patients had a poor compensatory increase in their HR, despite their critical status. Relative bradycardia could be a cardiovascular complication and is an important clinical finding in patients with COVID-19. <Learning objective: We report two Japanese cases of COVID-19 pneumonia with relative bradycardia as a condition and no significant compensatory increase in heart rate despite high fever and severe hypoxemia. Relative bradycardia in COVID-19 might be associated with myocardial injury due to not only direct viral involvement but also systemic inflammation. We should carefully observe the occurrence of relative bradycardia because it could potentially be a clinical sign of COVID-19.>.

    DOI: 10.1016/j.jccase.2020.07.015

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Presentations 2

  1. 内科医の立場から見た,集中治療医が知っておきたい急性肝不全の診断と治療

    田中 卓

    第50回集中治療医学会総会  2023.3.3 

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    Event date: 2023.3

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:京都   Country:Japan  

  2. COVID-19ARDSにおける腹臥位の効果性に寄与する因子の検討

    田中卓

    第49回日本集中治療医学会学術集会  2022.3.20 

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    Event date: 2022.3

    Presentation type:Symposium, workshop panel (public)  

    Venue:仙台   Country:Japan  

KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 急性肝不全の病態解明と遺伝子治療を含めた新規創薬イノベーション

    Grant number:21K16571  2021.4 - 2026.3

    日本学術振興会  科学研究費助成事業  若手研究

    田中 卓

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    Authorship:Principal investigator 

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    急性肝不全は種々の原因に反応して、過剰な炎症と免疫異常、および肝虚血壊死を伴う肝機能不全である。救急・集中治療領域においても急性肝不全の重症化を阻止するために、多臓器不全管理の適正化と、肝機能再生における創薬科学的研究は重要な課題の一つである。
    本研究は、種々の動物急性肝不全モデルの肝臓でどのような炎症性分子や転写因子がどのような時系列で活性化されるのかを明らかにし、その病態生理学的解釈を分子生化学・分子薬理学および病態解剖学的観点より解明することにより、遺伝子治療を含めた創薬科学的発展、そして急性肝不全治療としての臨床研究へのトランスレーショナルリサーチを目的とする。
    2022年度はアセトアミノフェンモデル、四塩化炭素モデルにおける、トランスクリプトーム解析を行い、変動遺伝子群の同定およびパスウェイ解析を行った。
    前年度の検討において、ConAモデルでは投与後6時間後より肝逸脱酵素であるAST及びALTの上昇を認め、概ね12時間後~24時間後をピークに肝逸脱酵素の軽減を認めた。CCl4モデルおよび、アセトアミノフェンでは12時間後より緩やかにAST・ALTの上昇をみとめ36時間~48時間後がピークであったため、肝不全の進行過程の転写因子の動向を確認するために、6時間・12時間に2ポイントでの組織を採取しトランスクリプトーム解析を行った。
    トランスクリプトーム解析にあたり、おけるライブラリ調整時におけるRNAの断片化が安定化せず、従ってライブラリ長の安定化が思うように進まず、ライブラリ調整の安定化に難渋したが、最終的にプロトコル調整も確立することができた。
    トランスクリプトーム解析では、モデル群において発現増加した遺伝子は150個近く認め、発現低下した遺伝子が80個ほど認めた。マクロファージ関連遺伝子に着目して発現遺伝子解析を行い、Jun、Hspd1、Sphk1などの遺伝子発現が増加を認め、Sucnr1、Ldlr遺伝子の発現低下を認めた。今後さらに複数のモデルでの発現遺伝子において共通変動遺伝子を同定し、より関連の強い遺伝子について同定を行い、次年度の研究へつなげていく土台となった。
    昨年度作成し確立しているモデルを再現性を確認しつつ、RNAの網羅的解析に進んだため、モデル再現自体は概ね順調に推移した。しかし、トランスクリプトーム解析時のライブラリ作成・調整に難渋し、やや遅れを生じた。したがって、当初、2022年度にチオアセトアミドモデル肝障害モデルを確立する予定であったが、計画に遅れが生じた。
    2023年度はチオアセトアミドモデル、免疫性急性肝炎モデルとして盲腸結紮穿孔+Propionibacterium acnes、モデルで2022年度と同様のモデル作成・解析を進め、共通して発言する転写因子・遺伝子を同定し、定量的 RT-PCR 解析およびその関連タンパク質の肝臓内分布の免疫組織染色を行う予定である。

  2. 敗血症性急性腎障害における好中球エラスターゼ阻害薬の治療効果の検討

    Grant number:15K20337  2015 - 2017

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    田中 卓

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    LPS投与(20mg/kg)により敗血症モデルマウス(BL6 background、10週齢、オス)を作製した。マウスはシベレスタット治療群とコントロール群に分け、LPS投与3、6、9、12時間後にシベレスタット群では0.2mg/kgのdoseで、コントロール群についてはPBSを腹腔投与し、LPS投与48時間後の生存率を比較したについては未治療マウスの生存率が24%であったのに対し治療群で83.3%と有意な改善を認めた。腎機能については腎障害のマーカーであるKIM-1の尿細管上での発現が治療群で抑制されており、血清クレアチニン、尿素窒素の上昇も有意に抑制されていた。レジンを用いた腎血管鋳型を作製したところコントロール群では明らかに腎毛細血管の鋳型形成が阻害されており微小血管障害が生じていることが確認できたが、治療群では鋳型の形成不全が減弱しており、治療により微小血管障害が軽減されていることが示唆された。走査型ならびに透過型電子顕微鏡により敗血症性腎障害の超微形態を確認したところ、正常な腎糸球体毛細血管は有窓型といわれる小孔構造が認められたが、コントロール群ではこの構造が破壊され、毛細血管壁の肥厚が認められた。また、基底膜とたこ足細胞の乖離が認められ腎機能障害を強く疑わせる所見が確認できた一方で、治療群においては小孔構造が保たれ、基底膜とたこ足細胞の乖離は認められず血管内皮細胞の浮腫様変化も抑制されていた。また、血管内皮傷害を定量的に評価するためにトロンボモジュリン(TM)の発現についても検討した。正常な糸球体血管内皮にはTMが発現していたが、敗血症モデルマウスにおいては糸球体血管内皮でのTMの発現が低下する一方で尿細管での集積が認められた。これは障害を受けたTMが尿により排泄されることを示唆する所見であると考えられた。治療群では糸球体血管内皮でのTMの発現が保たれており、シベレスタットは血管内皮傷害を減弱することを示唆した。

 

Social Contribution 2

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    Role(s):Lecturer

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  2. 病院前救急診療・胸腹部外傷の特徴とその対応

    Role(s):Lecturer

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