Updated on 2024/07/03

写真a

 
TAKATSUKA Hisakazu
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Professor
Faculty of Medicine School of Medicine Professor
Graduate School of Medical and Dental Sciences Community Disease Control Community Preventive Medicine Professor
Title
Professor
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Degree

  • 博士(医学) ( 1998.3   新潟大学 )

Research Interests

  • 法医病理学

Research Areas

  • Life Science / Applied biochemistry

Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Community Disease Control Community Preventive Medicine   Professor

    2015.5

  • Niigata University   Faculty of Medicine School of Medicine   Professor

    2015.5

  • Niigata University   Faculty of Medicine School of Medicine   Associate Professor

    2009.11 - 2015.5

  • Niigata University   Graduate School of Medical and Dental Sciences Community Disease Control Community Preventive Medicine   Associate Professor

    2009.11 - 2015.5

Education

  • Toyama Medical and Pharmaceutical University   Faculty of Medicine

    - 1992.3

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    Country: Japan

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Professional Memberships

 

Papers

  • Bleeding-Source Exploration in Subdural Hematoma: Observational Study on the Usefulness of Postmortem Computed Tomography Angiography. International journal

    Kazuhisa Funayama, Akihide Koyama, Rieka Katsuragi-Go, Takashi Aoyama, Hiraku Watanabe, Naoya Takahashi, Hisakazu Takatsuka

    Diagnostics (Basel, Switzerland)   13 ( 13 )   2023.7

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    In a few cases, postmortem computed tomography angiography (PMCTA) is effective in postmortem detection of cortical artery rupture causing subdural hematoma (SDH), which is difficult to detect at autopsy. Here, we explore the usefulness and limitations of PMCTA in detecting the sites of cortical arterial rupture for SDH. In 6 of 10 cases, extravascular leakage of contrast material at nine different places enabled PMCTA to identify cortical arterial rupture. PMCTA did not induce destructive arterial artifacts, which often occur during autopsy. We found that, although not in all cases, PMCTA could show the site of cortical arterial rupture causing subdural hematoma in some cases. This technique is beneficial for cases of SDH autopsy, as it can be performed nondestructively and before destructive artifacts from the autopsy occur.

    DOI: 10.3390/diagnostics13132286

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  • Detection and Morphological Analysis of Micro-Ruptured Cortical Arteries in Subdural Hematoma: Three-Dimensional Visualization Using the Tissue-Clearing Clear, Unobstructed, Brain/Body Imaging Cocktails and Computational Analysis Method. Reviewed International journal

    Kazuhisa Funayama, Kazuki Tainaka, Akihide Koyama, Rieka Katsuragi-Go, Natsumi Nishikawa-Harada, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Naoya Takahashi, Hisakazu Takatsuka

    Diagnostics (Basel, Switzerland)   12 ( 11 )   2022.11

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    One of the causes of bleeding in subdural hematoma is cortical artery rupture, which is difficult to detect at autopsy. Therefore, reports of autopsy cases with this condition are limited and hence, the pathogenesis of subdural hematoma remains unclear. Herein, for the detection and morphological analysis of cortical artery ruptures as the bleeding sources of subdural hematoma, we used the tissue-clearing CUBIC (clear, unobstructed, brain/body imaging cocktails and computational analysis) method with light-sheet fluorescence microscopy and reconstructed the two-dimensional and three-dimensional images. Using the CUBIC method, we could clearly visualize and detect cortical artery ruptures that were missed by conventional methods. Indeed, the CUBIC method enables three-dimensional morphological analysis of cortical arteries including the ruptured area, and the creation of cross-sectional two-dimensional images in any direction, which are similar to histopathological images. This highlights the effectiveness of the CUBIC method for subdural hematoma analysis.

    DOI: 10.3390/diagnostics12112875

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  • PROS1 variant in sudden death case of pulmonary embolism caused by calcification in the inferior vena cava: The importance of postmortem genetic analysis. International journal

    Aya Miura, Kazuhisa Funayama, Hiromi Nyuzuki, Naoya Takahashi, Takuma Yamamoto, Akihide Koyama, Takeshi Ikeuchi, Hisakazu Takatsuka, Hajime Nishio

    Legal medicine (Tokyo, Japan)   55   102029 - 102029   2022.3

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    A Japanese man in his 30s died suddenly. Postmortem computed tomography and autopsy revealed a pulmonary embolism from an organizing thrombus in the inferior vena cava as the cause of death. Genomic analysis of congenital thrombophilia-related genes (i.e., SERPINC1, PROC, PROS1, F2, F5, PLG, and MTHFR) revealed a heterozygous variant of PROS1 (p.A139V), which has been reported in patients with congenital protein S deficiency. After a genetic conference that included forensic pathologists, molecular scientists, genetic researchers, genetic clinicians, and clinical physicians, the results of the genetic analysis were explained to the family. Biochemical analyses of protein S (PS) activity and total PS antigen levels were performed with samples from the deceased's family and genetic analysis was not performed until clinical symptoms appear. Herein we demonstrate the importance of genetic background in cases of a sudden death due to pulmonary embolism.

    DOI: 10.1016/j.legalmed.2022.102029

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  • The usefulness of postmortem computed tomography angiography for subdural hematoma caused by rupture of the cortical artery: A report of two autopsy cases and a literature review. International journal

    Kazuhisa Funayama, Kazuki Harada, Akihide Koyama, Rieka Katsuragi-Go, Natsumi Nishikawa-Harada, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Naoya Takahashi, Hisakazu Takatsuka

    Legal medicine (Tokyo, Japan)   53   101941 - 101941   2021.7

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    Acute subdural hematoma (SDH) occurs following severe head trauma with brain contusion or rupture of bridging veins. Conversely, SDH caused by rupture of a cortical artery without trauma or with minor trauma is also possible. Although over 150 cases of the latter SDH have been reported, they were predominantly diagnosed only during surgery, and therefore, no adequate histological evaluation has been performed. Therefore, essential etiology of this SDH type has remained unclear. In addition, the scarcity of autopsy cases may be attributed to arterial rupture being missed if the macroscopic findings are too minimal to detect during autopsy. Here, we describe two autopsy cases of SDH of cortical artery origin. Extravasation on postmortem computed tomography angiography and arterial leakage on macroscopic observation during autopsy facilitated detection of the ruptured artery and allowed detailed histological evaluation of the ruptured artery and adjacent dura mater. The etiology of arterial rupture is briefly described on the basis of histopathological findings in this study and the available literature.

    DOI: 10.1016/j.legalmed.2021.101941

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  • 【オートプシー・イメージング2021】臨床Aiと法医学Aiはパラレル!イメージング?

    高橋 直也, 高塚 尚和, 舟山 一寿

    Rad Fan   19 ( 3 )   57 - 60   2021.2

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    Language:Japanese   Publisher:(株)メディカルアイ  

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  • Postmortem volume change of the spleen and kidney on early postmortem computed tomography: comparison with antemortem computed tomography. Reviewed

    Naoya Takahashi, Keisuke Yajima, Madoka Otaki, Yurina Yoshikawa, Ayumi Ishihara, Yuki Sato, Takeshi Higuchi, Hisakazu Takatsuka

    Japanese journal of radiology   37 ( 7 )   534 - 542   2019.7

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    PURPOSE: To clarify an early postmortem change, we investigated the volume changes of the spleen and kidney on postmortem CT compared with antemortem CT in the same patients. MATERIALS AND METHODS: We retrospectively evaluated the volumes of 56 spleens (56 cases) and 50 kidneys (25 cases) using antemortem and postmortem CT, which were performed within 168 min after death. We divided the cases of spleen analysis into a hemorrhagic group (n = 12) and a non-hemorrhagic group (n = 44). RESULTS: The volumes of the organs before and after death were 101.0 ± 70.9 (cm3, mean ± standard deviation) and 81.1 ± 57.8 in spleens, 120.3 ± 49.2 and 109.2 ± 39.2 in kidneys, respectively. Both spleens and kidneys shrank after death (p < 0.05). The volumes of spleens before and after death were 111 ± 66.5 and 67.5 ± 27.7 in the hemorrhagic group, and 98.2 ± 72.5 and 84.9 ± 63.3 in the non-hemorrhagic group, respectively. The median value of the ratio of postmortem splenic volume to antemortem volume in the hemorrhagic group (65.0%) was smaller than the one in the non-hemorrhagic group (90.5%) (p < 0.05). CONCLUSION: We demonstrated that spleens and kidneys significantly reduced in size after death. The rate of shrinkage of spleens in the hemorrhagic group significantly became larger than the one in the non-hemorrhagic group.

    DOI: 10.1007/s11604-019-00841-3

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  • An autopsy case of peliosis hepatis with X-linked myotubular myopathy. Reviewed International journal

    Kazuhisa Funayama, Hiroshi Shimizu, Hidetomo Tanaka, Izumi Kawachi, Ichizo Nishino, Kou Matsui, Naoya Takahashi, Akihide Koyama, Rieka Katsuragi-Go, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Akiyoshi Kakita, Hisakazu Takatsuka

    Legal medicine (Tokyo, Japan)   38   77 - 82   2019.5

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    This report describes the autopsy case of a 4-year-old boy who died from hepatic hemorrhage and rupture caused by peliosis hepatis with X-linked myotubular myopathy. Peliosis hepatis is characterized by multiple blood-filled cavities of various sizes in the liver, which occurs in chronic wasting disease or with the use of specific drugs. X-linked myotubular myopathy is one of the most serious types of congenital myopathies, in which an affected male infant typically presents with severe hypotonia and respiratory distress immediately after birth. Although each disorder is rare, 12 cases of pediatric peliosis hepatis associated with X-linked myotubular myopathy have been reported, including our case. Peliosis hepatis should be considered as a cause of hepatic hemorrhage despite its low incidence, and it requires adequate gross and histological investigation for correct diagnosis.

    DOI: 10.1016/j.legalmed.2019.04.005

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  • Assessment of a simple method of heart weight estimation by postmortem computed tomography. Reviewed International journal

    Rei Ogawa, Naoya Takahashi, Takeshi Higuchi, Hiroyuki Shibuya, Motohiko Yamazaki, Norihiko Yoshimura, Hisakazu Takatsuka, Hidefumi Aoyama

    Forensic science international   296   22 - 27   2019.3

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    BACKGROUND: Measurement of heart weight is important when investigating cause of death, but there is presently no satisfactory method of heart weight estimation by postmortem computed tomography (PMCT). METHOD: We investigated 33 consecutive cases that underwent both PMCT and autopsy between February 2008 and June 2014. Heart and left ventricular (LV) weights were calculated by PMCT morphometry. We used a simple method to estimate LV weight: We assumed that LV was an ellipsoid and multiplied its volume on PMCT with myocardial specific gravity. We then compared the various heart and LV weights using linear regression. The calculated and estimated LV weights on PMCT were also compared. RESULTS: It was not possible to predict heart weight at autopsy from PMCT (R2 = 0.53). However, heart weight at autopsy could be accurately predicted from LV weight calculated by PMCT (R2 = 0.77). In addition, there was a strong correlation between the estimated and calculated LV weights by PMCT (R2 = 0.92). Heart weight at autopsy could also be accurately predicted using the PMCT-estimated LV weight (R2 = 0.72). CONCLUSION: Heart weight at autopsy could be accurately predicted using a simple method in which LV volume was assumed to be an ellipsoid on PMCT.

    DOI: 10.1016/j.forsciint.2018.12.019

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  • 【Multislice CT 2018 BOOK】Dual Energy CT オートプシー・イメージング(Ai)用Dual Energy CT使用の初期経験

    高橋 直也, 高塚 尚和, 舟山 一寿, 大澤 阿紋

    映像情報Medical   50 ( 8 )   85 - 89   2018.7

  • 皮質動脈破綻による亜急性特発性硬膜下血腫の1例

    舟山 一寿, 原田 一樹, 高橋 直也, 青山 崇, 樋口 涼子, 渡辺 拓, 川井 桂, 高塚 尚和

    法医病理   23 ( 1 )   8 - 9   2017.7

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    Language:Japanese   Publisher:日本法医病理学会  

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  • 皮質動脈破綻による急性硬膜下血腫の1例

    舟山 一寿, 原田 一樹, 高橋 直也, 樋口 涼子, 青山 崇, 渡辺 拓, 高塚 尚和

    日本法医学雑誌   71 ( 1 )   60 - 60   2017.5

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    Language:Japanese   Publisher:(NPO)日本法医学会  

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  • 皮質動脈破綻による亜急性特発性硬膜下血腫の1例

    舟山 一寿, 原田 一樹, 高橋 直也, 渡辺 拓, 川井 桂, 高塚 尚和

    日本法医学雑誌   70 ( 1 )   74 - 74   2016.5

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  • Changes in aortic shape and diameters after death: comparison of early postmortem computed tomography with antemortem computed tomography. Reviewed International journal

    Naoya Takahashi, Takeshi Higuchi, Yasuo Hirose, Haruo Yamanouchi, Hisakazu Takatsuka, Kazuhisa Funayama

    Forensic science international   225 ( 1-3 )   27 - 31   2013.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER IRELAND LTD  

    PURPOSE: The purpose of this study is to evaluate the postmortem deformation of the aorta on postmortem computed tomography (CT) by comparison with the antemortem CT in the same patient. MATERIALS AND METHODS: A total of 58 non-traumatic patients without hemorrhagic events who underwent torso CT before and shortly after death were enrolled. Antemortem chest and abdominal CT were obtained in 44 cases and in 57 cases, respectively. The lengths of the major and minor axes of the ascending and descending thoracic aorta and the abdominal aorta were measured on both antemortem and postmortem CT in the same patient. To evaluate the shape of the aorta, the major axis-minor axis ratio (Ma-MiR) was calculated. Mean values of the diameters of the aorta and Ma-MiRs on postmortem CT were compared with those on antemortem CT using the Wilcoxon signed-rank test. We also evaluated the major and minor axes and Ma-MiRs on both antemortem and postmortem CT in two age groups: 65 years and under (n=13) and over 65 years (n=45). RESULTS: At each level tested, the aorta significantly shrank after death (p<0.001) (ascending thoracic aorta, descending thoracic aorta, and abdominal aorta: 38.5 mm × 33.5 mm, 28.0 mm × 25.9 mm, and 24.4 mm × 21.8 mm on antemortem CT, 30.0 mm × 26.2 mm, 24.4 mm × 20.7 mm, and 21.5 mm × 14.5 mm on postmortem CT, respectively). The postmortem Ma-MiRs significantly increased at the descending thoracic aorta and the abdominal aorta (p<0.001). The diameters of the aorta are longer in older cases at all levels on both antemortem and postmortem CT. The reduction rates were larger in younger cases than older cases at all levels. CONCLUSIONS: After death, the aorta shrunk at all levels, and became oval in shape in descending thoracic and abdominal aorta. The contraction was greater in younger cases than older cases. Investigators who interpret postmortem imaging should be aware of the postmortem deformation of the aorta.

    DOI: 10.1016/j.forsciint.2012.04.037

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  • 超音波画像診断装置(エコー)の死因診断への応用

    舟山 一寿, 高塚 尚和, 山内 春夫, 内ヶ崎 西作, 高橋 直也

    新潟県医師会報   ( 732 )   5 - 7   2011.3

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    2008年5月から2年4ヵ月間に超音波画像診断装置を用いて死因診断(死後エコー)を行った92例(検死41例、解剖51例)の死後エコーの状況と結果を報告した。外傷初期診療の超音波検査法FASTの6点に傍胸骨肋骨間操作を加えた計7点でecho free spaceの有無を判定し、死因との関連を推定した結果、92例中24例に1ヶ所以上のecho free spaceを認め、外傷死の約65%と非外傷死の約0.3%で死因との直接的関連を認めた。また、検死例におけるエコーガイド下穿刺では正確な部位からの採取が可能で、特に心腔や大血管を穿刺することで動静脈血の選択的採取が可能となり、死因推定の一助となった。死後エコーは検査そのものの制約や精度などに関して欠点を有するものの、非侵襲的に内部の形態的情報が得られるほかにも機動性という独自の利点があり、その有用性が示唆された。

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  • 超音波画像診断装置(エコー)を用いた死体の観察と死因診断への応用

    舟山 一寿, 内ヶ崎 西作, 高橋 直也, 須貝 壮朗, 西川 有紀子, 高塚 尚和, 山内 春夫

    日本法医学雑誌   64 ( 1 )   88 - 88   2010.5

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  • Classification of Sphenoid Sinus Using Head Computed Tomography Images for Preliminary of Personal Identification(和訳中)

    Malkanthi Appu Gammahelage Chandani, Takahashi Naoya, Fuse Tomoya, Ohsawa Amon, Takatsuka Hisakazu, Higuchi Takeshi

    新潟大学保健学雑誌   17 ( 1 )   1 - 6   2020.3

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  • Increased susceptibility of thymocytes to apoptosis in mice lacking AIM, a novel murine macrophage-derived soluble factor belonging to the scavenger receptor cysteine-rich domain superfamily

    T Miyazaki, Y Hirokami, N Matsuhashi, H Takatsuka, M Naito

    JOURNAL OF EXPERIMENTAL MEDICINE   189 ( 2 )   413 - 422   1999.1

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    Language:English   Publisher:ROCKEFELLER UNIV PRESS  

    Apoptosis of cells must be regulated both positively and negatively in response to a variety of stimuli in the body. Various environmental stresses are known to initiate apoptosis via differential signal transduction cascades. However, induction of signals that may inhibit apoptosis is poorly understood, although a number of intracellular molecules that mediate inhibition of apoptosis have been identified. Here we present a novel murine macrophage-specific 54-kD secreted protein which inhibits apoptosis (termed AIM, for apoptosis inhibitor expressed by macrophages). AIM belongs to the macrophage scavenger receptor cysteine-rich domain superfamily (SRCR-SF), members of which share a highly homologous conserved cysteine-rich domain. In AIM-deficient mice, the thymocyte numbers were diminished to half those in wild-type mice, and CD4/CD8 double-positive (DP) thymocytes were strikingly more susceptible to apoptosis induced by both dexamethasone and irradiation in vivo. Recombinant AIM protein significantly inhibited cell death of DP thymocytes in response to a variety of stimuli in vitro. These results indicate that in the thymus, AIM functions in trans to induce resistance to apoptosis within DP cells, and thus supports the viability of DP thymocytes before thymic selection.

    DOI: 10.1084/jem.189.2.413

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  • Granuloma formation in scavenger receptor-deficient mice in response to BCG infection

    Y Kobayashi, T Nomura, H Takatsuka, H Umezu, G Hasegawa, Kawamura, I, M Mitsuyama, M Arakawa, N Kamata, H Suzuki, T Kodama, M Naito

    CELLS OF THE HEPATIC SINUSOID, VOL 7   Vol.7, 243-244   243 - 244   1999

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    Language:English   Publisher:KUPFFER CELL FOUNDATION  

    To elucidate the role of scavenger receptors in host defense mechanisms against Mycobacterium bovis Bacillus Calmette-Guerin (BCG), macrophage scavenger receptor class A type I and II-deficient (MSR-A(-/-)) mice were used. MSR-A(-/-) mice were found to be more susceptible to BCG infection compared to wild type MSR-A(+/+) mice. The number and the size of hepatic granulomas were larger in the MSR-A(+/+) mice than in the MSR-A(-/-) mice. In contrast, exudative lesions expanded in the lungs of the the MSR-A(-/-) mice more remarkably than in the MSR-A(+/+) mice. The BCG proliferation was much more marked in the liver and lungs of the MSR-A(-/-) mice than the MSR-A(+/+) mice. The expressions of cytokine mRNAs and the serum levels of cytokines were similar in the MSR-A(-/-) and MSR-A(+/+) mice except that the serum levels of interferon (IFN)-gamma were lower in the MSR-A(-/-) mice. In the liver and lung lesions, the T lymphocyte recruitment in the MSR-A(-/-) mice was less remarkable than thar in the MSR-A(+/+) mice. In vitro, peritoneal macrophages from MSR-A(-/-) mice incorporated BCG less actively compared to those from MSR-A(+/+) mice. These results imply that macrophages in MSR-A(-/-) mice are defective in the recruitment of T lymphocytes, the production of IFN-gamma, and bactericidal capacity against BCG. The MSR-A-mediated uptake of BCG is closely related to the bactericidal mechanisms of macrophages.

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  • Granuloma formation in scavenger receptor-deficient mice in response to BCG.(jointly worked)

    Cells of the Hepatic Sinusoid   Vol.7, 243-244   1999

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  • Gene transduction into the liver - Present and perspective - Immunomodulation gene therapy for hepatic micrometastasis

    Y Shiratori, F Kanai, Y Hikiba, H Takatsuka, H Hamada, M Matsumura, KH Lan, M Ohashi, M Naito, K Kamii, M Omata

    CELLS OF THE HEPATIC SINUSOID, VOL 7   Vol.7, 272-277   272 - 277   1999

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    Language:English   Publisher:KUPFFER CELL FOUNDATION  

    Recent advance in cellular, biochemical, and molecular techniques provide various tools for clarification of intracellular, cellular, intracellular mechanisms for pathophysiology of liver diseases.
    Sine liver consists of both parenchymal and nonparenchymal cells (including sinusoidal cells), the roles of these cells in various liver diseases have been elucidated. These techniques are not used for the understanding of basic sciences, but also be clinically used for treatment of diseases. One of the recent advance is gene targeting into the liver for treatment of various liver diseases.
    In this context, we briefly summarized the application of these techniques from the view of gene therapy for metastatic liver tumor.

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  • Expression of macrophage colony-stimulating factor, scavenger receptors, and macrophage proliferation in the pregnant mouse uterus

    Y Kyaw, G Hasegawa, H Takatsuka, M Shimada-Hiratsuka, H Umezu, M Arakawa, M Naito

    ARCHIVES OF HISTOLOGY AND CYTOLOGY   61 ( 5 )   383 - 393   1998.12

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    Language:English   Publisher:INT SOC HISTOLOGY & CYTOLOGY  

    During pregnancy, mouse uterine epithelial cells produce and secrete a large amount of macrophage colony-stimulating factor (M-CSF/CSF-1), Macrophages accumulate and proliferate in the undecidualized endometrium of the pregnant uterus. Observations showed that macrophages expressed scavenger receptor class A (type I and type II) and class C (macrosialin). Scavenger receptors appeared to be involved in the removal of apoptotic cells in the degenerated decidual tissue. The expression of class A and class C scavenger receptor mRNAs in the uterus of pregnant mice was elevated but the expression of class B scavenger receptor (CD36) mRNA was similar to that of non-pregnant mice. The expression of various cytokines and chemokines, including M-CSF, monocyte cheomattractant protein-1 (MCP-1) and macrophage inflammatory protein 1-alpha (MIP1-alpha), was enhanced in the uterus of pregnant mice, suggesting that these molecules regulate macrophage chemotaxis and immunological function in the uterus. These findings imply that the pregnant uterus provides a microenvironment for the recruitment, differentiation, and proliferation of macrophages and the regulation of scavenger receptor and cytokine expression for a successful pregnancy.

    DOI: 10.1679/aohc.61.383

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  • Expression of macrophage colony-stimulating factor, scavenger receptors, and macrophage proliferation in the pregnant mouse uterus

    Y Kyaw, G Hasegawa, H Takatsuka, M Shimada-Hiratsuka, H Umezu, M Arakawa, M Naito

    ARCHIVES OF HISTOLOGY AND CYTOLOGY   61 ( 5 )   383 - 393   1998.12

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    During pregnancy, mouse uterine epithelial cells produce and secrete a large amount of macrophage colony-stimulating factor (M-CSF/CSF-1), Macrophages accumulate and proliferate in the undecidualized endometrium of the pregnant uterus. Observations showed that macrophages expressed scavenger receptor class A (type I and type II) and class C (macrosialin). Scavenger receptors appeared to be involved in the removal of apoptotic cells in the degenerated decidual tissue. The expression of class A and class C scavenger receptor mRNAs in the uterus of pregnant mice was elevated but the expression of class B scavenger receptor (CD36) mRNA was similar to that of non-pregnant mice. The expression of various cytokines and chemokines, including M-CSF, monocyte cheomattractant protein-1 (MCP-1) and macrophage inflammatory protein 1-alpha (MIP1-alpha), was enhanced in the uterus of pregnant mice, suggesting that these molecules regulate macrophage chemotaxis and immunological function in the uterus. These findings imply that the pregnant uterus provides a microenvironment for the recruitment, differentiation, and proliferation of macrophages and the regulation of scavenger receptor and cytokine expression for a successful pregnancy.

    DOI: 10.1679/aohc.61.383

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  • Bone remodeling and macrophage differentiation in osteopetrosis (op) mutant mice defective in the production of macrophage colony-stimulating factor

    H Takatsuka, H Umezu, G Hasegawa, H Usuda, Y Ebe, M Naito, LD Shultz

    JOURNAL OF SUBMICROSCOPIC CYTOLOGY AND PATHOLOGY   30 ( 2 )   239 - 247   1998.4

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    Language:English   Publisher:EDITRICE COMPOSITORI BOLOGNA  

    Mice homozygous for the osteopetrosis top) mutation are characterized by defective differentiation of osteoclasts, monocytes, and tissue macrophages due to a lack of functional macrophage colony-stimulating factor (M-CSF/CSF-1) activity. In young (4-6 week-old) op/op mice, the bone marrow cavities were filled with spongious Lone. In aged (50-72 week-old) op/op mice, the bone marrow cavities were markedly reconstructed and marrow hematopoiesis was expanded. Numbers of osteodasts and bone marrow macrophages in aged op/op mice were increased but most of the osteoclasts were mononuclear cells and showed poorly developed ruffled borders. Lysosomes of bone marrow macrophages were laden with abundant cry stalloid materials in aged op/op mice and aged littermate mice. However, such macrophages were not ob served in young op/op mice nor in young littermates. In contrast to the marked increase in numbers of osteoclasts and macrophages in the bone marrow the number of Kupffer cells in the liver did not increase in aged op/op mice. Kupffer cells in aged op/op mice did not show ultrastructural maturation with aging and contained a few crystalloid structures. M-CSF administration to aged op/op mice induced numerical increases in Kupffer sells and lysosomes in Kupffer cells, disappearance of crystalloid structures in lysosomes of Kupffer cells, and the development of ruffled border in osteoclasts. These findings indicate that M-CSF-independent mechanisms for macrophage and osteoclast development in aged op/op mice are restricted to bone marrow. M-CSF plays important roles in the differentiation of macrophage and osteoclast and the production and function of lysosomes.

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  • Bone remodeling and macrophage differentiation in osteopetrosis (op) mutant mice defective in the production of macrophage colony-stimulating factor

    H Takatsuka, H Umezu, G Hasegawa, H Usuda, Y Ebe, M Naito, LD Shultz

    JOURNAL OF SUBMICROSCOPIC CYTOLOGY AND PATHOLOGY   30 ( 2 )   239 - 247   1998.4

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    Language:English   Publisher:EDITRICE COMPOSITORI BOLOGNA  

    Mice homozygous for the osteopetrosis top) mutation are characterized by defective differentiation of osteoclasts, monocytes, and tissue macrophages due to a lack of functional macrophage colony-stimulating factor (M-CSF/CSF-1) activity. In young (4-6 week-old) op/op mice, the bone marrow cavities were filled with spongious Lone. In aged (50-72 week-old) op/op mice, the bone marrow cavities were markedly reconstructed and marrow hematopoiesis was expanded. Numbers of osteodasts and bone marrow macrophages in aged op/op mice were increased but most of the osteoclasts were mononuclear cells and showed poorly developed ruffled borders. Lysosomes of bone marrow macrophages were laden with abundant cry stalloid materials in aged op/op mice and aged littermate mice. However, such macrophages were not ob served in young op/op mice nor in young littermates. In contrast to the marked increase in numbers of osteoclasts and macrophages in the bone marrow the number of Kupffer cells in the liver did not increase in aged op/op mice. Kupffer cells in aged op/op mice did not show ultrastructural maturation with aging and contained a few crystalloid structures. M-CSF administration to aged op/op mice induced numerical increases in Kupffer sells and lysosomes in Kupffer cells, disappearance of crystalloid structures in lysosomes of Kupffer cells, and the development of ruffled border in osteoclasts. These findings indicate that M-CSF-independent mechanisms for macrophage and osteoclast development in aged op/op mice are restricted to bone marrow. M-CSF plays important roles in the differentiation of macrophage and osteoclast and the production and function of lysosomes.

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  • Expression of macrophage colony-stimulating factor and its receptor in hepatic granulomas of Kupffer-cell-depleted mice

    H Moriyama, T Yamamoto, H Takatsuka, H Umezu, K Tokunaga, T Nagano, M Arakawa, M Naito

    AMERICAN JOURNAL OF PATHOLOGY   150 ( 6 )   2047 - 2060   1997.6

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    Language:English   Publisher:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    In mice administered with liposome-entrapped dichloromethylene diphosphonate, which depletes Kupffer cells, the size and the number of zymosan-induced granulomas in the liver were smaller than in untreated mice. The number of macrophage precursors, as detected by the monoclonal antibodies for macrophage precursors, increased after zymosan injection in both groups of mice, proliferated, and differentiated into macrophages. Expression of macrophage colony-stimulating factor (M-CSF), interleukin-1, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interferon-gamma mRNA was enhanced in the stage of granuloma formation in the control mouse liver, whereas it was suppressed in Kupffer-cell-depleted mice. However, M-CSF mRNA expression was increased in the Kupffer-cell-depleted mice to form granulomas in the late stages. In situ hybridization demonstrated the expression of M-CSF mRNA and c-fms mRNA in Kupffer cells and monocyte-derived macrophages in the sinusoid and granulomas. The concentration of M-CSF in serum of zymosan-injected control mice was within normal range, but that of zymosan-treated or untreated Kupffer-cell-depleted mice was markedly elevated at day 1. These findings imply that Kupffer cells are indispensable for granuloma formation and produce various cytokines including M-CSF. The local production and consumption of M-CSF in the liver may play a crucial role in granulomtous inflammation.

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  • Expression of macrophage colony-stimulating factor and its receptor in hepatic granulomas of Kupffer-cell-depleted mice

    H Moriyama, T Yamamoto, H Takatsuka, H Umezu, K Tokunaga, T Nagano, M Arakawa, M Naito

    AMERICAN JOURNAL OF PATHOLOGY   150 ( 6 )   2047 - 2060   1997.6

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    Language:English   Publisher:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    In mice administered with liposome-entrapped dichloromethylene diphosphonate, which depletes Kupffer cells, the size and the number of zymosan-induced granulomas in the liver were smaller than in untreated mice. The number of macrophage precursors, as detected by the monoclonal antibodies for macrophage precursors, increased after zymosan injection in both groups of mice, proliferated, and differentiated into macrophages. Expression of macrophage colony-stimulating factor (M-CSF), interleukin-1, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interferon-gamma mRNA was enhanced in the stage of granuloma formation in the control mouse liver, whereas it was suppressed in Kupffer-cell-depleted mice. However, M-CSF mRNA expression was increased in the Kupffer-cell-depleted mice to form granulomas in the late stages. In situ hybridization demonstrated the expression of M-CSF mRNA and c-fms mRNA in Kupffer cells and monocyte-derived macrophages in the sinusoid and granulomas. The concentration of M-CSF in serum of zymosan-injected control mice was within normal range, but that of zymosan-treated or untreated Kupffer-cell-depleted mice was markedly elevated at day 1. These findings imply that Kupffer cells are indispensable for granuloma formation and produce various cytokines including M-CSF. The local production and consumption of M-CSF in the liver may play a crucial role in granulomtous inflammation.

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  • Macrophage differentiation and expression of macrophage colony-stimulating factor in murine milky spots and omentum after macrophage elimination

    H Zhu, M Naito, H Umezu, H Moriyama, H Takatsuka, K Takahashi, LD Shultz

    JOURNAL OF LEUKOCYTE BIOLOGY   61 ( 4 )   436 - 444   1997.4

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    Language:English   Publisher:FEDERATION AMER SOC EXP BIOL  

    To elucidate the differentiation mechanisms of macrophages in the murine omentum, we studied the repopulation of these cells and the expression of macrophage colony-stimulating factor (M-CSF) in the milky spots and omental tissues in mice depleted of macrophages following administration of liposome-encapsulated dichloromethylene diphosphonate (clodronate). The macrophages in the omentum were spindle or dendritic in shape, expressed several macrophage-specific antigens and Ia antigen, and phagocytized intraperitoneally injected carbon particles. In the milky spots, macrophages and macrophage precursors were detected, and the number of precursors increased after elimination of macrophages by intraperitoneal injection of liposome-encapsulated clodronate. Macrophage precursors in the milky spots proliferated, moved to the omentum, and transformed into dendritic-shaped macrophages. Expression of M-CSF mRNA extracted from the milky spots was markedly enhanced at 2 and 3 days after macrophage depletion. Localization of M-CSF protein and mRNA was observed iu the stromal cells of the milky spots. In osteopetrosis (op/op) mutant mice that are defective in the production of functional M-CSF omental macrophages were absent. These results indicate that M-CSF locally produced in the milky spots plays an important role in providing a microenvironment for development and differentiation of omental macrophages.

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  • Macrophage differentiation and expression of macrophage colony-stimulating factor in murine milky spots and omentum after macrophage elimination

    H Zhu, M Naito, H Umezu, H Moriyama, H Takatsuka, K Takahashi, LD Shultz

    JOURNAL OF LEUKOCYTE BIOLOGY   61 ( 4 )   436 - 444   1997.4

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    Language:English   Publisher:FEDERATION AMER SOC EXP BIOL  

    To elucidate the differentiation mechanisms of macrophages in the murine omentum, we studied the repopulation of these cells and the expression of macrophage colony-stimulating factor (M-CSF) in the milky spots and omental tissues in mice depleted of macrophages following administration of liposome-encapsulated dichloromethylene diphosphonate (clodronate). The macrophages in the omentum were spindle or dendritic in shape, expressed several macrophage-specific antigens and Ia antigen, and phagocytized intraperitoneally injected carbon particles. In the milky spots, macrophages and macrophage precursors were detected, and the number of precursors increased after elimination of macrophages by intraperitoneal injection of liposome-encapsulated clodronate. Macrophage precursors in the milky spots proliferated, moved to the omentum, and transformed into dendritic-shaped macrophages. Expression of M-CSF mRNA extracted from the milky spots was markedly enhanced at 2 and 3 days after macrophage depletion. Localization of M-CSF protein and mRNA was observed iu the stromal cells of the milky spots. In osteopetrosis (op/op) mutant mice that are defective in the production of functional M-CSF omental macrophages were absent. These results indicate that M-CSF locally produced in the milky spots plays an important role in providing a microenvironment for development and differentiation of omental macrophages.

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  • Bone reconstruction and crystal storage in bone marrow macrophages of aged osteopetrosis (op) mice.(共著)

    Dendritic Cells   Vol.7, 43-46   1997

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  • Bone reconstruction and crystal storage in bone marrow macrophages of aged osteopetrosis (op) mice.(jointly worked)

    Dendritic Cells   Vol.7, 43-46   1997

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  • Liposome-encapsulated dichloromethylene diphosphonate induces macrophage apoptosis in vivo and in vitro

    M Naito, H Nagai, S Kawano, H Umezu, H Zhu, H Moriyama, T Yamamoto, H Takatsuka, Y Takei

    JOURNAL OF LEUKOCYTE BIOLOGY   60 ( 3 )   337 - 344   1996.9

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    Dichloromethylene diphosphonate (MDPCl(2)) encapsulated in multilamellar liposomes was selectively incorporated by macrophages, immediately transferred to lysosomes, then released from liposomes into lysosomes by enzymatic digestion of the Liposomal lipid layers. From 4 h after ingesting Liposome-encapsulated MDPCl(2) murine macrophages in vivo and in vitro acquired the ultrastructural features of apoptosis, such as condensed nuclear chromatin, nuclear fragmentation, cell shrinkage, and blebbing of the plasma membrane. Murine peritoneal macrophages and isolated rat Kupffer cells incubated in the medium containing liposome-encapsulated MDPCl(2) increased DNA fragmentation in a dose-dependent manner. Electrophoretic analysis of extracted DNA from the isolated Kupffer cells showed DNA fragmentation. Another diphosphonate, Alendronate (4-amino-1-hydroxy-butylidene-1,1- diphosphonate) had less potent macrophage cytotoxicity. However, MDPCl(2), Alendronate, and gadolinium chloride in solution were not cytotoxic to macrophages. These results implied that the intralysosomal accumulation of MDPCl(2) generates signals to induce macrophage apoptosis.

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  • Liposome-encapsulated dichloromethylene diphosphonate induces macrophage apoptosis in vivo and in vitro

    M Naito, H Nagai, S Kawano, H Umezu, H Zhu, H Moriyama, T Yamamoto, H Takatsuka, Y Takei

    JOURNAL OF LEUKOCYTE BIOLOGY   60 ( 3 )   337 - 344   1996.9

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    Language:English   Publisher:FEDERATION AMER SOC EXP BIOL  

    Dichloromethylene diphosphonate (MDPCl(2)) encapsulated in multilamellar liposomes was selectively incorporated by macrophages, immediately transferred to lysosomes, then released from liposomes into lysosomes by enzymatic digestion of the Liposomal lipid layers. From 4 h after ingesting Liposome-encapsulated MDPCl(2) murine macrophages in vivo and in vitro acquired the ultrastructural features of apoptosis, such as condensed nuclear chromatin, nuclear fragmentation, cell shrinkage, and blebbing of the plasma membrane. Murine peritoneal macrophages and isolated rat Kupffer cells incubated in the medium containing liposome-encapsulated MDPCl(2) increased DNA fragmentation in a dose-dependent manner. Electrophoretic analysis of extracted DNA from the isolated Kupffer cells showed DNA fragmentation. Another diphosphonate, Alendronate (4-amino-1-hydroxy-butylidene-1,1- diphosphonate) had less potent macrophage cytotoxicity. However, MDPCl(2), Alendronate, and gadolinium chloride in solution were not cytotoxic to macrophages. These results implied that the intralysosomal accumulation of MDPCl(2) generates signals to induce macrophage apoptosis.

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  • Macrophage Differentiation in Osteopetrotic Mice (op/op) Defective inthe Production of Macrophage Colony-Stimulating Factor (M-CSF/CSF-1)

    Makoto NAITO, Hiroyuki USUDA, Hajime UMEZU

    Niigata medical journal   110巻1号 1-12項 ( 1 )   1 - 12   1996

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    Language:Japanese   Publisher:Niigata University  

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    Other Link: http://search.jamas.or.jp/link/ui/1996229042

  • Expression of Scavenger Receptors in macrophages and Endothelial Cells.(jointly worked)

    Niigata Medical Journal   Vol. 110(6), 216-220   1996

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  • Macrophage Differentiation in Osteopetrotic mice (op/op) Defective in the Production of Macrophage Colony-Stimulating Factor (M-CSF/CSF-1).(jointly worked)

    Makoto NAITO, Hiroyuki USUDA, Hajime UMEZU

    Niigata Medical Journal   Vol. 110(1), 1-12 ( 1 )   1 - 12   1996

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    Language:Japanese   Publisher:Niigata University  

    CiNii Article

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    Other Link: http://search.jamas.or.jp/link/ui/1996229042

  • Osteopetrotic (op/op) Mice: An animal model for investigating the biology of colony-stimulating factor-1 (CSF-1/M-CSF).(jointly worked)

    Acta Medica et Biologica   Vol.44(1), 1-11   1996

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Teaching Experience

  • 医学序説 I

    2022
    Institution name:新潟大学

  • 歯科法医学

    2021
    Institution name:新潟大学

  • 医学論文を読む(ジャーナルクラブ)A

    2021
    Institution name:新潟大学

  • 医学序説 II

    2021
    Institution name:新潟大学

  • 医学序説 I

    2020
    Institution name:新潟大学

  • 特別授業 歯科法医学

    2018
    -
    2020
    Institution name:新潟大学

  • 特殊講義(法医学Ⅰ)

    2016
    Institution name:新潟大学

  • 特殊講義(法医学Ⅱ)

    2016
    Institution name:新潟大学

  • 法医学

    2015
    Institution name:新潟大学

  • 医療と法

    2014
    Institution name:新潟大学

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