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肝硬変治療へ向けた細胞外小胞の分布・回収・容量依存性についての分析
Get PDF新潟大学Niigata University博士（医学）Background The progression of liver fibrosis leads to portal hypertension and liver dysfunction. However, no anti-fibrotic agents have been approved for cirrhosis to date, making them an unmet medical need. Small extracellular vesicles (sEVs) of mesenchymal stem cells (MSCs) are among these candidate agents. In this study, we investigated the effects of sEVs of MSCs, analyzed their distribution in the liver post-administration, whether their effect was dose-dependent, and whether it was possible to collect a large number of sEVs. Methods sEVs expressing tdTomato were generated, and their uptake into constituent liver cells was observed in vitro, as well as their sites of uptake and cells in the liver using a mouse model of liver cirrhosis. The efficiency of sEV collection using tangential flow filtration (TFF) and changes in the therapeutic effects of sEVs in a volume-dependent manner were examined. Results The sEVs of MSCs accumulated mostly in macrophages in damaged areas of the liver. In addition, the thera-peutic effect of sEVs was not necessarily dose-dependent, and it reached a plateau when the dosage exceeded a certain level. Furthermore, although ultracentrifugation was commonly used to collect sEVs for research purposes, we verified that TFF could be used for efficient sEV collection and that their effectiveness is not reduced. Conclusion In this study, we identified some unknown aspects regarding the dynamics, collection, and capac-ity dependence of sEVs. Our results provide important fundamentals for the development of therapies using sEVs and hold potential implications for the therapeutic applications of sEV-based therapies for liver cirrhosis.Inflammation and Regeneration. 2023, 43, 48.Published source is the following：Takeda, N., Tsuchiya, A., Mito, M. et al. Analysis of distribution, collection, and confirmation of capacity dependency of small extracellular vesicles toward a therapy for liver cirrhosis. Inflamm Regener 43, 48 (2023). https://doi.org/10.1186/s41232-023-00299-x新大院博（医）第1164
Pathological Analysis of Granulocyte Extracellular Trap in Neuromyelitis Optica Spectrum Disorders
Get PDF新潟大学Niigata University博士（医学）多発性硬化症 (multiple sclerosis; MS) と視神経脊髄炎スペクトラム (neuromyelitis optica spectrum disorders: NMOSD) は中枢神経系の代表的な自己免疫疾患である. MS ではミエリンオリゴデンドロサイトを標的とするが, 本質的な病態は未だ明らかにされていない. 一方, NMOSD では水チャネル分子アクアポリン4 (aquaporin-4: AQP4) 抗体と補体の活性化が病変形成に関与する. 両疾患は視神経や脊髄に病変を引き起こすが, NMOSD は, MS に比べて広範囲な脊髄炎や視神経炎をきたし, 重篤な神経障害を伴う. 近年の研究によれば, 全身性エリテマトーデスなどの自己免疫疾患で, 細胞外に網状の構造物を形成する好中球細胞外トラップ (neutrophil extracellular traps: NETs) が病原性に関連し, 自己免疫応答を増強することが知られている. NMOSD においても, 好中球由来の細胞外DNA が, Ⅰ型インターフェロン (interferon: IFN) 活性を促進し, 疾患重症度と関連することが指摘されている. 本研究では, 「NMOSD の病変内に浸潤した好中球がNETs を形成し, それが病変形成と重篤な神経障害に寄与する」という仮説を立て, 顆粒球のステージ依存的な組織学的解析を行った.対象はNMOSD 3 例, MS 3 例, 疾患対照 3 例とした. 既報に基づき, initial lesion (IL), early active lesion (EA), late active lesion (LA), inactive lesion (IA), mixed active/inactive lesions(ML) に分類した. 顆粒球評価のために好中球マーカーであるmyeloperoxidase (MPO), neutrophil elastase (NE), NETs の特異的マーカーであるシトルリン化ヒストン(citrullinated histone H3: CitH3) 発現を免疫組織化学法で評価した. Rosette & rim patternに活性化補体沈着血管を有するpattern-specific loss of AQP4 immunoreactivity はNMOSDの急性期病変の全てに認めたが, MS 全病変や他の疾患対照では認めなかった. 顆粒球浸潤は, 活性化補体が沈着する血管を中心にNMOSD IL/EA 病変, LA 病変で認めたが, MS 全病変や他の疾患対照では認めなかった. MPO またはNE を発現する好中球浸潤はNMOSD IL/EA 病変, LA 病変に認め, MPO とCitH3 の共染色で示されるNETs は, NMOSD IL/EA病変でのみ認めた. NMOSD の早期病変で, 顕著な活性化好中球およびNETs を認めたことから, NMOSD では, AQP4 抗体と活性化補体だけでなく, NETs を伴う顆粒球が病態形成に関与することが推測された.新大院博（医）第1168
造血幹細胞移植においてドナー細胞のコンドロイチン硫酸発現減少は、T 細胞の活性化を抑制することで、肝GVHD を抑制する
Get PDF新潟大学Niigata University博士（医学）Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4+ and CD8+ effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.Scientific reports. 2023, 13. 13098新大院博（医）第1176
交互脈を伴う拡張型心筋症患者におけるベースラインの血圧と左室逆リモデリングに関する研究
Get PDF新潟大学Niigata University博士（医学）Objective Spontaneous mechanical alternans (MA), or pulsus alternans, has been observed in heart failure patients with hypertension or tachycardia for 150 years and is considered a sign of a poor prognosis. How-ever, in some dilated cardiomyopathy (DCM) patients with MA, optimal medical therapy (OMT) brings left ventricular reverse remodeling (LVRR), a preferable prognostic indicator. This study examined the probability of LVRR in DCM patients with spontaneous MA and whether or not LVRR can be predicted by the baseline blood pressure or heart rate. Methods We conducted a single-center, retrospective observational study of newly diagnosed DCM patients from January 2017 to December 2020. Results Thirty-three newly diagnosed DCM patients were retrospectively examined. Spontaneous MA was observed during diagnostic cardiac catheterization in at least 1 of the pressure waveforms of the aorta, left ventricle, pulmonary artery, or right ventricle in 10 patients (30%) (MA-group). LVRR after OMT was achieved roughly equally in the MA group (6 of 10, 60%) and the non-MA group (12 of 23, 52%). In the MA group, those who achieved LVRR had a significantly higher baseline systolic aortic pressure (more than 120 mmHg in all 6 patients) than those who did not, although the baseline heart rate did not show a signifi-cant correlation with LVRR. In contrast, in the non-MA group, LVRR was unrelated to the baseline aortic pressure or heart rate. Conclusion The probability of LVRR in newly-diagnosed DCM patients with spontaneous MA was similar to that in those without spontaneous MA. Spontaneous MA may not necessarily be a sign of a poor progno-sis if observed in patients with a preserved blood pressure.Mitsuhiro Watanabe, Takeshi Kashimura, Mitsuo Ishizuka, Mayumi Kase, Ryohei Sakai, Shinya Fujiki, Tsugumi Takayama, Shiro Ishihara, Kazuyuki Ozaki, Takayuki Inomata, Baseline Blood Pressure and Left Ventricular Reverse Remodeling in Dilated Cardiomyopathy with Spontaneous Mechanical Alternans, Internal Medicine, 2023, Volume 62, Issue 12, Pages 1707-1713, Released on J-STAGE June 15, 2023, Advance online publication November 09, 2022, Online ISSN 1349-7235, Print ISSN 0918-2918, https://doi.org/10.2169/internalmedicine.0711-22, https://www.jstage.jst.go.jp/article/internalmedicine/62/12/62_0711-22/_article/-char/en新大博（医）第1189
術後のグローバルオフセットと人工股関節全置換術後成績の関連性
Get PDF新潟大学Niigata University博士（医学）Global femoral offset (GFO) and femoral offset (FO) reportedly affect outcomes following total hip arthroplasty (THA). However, FO assessed using plain radiography is affected by internal and external rotations of the hip joint. We investigated the relationship between leg length discrepancy and Harris hip score (HHS), and their influence on acetabular offset (AO), FO, GFO, anterior femoral offset, and outcomes after THA. We retrospectively evaluated 140 patients with hip osteoarthritis who underwent THA. A three-dimensional (3D) pelvis and femur model created from computed tomography (data using ZedHip software was used to investigate these parameters. The modified (m)HHS scores were significantly improved from 49.0 to 88.8 in total mHHS, 20.0–44.5 in pain, and 28.9–44.4 points in function. Significant correlations were found between the differences in AO, FO, GFO, and pain score in binominal, with maximum values of − 1.24, + 1.54, and + 0.90 mm/100 cm body height, respectively. The maximum value of GFO and mHHS in binominal was + 1.17 mm/100 cm body height (BH). The optimal range of difference of GFO was − 1.75 to 4.09 mm/100 cm BH. This is the first report using a 3D method for assessing FO. Preoperative planning using the system could improve postoperative function.Hirano, Y., Imai, N., Nozaki, A. et al. The association of postoperative global femoral offset with total hip arthroplasty outcomes. Sci Rep 13, 1621 (2023). https://doi.org/10.1038/s41598-023-28863-y新大博（医）第1191
関節リウマチによって破壊された膝関節では、大腿骨皮質骨厚は薄くなっている
Get PDF新潟大学Niigata University博士（医学）Background The examination of femoral cortical bone thickness in patients with rheumatoid arthritis (RA) has been notably limited in prior research. We aimed to compare femoral cortical thickness in patients with rheumatoid arthritis (RA) and healthy controls and to investigate the association between femoral cortical thickness and clinical param-eters within the RA group. Methods Forty-four patients (58 limbs) with RA who underwent total knee arthroplasty were enrolled. Preoperative computed tomography images of the lower limbs were analyzed. The femoral cortex was divided into the proximal, central, and distal diaphysis regions and further into the anterior, posterior, medial, and lateral regions. The divisions were measured using Stradwin® software and standardized by femoral length. Femoral cortical thickness was com-pared between RA and healthy control (n = 25) groups. Correlation analyses between standardized cortical thickness and disease parameters were performed in the RA group. Results The RA group had significantly lower standardized femoral cortical thickness at the anterior and medial distal diaphysis than healthy controls. Standardized proximal lateral and central lateral in the RA group were significantly larger than those in the healthy control groups. Standardized femoral cortical thickness was significantly correlated with bone mineral density (BMD) in 11 areas, except the posterior central diaphysis, and with body mass index in 8 areas, except the central posterior, distal lateral, distal anterior, and distal medial diaphysis. Conclusions Femoral cortical thinning was noted in patients with RA complicated with destructive knee, particularly at the anterior and medial distal diaphysis. Femoral cortical thickness was significantly correlated with BMD and body mass index (BMI); thus, patients with RA and low BMD and BMI should be cared for to prevent fragility fractures.The version of record of this article, first published in Journal of Orthopaedic Surgery and Research, is available online at Publisher’s website: https://doi.org/10.1186/s13018-023-04340-0Kakutani, R., Kondo, N., Yamako, G. et al. Thinner femoral cortical thickness in patients with destructive rheumatoid arthritis of the knee. J Orthop Surg Res 18, 850 (2023). https://doi.org/10.1186/s13018-023-04340-0新大博（医）第1193
中高年及び高齢女性における脊椎矢状面アライメント不良がロコモティブシンドロームと身体機能に及ぼす影響
Get PDF新潟大学Niigata University博士（医学）Background Adult spinal deformity has a substantially debilitating effect on older people’s physical and mental health. However, the impact of sagittal malalignment on locomotive syndrome (LS), sarcopenia, and physical func-tion in community-dwelling older women has not yet been clarified. This study aimed to investigate the association between these factors in community-dwelling middle aged and older women. Methods A total of 361 women were recruited from participants performing aquatic exercises in a rural area of Japan. The body mass index, skeletal muscle mass index, trunk muscle mass, spinal inclination angle (SIA), grip strength, timed up-and-go test (TUG), maximum stride of the participants, and one-leg standing time were measured. Low back pain (LBP)- and health-related quality of life (HRQOL) were evaluated using the Oswestry Disability Index (ODI) and the Short-Form 8 questionnaire. Associations between the global sagittal alignment using SIA and investi-gating parameters were analyzed. Results The prevalence of sarcopenia was 3.6%. The prevalence of LS (stages 1, 2, and 3) was 43.8% (158 of 361), and the number of participants in each LS stage was 203 (stage 0), 95 (stage 1), 28 (stage 2), and 35 (stage 3). The SIA was significantly correlated with the 25-question geriatric locomotive function scale (r′= 0.292, p < 0.001), ODI (r′= 0.267, p < 0.001), and TUG (r′ = 0.453, p < 0.001) after adjusting for age. In the receiver-operating characteristic curve analysis, the cutoff values of SIA for LS ≥ stage 2 and ODI ≥ 20% were 5°. Conclusions LBP-related QOL and physical performance were significantly associated with global sagittal alignment. Global sagittal alignment was correlated with the three-stage category of LS. The spinal inclination of 5° was a cutoff value to predict exacerbation of mobility function and HRQOL status.Yahata, M., Watanabe, K., Tashi, H. et al. Impact of spinal sagittal malalignment on locomotive syndrome and physical function in community-dwelling middle aged and older women. BMC Musculoskelet Disord 24, 620 (2023). https://doi.org/10.1186/s12891-023-06686-2新大博（医）第1198