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脳皮質静脈梗塞ラットモデルを用いた脳静脈虚血による神経細胞および神経前駆細胞の発現と分布
Get PDFNeurogenesis in the subventricular zone (SVZ), subgranular zone (SGZ), and cerebral cortex is now a familiar
event to confirm by cerebral arterial ischemia in rat models. However, it remains unclear whether cerebral
venous ischemia (CVI) alone causes neurogenesis, and where that neurogenesis occurs. After creating CVI rat
models via a two-vein occlusion (2-VO) method, neurogenesis was immunohistochemically evaluated by doublelabeling
5-bromo-2′ -deoxyuridine (BrdU)-positive cells with neuronal nuclei (NeuN) or doublecortin (DCX)
antibody. Fifty Wistar rats were divided into two major groups (BrdU-NeuN and BrdU-DCX) and then separated
into two subgroups (2-VO or sham). The total number of double-positive cells expressed inside a predefined
region of interest (ROI) covering the ischemic area was compared between the two subgroups. Then, we divided
the ROI into six sections to evaluate and compare the distribution of double-positive cells generated in each
section between the two subgroups. The 2-VO subgroup presented more double-positive cells than the sham
group in both BrdU-NeuN and BrdU-DCX groups, while the BrdU-DCX+2-VO group showed a characteristic
distribution of double-positive cells in ROI 2 and ROI 3, suggesting areas of the ischemic core and penumbra,
with a significant difference compared to the BrdU-DCX+sham group. This study demonstrates that CVI has the
potential to induce endogenous neurogenesis, with significant numbers of both newly generated neurons and
precursors observed in the ischemic area. The distribution of these cells suggests that the cortex could be the
main origin of neurogenesis after cortical CVI.博士（医学）・甲第872号・令和5年3月15日© 2022 The Authors. Published by Elsevier Ltd on behalf of International Brain Research Organization.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
ADAMTS13によるvon Willebrand因子の切断増加は、本態性血小板血症患者における後天性von Willebrand症候群の発症に強く寄与する。
Get PDFBackground: Patients with essential thrombocythemia (ET) often experience bleeding
associated with acquired von Willebrand syndrome (AVWS) when the platelet
count is markedly increased.
Objective: We investigated whether von Willebrand factor (VWF) degradation is enhanced
in patients with ET.
Methods: Seventy patients with ET underwent VWF multimer (VWFM) analysis and
measurement of VWF-related
parameters. We calculated the VWFM index, defined
as the ratio of intensities of a patient's molecular weight-categorized
VWFMs, and
those of a healthy subject's, using densitometric analysis. VWF degradation product
(DP) was measured via ELISA using a monoclonal antibody that specifically recognizes
Y1605 at the C-terminal
boundary, which is exposed following ADAMTS13-mediated
cleavage of the Y1605-M1606
bond of the VWF A2 domain.
Results: Patients with higher platelet counts had a significantly reduced high molecular
weight (HMW)-VWFM
index and an increased VWF-DP:
VWF antigen (Ag) ratio
compared to those with lower platelet counts. On multivariate analysis, the VWF-DP/
VWF:Ag ratio was an independent predictor of the HMW-VWFM
index. Patients who
underwent cytoreductive therapy had a significantly higher HMW-VWFM
index and
lower VWF-DP/
VWF:Ag ratio than those who did not. Among individual patients,
there was also a significant increase in the HMW-VWFM
index and a decrease in the
VWF-DP/
VWF:Ag ratio after cytoreductive therapy compared to pre-therapy
values.
Conclusion: In patients with ET, an increased platelet count is associated with enhanced
cleavage of VWF at the Y1605-M1606
bond, primarily by ADAMTS13, leading
to AVWS. Cytoreductive therapy reduces the platelet count, prevents excessive VWF
cleavage, and improves VWFM distributions.博士（医学）・甲第881号・令和5年3月15日This is the peer reviewed version of the following article: [Masayuki Kubo et al. Increased cleavage of von Willebrand factor by ADAMTS13 may contribute strongly to acquired von Willebrand syndrome development in patients with essential thrombocythemia. Journal of Thrombosis and Haemostasis. 2022, 20(7), p.1589-1598.], which has been published in final form at [https://doi.org/10.1111/jth.15717]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited
アンジオテンシン受容体拮抗薬は、肝硬変ラットの骨格筋萎縮に対して、分岐鎖アミノ酸製剤による保護効果を増強する。
Get PDFScope: This study investigated the combined effect of the angiotensin II
(AT-II) receptor blocker losartan and branched-chain amino acids (BCAAs) on
skeletal muscle atrophy in rats with cirrhosis and steatohepatitis.
Method and Results: Fischer 344 rats are fed a choline-deficient l-amino
acid-defined (CDAA) diet for 12 weeks and treated with oral losartan (30 mg
kg−1 day−1) and/or BCAAs (Aminoleban EN, 2500 mg kg−1 day−1). Treatment
with losartan and BCAAs attenuated hepatic inflammation and fibrosis and
improved skeletal muscle atrophy and strength in CDAA-fed rats. Both agents
reduced intramuscular myostatin and pro-inflammatory cytokine levels,
resulting in inhibition of the ubiquitin–proteasome system (UPS) through
interference with the SMAD and nuclear factor-kappa B pathways,
respectively. Losartan also augmented the BCAA-mediated increase of skeletal
muscle mass by promoting insulin growth factor-I production and
mitochondrial biogenesis. Moreover, losartan decreased the intramuscular
expression of transcription factor EB (TFEB), a transcriptional inducer of E3
ubiquitin ligase regulated by AT-II. In vitro assays illustrated that losartan
promoted mitochondrial biogenesis and reduced TFEB expression in
AT-II-stimulated rat myocytes, thereby potentiating the inhibitory effects of
BCAAs on the UPS and caspase-3 cleavage.
Conclusion: These results indicate that this regimen could serve as a novel
treatment for patients with sarcopenia and liver cirrhosis.博士（医学）・甲第861号・令和5年3月15日This is the peer reviewed version of the following article: [Soichi, Takeda et al. Angiotensin Receptor Blockers Potentiate the Protective Effect of Branched-Chain Amino Acids on Skeletal Muscle Atrophy in Cirrhotic Rats. Molecular Nutrition & Food Research. 2021, 65(24), 2100526.], which has been published in final form at [https://doi.org/10.1002/mnfr.202100526]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited
心室中隔欠損症に対する小児心臓カテーテル検査における麻酔方法と重症合併症の関連
Get PDFPediatric cardiac catheterization requires unconsciousness and immobilization through
general anesthesia or sedation. This study aimed to compare the occurrence of severe complications
in pediatric diagnostic cardiac catheterization for ventricular septal defect between general anesthesia
and sedation performed under similar institutional environments. Using the Japanese Diagnosis
Procedure Combination database, we retrospectively identified pediatric patients (aged <2
years) who underwent diagnostic cardiac catheterization for ventricular septal defect between July
2010 and March 2019. The composite outcome was the occurrence of severe complications, including
catecholamine use and intensive care unit admission, within seven days after catheterization.
Overlap weighting based on propensity scores was used to adjust for patient- and hospital-level
confounding factors. We identified 3159 patients from 87 hospitals, including 930 under general
anesthesia and 2229 under sedation. The patient- and hospital-level baseline characteristics differed
between the groups. After adjustment, the proportion of patients with severe complications was
significantly higher in the general anesthesia group than in the sedation group (2.4% vs. 0.6%; risk
difference, 1.8% [95% confidence interval, 0.93–2.6%]). Severe complications occurred more frequently
in the general anesthesia group than in the sedation group. Further research on anesthetic
methods is necessary to assess the safety and accuracy of pediatric diagnostic cardiac catheterization.博士（医学）・甲第867号・令和5年3月15日© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)
外側環軸関節の関節症性変化のリスク増加に関連する要因; 後ろ向き研究
Get PDFPurpose Atlantodens osteoarthritis and atlantoaxial osteoarthritis cause neck pain and suboccipital headaches. Currently,
knowledge on the risk factors for atlantoaxial osteoarthritis is lacking. This study aimed to investigate the factors related
to the increased risk of atlantoaxial osteoarthritis. Methods We analyzed computed tomography (CT) images of the upper
cervical spine of 1266 adult trauma patients for whom upper cervical spine CT was performed at our hospital between 2014
and 2019. The degree of atlantoaxial osteoarthritis was quantified as none-to-mild (not having osteoarthritis) or moderateto-
severe (having osteoarthritis). Risk factors associated with atlantoaxial osteoarthritis were identified using univariate and
multivariable logistic regression analyses. Results The study group included 69.4% men, and the overall average age of the
study population was 54.9 ± 20.4 years. The following factors were independently and significantly associated with atlantoaxial
osteoarthritis in the multivariable logistic regression analysis: age in the sixth decade or older (odds ratio [OR], 20.5;
95% confidence interval [CI], 6.2‒67.2, p < 0.001), having calcific synovitis (OR, 4.9; 95% CI, 2.4‒9.9, p < 0.001), women
sex (OR, 3.3; 95% CI, 1.9‒5.7, p = 0.002), and not having atlantodens osteoarthritis (OR, 2.1; 95% CI, 1.2‒3.8, p = 0.014).
Conclusion In the multivariable logistic regression analysis, age in the sixth decade or older, calcification of the transverse
ligament, being women, and not having atlantodens osteoarthritis were found to be significantly associated with atlantoaxial
osteoarthritis. Delayed diagnosis and treatment can be avoided by focusing on these risk factors.博士（医学）・甲第873号・令和5年3月15日This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00586-022-07414-
酸化型HMGB-1は間葉系幹細胞/間葉系細胞を介して大腸癌の転移性を促進する
Get PDFHigh mobility group box-1
(HMGB1) is known to be a chemotactic factor for mesenchymal
stem/stromal cells (MSCs), but the effect of post-translational
modification on
its function is not clear. In this study, we hypothesized that differences in the oxidation
state of HMGB1 would lead to differences in the function of MSCs in cancer. In
human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver
metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three-fold
fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced
HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM-MSCs)
and
induced differentiation into osteoblasts and vascular pericytes, whereas oxidized
HMGB1 promoted proliferation and increased stemness, and no differentiation was
observed. When BM-MSCs
pretreated with oxidized HMGB1 were co-cultured
with
syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased,
and tumorigenesis and drug resistance were promoted. In contrast, co-culture
with
reduced HMGB1-pretreated
BM-MSCs
did not enhance stemness. In an animal orthotopic
transplantation colorectal cancer model, oxidized HMGB1, but not reduced
HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore,
oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized
HMGB1–MSC
axis may be an important target for cancer therapy.博士（医学）・甲第874号・令和5年3月15日© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made