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フォン・ヴィレブランド因子の機能を調節することで、マウスの急性腎虚血再灌流障害を緩和できる
Get PDFAcute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and may become fatal. In addition to its hemostatic functions, von Willebrand factor (VWF) is known to play a role in cross-talk between inflammation and thrombosis. We hypothesized that VWF may be involved in the pathophysiology of AKI, major causes of which include insufficient renal circulation or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the role of VWF in AKI using a mouse model of acute ischemia-reperfusion (I/R) kidney injury. We analyzed renal function and blood flow in VWF-gene deleted (knock-out; KO) mice. The functional regulation of VWF by ADAMTS13 or a function-blocking anti-VWF antibody was also evaluated in this pathological condition. Greater renal blood flow and lower serum creatinine were observed after reperfusion in VWF-KO mice compared with wild-type (WT) mice. Histological analysis also revealed a significantly lower degree of tubular damage and neutrophil infiltration in kidney tissues of VWF-KO mice. Both human recombinant ADAMTS13 and a function-blocking anti-VWF antibody significantly improved renal blood flow, renal function and histological findings in WT mice. Our results indicate that VWF plays a role in the pathogenesis of AKI. Proper functional regulation of VWF may improve the microcirculation and vessel function in the kidney, suggesting a novel therapeutic option against AKI.博士（医学）・甲第744号・令和2年3月16日© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
妊娠高血圧症候群におけるRAGEの関与
Get PDFPreeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially life-threatening disease. Recently, PE/HDP has been considered to cause adipose tissue inflammation, but the detailed mechanism remains unknown. We exposed human primary cultured adipocytes with serum from PE/HDP and healthy controls for 24 h, and analyzed mRNA expression of several adipokines, cytokines, and ligands of the receptor for advanced glycation endproducts (RAGE). We found that the mRNA levels of interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), high mobility group box 1 (HMGB1), and RAGE were significantly increased by the addition of PE/HDP serum. Among RAGE ligands, advanced glycation endproducts (AGE) and HMGB1 increased mRNA levels of IL-6 and CCL2 in SW872 human adipocytes and mouse 3T3-L1 cells. The introduction of small interfering RNA for RAGE (siRAGE) into SW872 cells abolished the AGE- and HMGB1-induced up-regulation of IL-6 and CCL2. In addition, lipopolysaccharide (LPS), a ligand of RAGE, increased the expression of IL-6 and CCL2 and siRAGE attenuated the LPS-induced expression of IL-6 and CCL2. These results strongly suggest that the elevated AGE, HMGB1, and LPS in pregnant women up-regulate the expression of IL-6 and CCL2 via the RAGE system, leading to systemic inflammation such as PE/HDP.博士（医学）・乙第1451号・令和2年3月16日© 2019 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 (http://creativecommons.org/licenses/by/4.0/)
頚椎手術術中神経モニタリングにおける偽陽性減少を目的とした顔面運動誘発電位の応用
Get PDFObjective: False-positive intraoperative muscle motor evoked potential (mMEP) monitoring results due to systemic effects of anesthetics and physiological changes continue to be a challenging issue. Although control MEPs recorded from the unaffected side are useful for identifying a true-positive signal, there are no muscles on the upper or lower extremities to induce control MEPs in cervical spine surgery. Therefore, this study was conducted to clarify if additional MEPs derived from facial muscles can feasibly serve as controls to reduce false-positive mMEP monitoring results in cervical spine surgery. Methods: Patients who underwent cervical spine surgery at the authors' institution who did not experience postoperative neurological deterioration were retrospectively studied. mMEPs were induced with transcranial supramaximal stimulation. Facial MEPs (fMEPs) were subsequently induced with suprathreshold stimulation. The mMEP and subsequently recorded fMEP waveforms were paired during each moment during surgery. The initial pair was regarded as the baseline. A significant decline in mMEP and fMEP amplitude was defined as > 80% and > 50% decline compared with baseline, respectively. All mMEP alarms were considered false positives. Based on 2 different alarm criteria, either mMEP alone or both mMEP and fMEP, rates of false-positive mMEP monitoring results were calculated. Results: Twenty-three patients were included in this study, corresponding to 102 pairs of mMEPs and fMEPs. This included 23 initial and 79 subsequent pairs. Based on the alarm criterion of mMEP alone, 17 false-positive results (21.5%) were observed. Based on the alarm criterion of both mMEP and fMEP, 5 false-positive results (6.3%) were observed, which was significantly different compared to mMEP alone (difference 15.2%; 95% CI 7.2%-23.1%; p < 0.01). Conclusions: fMEPs might be used as controls to reduce false-positive mMEP monitoring results in cervical spine surgery.博士（医学）・甲第746号・令和2年6月30日© Copyright 2019 American Association of Neurological SurgeonsThe definitive version is available at " http://dx.doi.org/10.3171/2019.9.SPINE19800
日本における小児血友病患者の日本語版KIDSCREEN-52を用いたQOLの自己評価および保護者による評価
Get PDFIntroduction: Assessing health-related quality of life (HRQOL) is critical for providing comprehensive clinical care to patients with haemophilia. HRQOL in individuals with similar cultural backgrounds should be compared using internationally standardized, generic questionnaires. Aim: To evaluate self-/parent-assessed HRQOL in Japanese children and adolescents with haemophilia A or B. Methods: Children and adolescents aged 8-18 years were enrolled. The haemophilia group comprised families with haemophilia, and the control group comprised those without chronic illness. HRQOL was assessed using the self-/parent-reported questionnaire KIDSCREEN-52, the Japanese version. The Oslo 3-Item Social Support Scale was investigated. Results: The questionnaire was completed by 36 families in the haemophilia group and 160 parents and children in the control group. Haemophilia children aged 8-12 years had lower scores for 'moods and emotions' than control children; the parents had lower scores in the haemophilia group than in the control group for 'moods and emotions', 'social support and peers', and 'school environment'. No significant differences in HRQOL were observed between both groups of adolescents aged 13-18 years or their parents. Neck-shoulder pain was associated with a low psychological state, including 'self-perception', but other joint pains did not affect the outcomes of the HRQOL indices. Social support weaknesses were associated with low physical and psychological states, whereas unexpected hospital visits identified low values for 'self-perception', 'autonomy', and 'school environment'. Conclusion: Proactive mental and clinical care in haemophilia families, especially with young children, will foster a better environment for patients and their parents and ease concerns about progress in haemophilia.博士（医学）・甲第747号・令和2年6月30日© 2020 John Wiley & Sons Ltd.This is the peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1111/hae.13945], which has been published in final form at [https://doi.org/10.1111/hae.13945]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
液状化細胞診材料を用いた遺伝子解析による腫瘍特異的遺伝子検出感度の検討
Get PDFLiquid-based cytology (LBC) analysis of sputum is a useful diagnostic and prognostic tool for detecting lung cancer. DNA and RNA derived from lung cancer cells can be used for this diagnosis. However, the quality of cytological material is not always adequate for molecular analysis due to the effect of formalin in the commercially available fixation kits. In this study, we examined DNA and RNA extraction methods for LBC analysis with formalin fixation, using lung carcinoma cell lines and sputum. The human non-small cell lung cancer cell lines were fixed with LBC fixation reagents, such as CytoRich red preservative. Quantification of thyroid transcription factor-1 (TTF-1) and actin mRNA, epidermal growth factor receptor (EGFR) DNA in HCC827, H1975, and H1299 cells, and mutation analysis of EGFR in HCC827 and H1975 cells were performed by quantitative PCR (qPCR) and fluorescence resonance energy transfer (FRET)-based preferential homoduplex formation assay (F-PHFA) method, respectively. mRNA and DNA extracted from cell lines using RNA and/or DNA extraction kits for formalin-fixed paraffin-embedded (FFPE) fixed with various LBC solutions were efficiently detected by qPCR. The detection limit of EGFR mutations was at a rate of 5% mutated positive cells in LBC. The detection limit of the EGFR exon 19 deletion in HCC827 was detected in more than 1.5% of the positive cells in sputum. In contrast, the detection limit of the T790M/L858R mutation in H1975 was detected in more than 13% of the positive cells. We also detected EGFR mutations using next generation sequencing (NGS). The detection limit of NGS for EGFR mutation was lower than that of the F-PHFA method. Furthermore, more than 0.1% of positive cells could be cytomorphologically detected. Our results demonstrate that LBC systems are powerful tools for cytopathological and genetic analyses. However, careful attention should be paid to the incidence of false negative results in the genetic analysis of EGFR mutations detected by LBC.博士（医学）・甲第750号・令和2年6月30日© 2020 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 (http://creativecommons.org/licenses/by/4.0/)
Betulinic acidのラット静脈虚血進行抑制効果について
Get PDFBackground/Objectives: Betulinic acid is a component of a Chinese traditional herb that upregulates endothelial nitric oxide (NO) synthase (eNOS) and reduces NADPH expression. Increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) after cerebral arterial ischemia is a major cause of neuronal damage. Local venous ischemia can arise that slowly damages surrounding brain tissue during surgical procedures. The present study investigated the effects on infarct size when betulinic acid was administered after inducing two-vein occlusion (2VO) with a slowly developing lesion in rats. Methods: We elicited 2VO in 18 male Wistar rats by the photochemical thrombosis of two adjacent cortical veins combined with KCL-induced cortical spreading depression (CSD). The rats were then randomized into groups (n=9 each) to receive either dimethyl sulfoxide (DMSO) vehicle (control) or betulinic acid (30mg/kg/day; n=9) by daily gavage for seven days, and then infarct volume and 3-nitrotyrosine expression were assessed. Results: Daily administration of betulinic acid for seven days significantly reduced infarct volume from 3.81 ± 0.7 to 1.90 ± 0.3mm³ (p=0.017). Physiological data and regional cerebral blood flow did not significantly differ between the two groups during the study. We found 3-nitrotyrosine expression within the border zone of the infarct area and cleaved caspase-3 only within the lesion at the ipsilateral hemisphere in both groups. However, 3-nitrotyrosine/caspase-3 expression did not significantly differ at any time between the groups. Conclusions: Betulinic acid reduced neuronal damage in a rat model of cerebral venous ischemia.博士（医学）・乙第1460号・令和2年6月30
卵巣チョコレート嚢胞とその悪性転化における酸化抗酸化パラメーターの比較
Get PDFThe present study aimed to evaluate the levels of oxidative stress and antioxidant markers in benign endometrioma (OE) and its malignant transformation [endometriosis-associated ovarian cancer (EAOC)] by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG), heme oxygenase-1 (HO-1) and total antioxidant capacity (TAC/Heme-iron) alterations associated with disease progression. Cyst fluid samples from 44 patients with OE and 14 patients with EAOC were studied using an enzyme-linked immunosorbent assay. A χ2 test, t-test and Pearson correlation test were performed using SPSS version 22.0. The cut-off point, sensitivity and specificity of each marker for EAOC diagnosis were evaluated by receiver operating characteristic curve analysis. Cyst fluid 8-OHdG and HO-1 levels in the EAOC group were significantly decreased compared with the OE subjects (P=0.013 and P<0.001, respectively). The levels of TAC/Heme-iron in patients with EAOC were significantly higher compared with those in the OE subjects (P<0.001). The present study demonstrated a positive correlation between 8-OHdG and HO-1 levels (P=0.012). HO-1 exhibited the highest discriminant value for EAOC (Area Under the Curve=0.901). The optimal cut-off point of HO-1 for the diagnosis of EAOC was 2.314 ng/ml, with a sensitivity and specifity of 95.2 and 85.7%, respectively. The present study revealed a clear separation between the overall redox state in OE and EAOC. It was concluded that characteristic alterations in important factors in redox may be helpful for understanding the pathogenesis of the malignant transformation of endometriosis.博士（医学）・乙第1472号・令和2年9月30日Copyright © 2018, Spandidos PublicationsArticles from Oncology Letters are provided here courtesy of Spandidos Publications.The publication is available at Spandidos Publications via https://doi.org/10.3892/ol.2018.924
Preparations for childcare made by the husbands of primiparas.
Get PDF目的：妻の妊娠期において、初産婦の夫が育児に関する準備行動をどのように行っているのかについて夫自身の語りから明らかにする。方法：初産婦の夫5名に半構成的面接を実施し、Modified Grounded Theory Approachの方法を用いて分析した。結果：5個のカテゴリーと16個の概念があった。初産婦の夫は、妊娠初期から後期の全期を通して、【父親役割の模索】を行っていた。【父親なりに知識を得るための情報収集】を行い、長期的な視点で子どもの成長過程を考え、子どものために安心・安全な環境を作りたいという想いで【育児用品の準備】を行っていた。また、【経済基盤の認識の変化】により、先を見据えた準備行動をとっていた。また、夫婦から家族に変化するために、妻と協力し【夫婦の関係性の中での役割再構築】を行っていた。考察：父親モデルは変化することが可能であり、助産師は必要時に、夫婦の新たな関係を構築するための支援が必要であると示唆された。また、ネットリテラシーの観点において、助産師からの正しい情報提供は重要である。夫への保健指導実施時に、夫に関する情報収集を行い、夫婦の関係性を高める両親学級の運営が必要であると示唆された。Purpose: To clarify the childcare preparations made durig pregnancy by the husbands of primiparas based on the husbands'own stories. Method: Semi-structured interviews were conducted with five husbands of primiparas and answers were analyzed using the Modified Grounded Theory Approach. Results: The analysis produced 5 categories and 16 concepts. The husbands of primiparas “explored the paternal role” throughout the entire pregnancy from the first to third trimesters. Husbands “gathered information to obtain as much knowledge as a father can,” considered the child's process of growth from a long-term perspective, and “prepared childcare supplies” with the desire to create a safe and secure environment for the child. Husbands also made forward-looking preparations in response to “changes to the recognition of household finances.” Furthermore, to transition from a married couple to a family, husbands worked in cooperation with their wifves to “restructure their roles within the couple's relationship.” Discussion: The findings suggested that the paternal model can change and that midwives must support couples in building a new relationship in times of need. Furthermore, it is important that midwives provide accurate information from the viewpoint of internet literacy. This study indicated the need to gather information on husbands when providing husbands with health guidance and to run classes for both parents to improve couples' relationships
