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術後急性痛に対する抑肝散の鎮痛効果とセロトニン神経系の関与 : モデルマウスによる検討
Get PDF新潟大学Niigata University博士（医学）Background Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, demen-tia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. Methods A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analge-sic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. Results Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administra-tion of 2.5 μg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. Conclusion This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postop-erative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the ser-otonin receptors, to produce analgesia.Kurita, S., Sasaki, M., Tanaka, M. et al. Analgesic effects of oral Yokukansan on acute postoperative pain and involvement of the serotonin nervous system: a mouse model study. BMC Complement Med Ther 24, 198 (2024). https://doi.org/10.1186/s12906-024-04501-6新大院博（医）第1217
乳汁プロゲステロンプロファイルと自動搾乳システムからの情報を用いた乳牛における鈍性発情の検出
Get PDF新潟大学Niigata University博士（学術）The objective of this study was to assess the reproductive profiles of dairy cows based on progesterone analysis and to evaluate the accuracy of activity monitoring devices (pedometers). The interval from calving to commencement of luteal activity postpartum averaged around 28.7 days, with the first ovulation around 23.7 days in the first experiment and luteal activity postpartum averaged 33.4 days, with the first ovulation around 28.4 days in the second experiment. Normal estrous cycles had an average duration of 20.5 days, the short cycle was 15.4 days, and the long cycle was 27.5 days in the first experiment. In the second experiment the estimated duration of normal cycles was 21.3 days. The duration of short cycles was 16.4 days, and long cycles was 28.1 days. Determination of cyclic patterns showed 66.7% of normal cycles, 22.2% luteal phases, and 11.1% delayed cyclicity, no cessation of cyclicity was observed in the herd. In the second study the pattern of cyclicity was: 41.7% (5/12) were normal, 25.0% (3/12) – prolonged luteal phase, 25.0% (3/12) – delayed cyclicity and cessation of cyclicity – 8.33% (1/12). The study assessed the pedometer's signals against progesterone profiles for estrus detection accuracy. Results in the first experiment indicated that 34.1% of expected estrus cases went undetected by pedometers, 17.0% of signals were false, and 48.9% of estrus signals were identified as correct. Our study suggested that the activity monitored by a pedometer is utilized for heat detection, to some degree and offers valuable insights into dairy cow reproductive profiles. However, some caution is needed when applying these findings more broadly, they stem from a single herd study with potential influences from diverse factors affecting estrus expression and device performance.新大院博(学)第231
NRAS のミスセンス変異は神経皮膚黒色症の悪性化に関与する
Get PDF新潟大学Niigata University博士（医学）Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a signi!cantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.Acta Neuropathologica Communications. 2024, 12, 14.Published source is the following :Takahashi, H., Natsumeda, M., Hara, N. et al. Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis. acta neuropathol commun 12, 14 (2024). https://doi.org/10.1186/s40478-024-01723-0新大院博（医）第1163
Cell therapy using oxygen-glucose deprived peripheral blood mononuclear cells acts in hypoxic lesions after ischemia-reperfusion
Get PDF新潟大学Niigata University博士（医学）近年，脳梗塞に対する機械的血栓除去術が行われているが，その効果は十分ではない．その原因として，虚血再灌流後の低酸素領域に着目した．主幹動脈の再灌流を行っても，低酸素状態に陥った脳組織は，微小循環障害を生じ，局所的な低酸素状態が生じる可能性がある．当研究室では，これまで脳梗塞後遺症を呈するラットに低酸素低糖刺激（OGD）を加えた末梢血単核球（PBMC）を投与すると，PBMCが脳内に移行しVEGF 発現と組織修復を促すことを報告してきた．そこで本研究では，一過性脳虚血モデルラットにおいて同治療法が虚血再灌流後の低酸素領域に作用するかを検討した．ヒト末梢血からPBMC を遠心分離し，18時間OGD 刺激を行った（OGD-PBMC）．一過性局所脳虚血モデルラットを作成し，脳虚血 7 日後にOGD-PBMC またはPBS を投与した．投与 3 日後または21 日後の脳標本を用いて免疫染色をおこなった．虚血再灌流後低酸素領域を，低酸素マーカーであるpimonidazole が発現している領域と定義し，解析をおこなった．細胞投与 3 日後の標本で，ヒト細胞質特異抗体（STEM121）陽性細胞はすべてpimonidazole 陽性領域に存在していた．またPBMC の走化性因子の一つであるstromal cell-derived factor-1（SDF 11）についても免疫染色を行った．STEM121 陽性細胞はすべてSDF-1 陽性領域に存在し，またSDF-1 陽性領域ではSDF-1 陰性領域に比し，pimonidazole の発現が多く認められた（p < 0.01）．OGD-PBMC 投与 21 日後の脳標本において，OGD-PBMC 投与群・対照群双方においてVEGF 発現はpimonidazole 陽性領域で亢進していた（各p＜0.01）．またpimonidazole 陽性領域において，対照群に比しOGD-PBMC投与群でVEGF発現が亢進した（p = 0.034）．虚血辺縁でのpimonidazole陽性細胞数は対照群に比してOGD-PBMC投与群で減少していた（p＜0.01）．以上から，虚血再灌流後低酸素領域がSDF-1を介しOGD-PBMCを病変部に誘導し，その部位でVEGF発現を促し，pimonidazole発現に影響を及ぼす可能性が示唆された．OGD-PBMC治療法は，虚血再灌流後低酸素領域に直接作用する．新大院博（医）第1166
3D characteristics of Aβ deposition in CAA : Quantitative analysis for vasculature
Get PDF新潟大学Niigata University博士（医学）脳アミロイド血管症（CAA）は，脳血管にアミロイドが沈着する疾患であり， 沈着するアミロイドはアルツハイマー病に合併するアミロイド β（Aβ）が最も多い．有病率は高く，高齢者の脳出血の重要な原因の一つである．しかし，ヒト脳では高解像度の経時的観察が難しく，薄切切片を用いた従来の病理解析では Aβの沈着血管を断片的にしか捉えられないため，Aβの血管への沈着の起点や進展パターンは不明である．本研究では，ヒト脳透明化技術と光シート顕微鏡を用い，脳血管網を立体的に連続的に観察し，皮質動脈／細動脈におけるAβの空間的分布とアミロイド沈着血管の病理学的特徴を解析した．CAA 患者 6 名の剖検脳の前頭葉と後頭葉のホルマリン固定脳を用い，約 0.5cm3の透明化サンプルを作製し，抗 smooth muscle actin（SMA）抗体と抗 Aβ17-24抗体を用いて動脈とそれに沈着したアミロイドを 3 次元的に可視化した．そして，各血管について，脳表から白質まで分岐ごとの血管分枝（セグメント）を同定し，Aβ沈着の有無やアミロイド沈着に伴う SMA 脱落の有無，そして Aβ陽性と陰性血管における血管外径を評価した．結果，1104 本の Aβ陽性血管と 535 本の Aβ陰性血管のデータを得た。前者では、Aβの沈着は分岐直前の軟髄膜動脈と実質に陥入直後の表在枝に高率に観察された（96.2%，99.5%）．SMA の脱落は 547 本の Aβ陽性血管に認められ，Aβの沈着と同様，脳表のセグメントに優位に多かった．また，Aβ陽性血管は Aβ陰性血管より有意に直径が大きかった（p < 0.0001）．本研究は，CAA 患者における血管への Aβ沈着が，脳内の排泄路として想定される Intramural arterial drainage pathway の下流にあたる脳表に選択的におこり，そこを起点として皮質と白質へ連続的に沈着が進展する可能性を明らかにした.新大院博（医）第1169
小児肥大型心筋症の心臓突然死予防におけるβ遮断薬と運動制限の効果
Get PDF新潟大学Niigata University博士（医学）Background: Risk assessment tools and effective prevention strategies for sudden cardiac death (SCD) in pediatric patients with hypertrophic cardiomyopathy (HCM) have not been established. This study aimed to evaluate the efficacy of beta-blockers and exercise restriction for SCD prevention in this population. Methods: We retrospectively reviewed the medical records of patients aged <18 years who were diagnosed with HCM at our center between January 1996 and December 2021. SCD and aborted SCD were defined as SCD equiv-alents. We divided patients based on whether they were prescribed beta-blockers or exercise restriction and compared the outcomes among the groups. The primary outcome was the overall survival (OS), and the second-ary outcome was the cumulative SCD equivalent rate. Outcomes were analyzed using Kaplan–Meier curves and Cox proportional hazard analysis. We also compared patients according to the occurrence of SCD equivalents to identify SCD risk predictors. Results: Among the 43 included patients [mean age, 7.7 (1.6–12.1) years; 23 male individuals], SCD equivalents occurred in 13 patients over 11.2 (4.5–15.6) years of follow-up, among whom 12 were resuscitated and 1 died. The OS rate was significantly higher in the beta-blocker and exercise restriction groups than in the non-beta-blocker and non-exercise restriction groups (81.3 % vs. 19.1 %, p < 0.01 and 57.4 % vs. 12.7 %, p < 0.01, respec-tively). Among the 13 patients with SCD equivalents, 5 had 9 recurrent SCD equivalents. A significant difference was observed between the SCD equivalent and non-SCD equivalent groups in the history of suspected arrhyth-mogenic syncope (p < 0.01) in the univariable but not in the multivariable analysis. Conclusions: Beta-blockers and exercise restriction may decrease the risk of SCD in pediatric patients with HCM and should be considered for SCD prevention in this population, particularly because predicting SCD in these pa-tients remains challenging.Journal of cardiology. 2024, 83(6), 407-414.新大院博（医）第1177
卵巣癌の肝転移様式における直腸間膜リンパ節の臨床的意義
Get PDF新潟大学Niigata University博士（医学）Background. Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical sig-nificance of MLN involvement in the pattern of liver metastasis in patients with OC. Methods. We included 85 stage II–IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteris-tics, including MLN involvement, was evaluated using univariate and multivariate analyses. Results. MLN involvement was detected in 14/85 patients with stage II–IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prog-nostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p< 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin. Conclusion. MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.Tanaka, K., Shimada, Y., Nishino, K. et al. Clinical Significance of Mesenteric Lymph Node Involvement in the Pattern of Liver Metastasis in Patients with Ovarian Cancer. Ann Surg Oncol 28, 7606–7613 (2021). https://doi.org/10.1245/s10434-021-09899-8
https://link.springer.com/article/10.1245/s10434-021-09899-8#citeasThis 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/10.1245/s10434-021-09899-8
Use is subject to Springer Nature re-use terms.新大院博（医）第1183