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日本における基質特異性拡張型β-ラクタマーゼ産生肺炎桿菌の分子遺伝学的特徴：CTX-M-15の優位性と高病原性クローンの出現
Get PDFObjective: To provide data on the molecular characteristics of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae clinical isolates in Japan. Methods: A total of 100 clinical isolates of ESBL-producing K. pneumoniae collected throughout Japan between June and July 2018 were studied. ESBL genes were analyzed using PCR and DNA sequencing. Transferability of ESBL genes was investigated by conjugation experiments. Plasmid replicon types, virulence genes (rmpA, rmpA2, iucA, iroB, and peg-344) associated with hypervirulent K. pneumoniae (hvKp), and capsule types were detected using PCR. Genotyping was performed using multilocus sequence typing. Results: All ESBL-producing isolates carried blaCTX-M genes. The most predominant CTX-M-type identified was CTX-M-15 (n=55). We identified 24 sequence types (STs) among the CTX-M-15 producers, with ST25 (n=8) being the most common. Most of the transconjugants carrying blaCTX-M-15 contained the FIIk replicon. Of the 100 ESBL-producing isolates, 31 were hvKp defined by the presence of the virulence genes. These ESBL-producing hvKp isolates belonged to eight STs (STs 23, 25, 36, 65, 86, 268, 412, and 4492), with five capsule types (K1, K2, K20, K57, and undefined). Conclusions: CTX-M-15 was the predominant ESBL among K. pneumoniae isolates from Japan. This study shows that ESBL-producing hvKp strains comprising various clones are emerging in Japan.博士（医学）・甲第769号・令和3年3月15日© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
HNF-1β過剰発現を呈する卵巣明細胞癌においてGSK-3βは新たなシグナル伝達経路を介在する
Get PDFDeubiquitinase USP28 is a target gene of the transcription factor HNF1 homeobox β (HNF-1β), which promotes the survival of ovarian clear cell carcinoma (OCCC) cell lines. However, the pharmacological inhibition of HNF-1β can cause several adverse effects as it is abundantly expressed in numerous organ systems, including the kidney, liver, pancreas and digestive tract. Therefore, small interfering RNA (siRNA) screening was performed in the current study to identify other potential downstream targets of the HNF-1β-mediated pathway. The results revealed that glycogen synthase kinase-3β (GSK-3β) may be a potential downstream target affecting cell viability. To further clarify the effects of GSK-3β, two human OCCC cell lines, TOV-21G (HNF-1β overexpressing line) and ES2 (HNF-1β negative) were transfected with siRNA targeting GSK-3β or control vectors. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated GSK-3β expression, resulting in the loss of phosphorylated nuclear factor-κB (p-NFκB) and the reduction of TOV-21G cell proliferation. The cell proliferation assay also revealed that GSK-3β inhibitors rescued the effects of HNF-1β silencing on cell viability in a dose-dependent manner. Furthermore, the GSK-3β inhibitor, AR-A014418, effectively inhibited tumor cell proliferation in a xenograft mouse model. In conclusion and to the best of our knowledge, the current study was the first to determine that GSK-3β is a target gene of HNF-1β. In addition, the results of the present study revealed the novel HNF-1β-GSK-3β-p-NFκB pathway, occurring in response to DNA damage. Targeting this pathway may therefore represent a putative, novel, anticancer strategy in patients with OCCC.博士（医学）・甲第785号・令和3年3月15日Copyright: © Kawaharaet al. This is an open access article distributed under theterms of CreativeCommons Attribution License(https://creativecommons.org/licenses/by-nc-nd/4.0/)
第VIII因子A1ドメインC末端酸性領域は、トロンビン惹起活性化とArg³⁷²開裂を制御する
No full textBackground: Factor VIII (FVIII) is activated by thrombin-catalyzed cleavage at three sites. Previous reports indicated that the A2 domain contained thrombin-interactive sites responsible for cleavage at Arg³⁷². We have also found that the A1 domain of FVIII bound to the anion-binding exosite I of thrombin. The present study focused, therefore, on thrombin interaction with A1 residues 337-372 containing clustered acidic and hirugen-like sequences. Aim: To identify specific thrombin-interactive site(s) within the A1 acidic region of FVIII. Methods and results: The synthetic peptide of residues 337-353 with sulfated Tyr³⁴⁶ (337-353S) significantly blocked thrombin-catalyzed FVIII activation and cleavage at Arg³⁷², while a corresponding peptide of residues 354-372 had no significant effect. Treatment with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide to cross-link thrombin and 340-350S suggested that the 344-349 clustered acidic region was involved in thrombin interaction. Alanine-substituted FVIII mutants, Y346A and D347A/D348A/D349A, depressed thrombin-catalyzed activation and cleavage at Arg³⁷², with peak activation at ~ 50% and cleavage rates of ~ 10% to 20% compared to wild type (WT). The peak level of thrombin-catalyzed activation and the cleavage rate at Arg³⁷² using FVIII mutants with 337-346 residues substituted with hirugen-sequences (MKNNEEAEDY337-346GDFEEIPEEY) were ~ 1.5- and ~ 2.5-fold of WT, respectively. Surface plasmon resonance-based analysis demonstrated that the Kd for active-site modified thrombin interactions using Y346A and D347A/D348A/D349A mutants was ~ 3- to 6-fold higher than that of WT, and that the hirugen-hybrid mutant facilitated association kinetics ~ 1.8-fold of WT. Conclusion: Residues 346-349 with sulfated Tyr provided a thrombin-interactive site responsible for activation and cleavage at Arg³⁷². A hirugen-hybrid A1 mutant showed more efficient thrombin-catalyzed cleavage at Arg³⁷².博士（医学）・甲第788号・令和3年3月15日© 2020 International Society on Thrombosis and Haemostasis.This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/10.1111/jth.15201, which has been published in final form at https://doi.org/10.1111/jth.15201. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
Tri-condylar形状人工膝関節において後方剥離手技が完全伸展獲得におよぼす影響：新鮮凍結屍体を用いた生体力学的評価
Get PDFBackground/objective: The continuous improvement of knee function during deep flexion remains a challenge in total knee arthroplasty. Tri-condylar total knee arthroplasty has been designed to achieve this goal. However, the introduction of a third nonanatomic spherical condyle might prevent the joint from reaching full extension due to posterior soft tissue tightening. This study aimed to address these issues related to soft tissue tightening and full extension limitation. Methods: Biomechanical tests were performed on six cadaveric specimens of the entire lower extremities. The tri-condylar design was compared with a posterior cruciate sacrificing design of the same shape without the ball structure. Knee joint kinematics was measured, including the extension and flexion angles, the extension balance, and the extension gap. The test was repeated after release of the medial and lateral posterior intercondylar soft tissues at a safe distance from the popliteal artery and nerves. Results: Both designs resulted in a knee flexion angle up to ∼130°. The tri-condylar design showed an extension angle of -11.2 ± 5.4°, which was a significantly greater limitation than that obtained with the cruciate sacrificing design (-3.8 ± 4.7°; p = 0.047). Moreover, the extension angle of the tri-condylar design was significantly improved after the release of posterior intercondylar soft tissues (-0.1 ± 6.7°; p = 0.028). Conclusion: The tri-condylar design efficiently allowed the full extension by the release of posterior intercondylar soft tissues at a safe distance from the popliteal artery and nerves.博士（医学）・乙第1499号・令和3年3月15日© 2017 The Authors. Published by Elsevier (Singapore) Pte Ltd on behalf of Chinese Speaking Orthopaedic Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
当院におけるヘロイン依存症者へのbuprenorphineによる解毒治療についての検討
Get PDFAim: We assessed the efficacy of buprenorphine replacement taper therapy in a psychiatric hospital in Japan. Methods: Based on the medical records, a retrospective analysis was performed to evaluate the outcomes of buprenorphine replacement taper therapy in 106 subjects with heroin dependence. Results: We found that replacement and taper therapy with buprenorphine could significantly reduce withdrawal symptoms during detoxification. In addition, the completion rate of detoxification was significantly improved and the length of hospital stay was significantly reduced relative to those who received conventional treatment without buprenorphine. However, the readmission rate increased after the introduction of detoxication therapy with buprenorphine. Conclusion: The present findings suggest not only the efficacy and safety of buprenorphine replacement and taper therapy, but also the requirement for maintenance therapy for individuals with heroin dependence.博士（医学）・乙第1502号・令和3年3月15日© 2020 The Authors. Neuropsycho pharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.
This is an open access article under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited
高齢男性における塩分摂取量と下肢浮腫、夜間頻尿との関連について
Get PDFAims: There is accumulating evidence that excessive salt intake contributes to nocturnal polyuria. We aimed to investigate the relationship between salt intake, leg edema, and nocturnal urine volume (NUV) to assess the etiology of nocturnal polyuria. Methods: A total of 56 men aged ≥60 years who were hospitalized for benign prostatic hyperplasia or with suspected prostatic cancer were enrolled. Urine frequency-volume charts of the patients were maintained, and they underwent bioelectrical impedance analysis twice daily (at 5:00 pm and 6:00 am) and examination of blood (brain natriuretic peptide levels) and urine (sodium and creatinine levels and osmotic pressure) samples once daily (at 6:00 am). Free-water clearance, solute clearance, and sodium clearance at night were measured, and daily salt intake was estimated. Results: The data of 52 patients were analyzed. Daily salt intake positively correlated with leg edema at 5:00 pm, differences in leg extracellular fluid levels between 5:00 pm and 6:00 am, and NUV, but not with diurnal urine volume. Partial correlation coefficients showed that salt intake was a factor of the correlation between NUV and change in extracellular volume in the legs between 5:00 pm and 6:00 am. A multivariate logistic model showed that sleep duration and sodium clearance were independent predictive factors for nocturnal polyuria. Conclusions: Sodium intake correlates with diurnal leg edema and NUV in elderly men. These results provide evidence supporting sodium restriction as an effective treatment for nocturnal polyuria.博士（医学）・乙第1507号・令和3年3月15日© 2020 Wiley Periodicals LLC.This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/10.1002/nau.24401, which has been published in final form at https://doi.org/10.1002/nau.24401. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
母体血中における分娩形式による分娩前後の、羊水塞栓症のバイオマーカーとなりうるSCC 抗原の大きな変化
Get PDFAmniotic fluid embolism (AFE) is a serious disease in which amniotic fluid components enter the maternal systemic circulation, causing cardiopulmonary collapse in pregnant women. It has been previously reported that amniotic fluid contains extremely high levels of squamous cell carcinoma antigen (SCCA), and that pregnant women who do not survive due to AFE have high blood SCCA levels. The aim of the present study was to determine the possible mechanisms through which SCCA in amniotic fluid enters the maternal blood, as well as the potential origin of SCCA. The prospective study included a cohort of 464 women (339 normal vaginal deliveries, 97 cesarean deliveries without labor, and 28 cesarean deliveries with labor). The dynamic changes in maternal serum SCCA levels were determined before and after delivery in relation to the mode of delivery, and SCCA levels were measured in the placenta, fetal skin, amniotic fluid cell components, amniotic fluid and neonatal urine. Serial serum samples collected at the time of admission, at 2 h postpartum, and on postpartum day 3 were quantitatively measured for SCCA by enzyme‑linked immunosorbent assay. Amniotic fluid and neonatal urine SCCA levels were also measured. The protein expression of SCCA in the placenta and fetal skin was assessed by immunohistochemistry. In vaginal deliveries, there was a significant increase in serum SCCA levels from admission to 2 h postpartum, and SCCA levels decreased on postpartum day 3. In cesarean deliveries, the SCCA levels at the time of admission and 2 h postpartum did not differ. The SCCA levels were significantly higher in women who underwent vaginal deliveries compared to those that underwent cesarean deliveries without labor (P=0.033). Immunohistochemical staining revealed no SCCA expression in the placenta and fetal skin. The SCCA levels in neonatal urine immediately after birth were as high as those in the amniotic fluid, suggesting that SCCA may originate from fetal urine. The present study thus suggests that amniotic fluid SCCA levels, which may be derived from fetal urine, can enter the maternal circulation during vaginal delivery. The onset of labor and full cervical dilatation are the main causes of entry of amniotic fluid components into the maternal circulation.博士（医学）・甲第796号・令和3年6月25日Copyright: © Nakano et al. This is an open access article distributed under the terms of Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc-nd/4.0/)