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卵巣癌の予後予測マーカーとしての組織経路インヒビター2 の有用性についての検討
Full text linkAbstract. Tissue factor pathway inhibitor‑2 (TFPI2) is a tumor marker for diagnosing ovarian cancer and ovarian clear cell carcinoma (OCCC); however, its effectiveness as a prognostic marker remains unclear. The present study aimed to investigate the utility of TFPI2 as a prognostic marker for ovarian cancer.
A total of 256 cases of ovarian cancer was collected at Nara Medical University (Kashihara, Japan) from January 2008 to
January 2022. The majority of cases were serous carcinoma (109, 42.6%), followed by OCCC (66, 25.8%), mucinous carcinoma (40, 15.6%), endometrial carcinoma (15, 5.9%), and other (26, 10.2%). The median preoperative serum TFPI2 for ovarian cancer was 219.0 (82.5‑5,824.2) pg/ml. Overall survival (OS) of patients with non‑OCCC and OCCC was calculated using the cut‑off value determined obtained through receiver operating characteristic curve analysis. Cut‑off values of TFPI2 for OS were 201 for non‑OCCC and 255 pg/ml for OCCC. In univariate analysis, OS was significantly elevated in patients with non‑OCCC and OCCC who had TFPI2 levels ≥201 pg/ml (P<0.001) and ≥255 pg/ml (P=0.036), respectively. Progression‑free survival (PFS) was significantly elevated in patients with non‑OCCC and OCCC who had TFPI2 levels ≥201 and ≥255 pg/ml (both P<0.001), respectively. Multivariate analysis revealed that OS was significantly higher in patients with non‑OCCC who had TFPI2 levels ≥201 pg/ml (P=0.021), while PFS was significantly higher in patients with OCCC who had TFPI2 levels ≥255 pg/ml (P=0.020). These findings suggest that TFPI2 is a potential prognostic marker for ovarian carcinoma.権利情報：© Maehana et al. This is an open access article distributed under the terms of Creative Commons Attribution License
健康なボランティアの無症候性内リンパ水腫の予後：5 年のコホート研究
Full text linkBackground: This study aimed to clarify the prognosis of asymptomatic endolymphatic
hydrops (EH) in healthy volunteers via five-year follow-ups with inner ear magnetic resonance imaging (MRI).
Methods: Inner ear MRI was performed on 115 participants recruited as controls in a
previous study on Meniere's disease. The endolymphatic space was visualized using
Naganawa's method of contrast-enhanced MRI with intravenous gadolinium injection and evaluated using Nakashima's method of 2D imaging analysis.
Results: Cochlear or vestibular EH was present in 7.0% of participants (n = 8), with all cases being unilateral (laterality), moderate (severity), and asymptomatic (onset).
Only cochlear-localized EH, only vestibular-localized EH, and both EH were present
in 1.7% (n = 2) (C group), 4.3% (n = 5) (V group), and 0.9% (n = 1) (CV group) of participants, respectively. Conducting inner ear MRI after 5 years showed that EH had
almost disappeared in two participants in the C and V groups (4/8, 50.0%). EH was still present in three participants in the V group and one in the CV group (4/8, 50.0%). One participant in the V group and another in the CV group presented with residual inner ear EH and developed typical symptomatic Meniere's disease
(2/8, 25.0%).
Conclusions: Approximately 7% of healthy participants showed asymptomatic EH. Therefore, EH is not the definitive marker for making a diagnosis of Meniere's disease or the suitable predictor for the development of Meniere's disease. Among these participants, 25% maintained EH and subsequently developed typical Meniere's disease within the next 5 years. Schellong-positive participants maintained persistent EH in the inner ear, and participants with higher scores on the self-rating depression scale developed Meniere's symptoms after 5 years.権利情報：© 2024 The Author(s). Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society. 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
日本人成人における黄色ブドウ球菌菌血症の分子疫学と臨床的特徴
Full text linkIntroduction: Staphylococcus aureus bacteremia (SAB), especially when caused by methicillin-resistant S. aureus (MRSA), is of considerable clinical importance. In recent years, the proportion of MRSA among S. aureus has
decreased, and a relative increase in the proportion of methicillin-susceptible S. aureus (MSSA) has been observed. It is therefore necessary to consider both MRSA and MSSA when assessing the microbiological and clinical significance of SAB.
Materials and methods: We included SAB cases from the Nara Medical University Hospital between January 2015 and February 2017. We performed drug susceptibility testing, toxicity gene analysis, multilocus sequence typing
(MLST), and polymerase chain reaction-based open reading frame typing (POT) of stored strains to integrate clinical and bacteriological characteristics.
Results: There were 90 cases during the experimental period (42 MRSA and 48 MSSA), with 30-day mortality rates of 19 % for MRSA and 10.4 % for MSSA. Deaths were more frequently complicated by septic shock and disseminated intravascular coagulation. MLST studies showed that ST8, ST764, ST1, and ST15 were prevalent in the MRSA group, whereas ST5, ST188, and ST12 were prevalent in MSSA. Infective endocarditis cases had a long time from onset to the initiation of effective antimicrobials and were all MSSA. MLST and POT results correlated
well, and POT appeared to have better discriminatory power.
Conclusions: The severity and mortality of SAB, along with the microbiological characteristics of causative iso lates, vary by location and time. Continued studies integrating clinical and microbiological investigations are thus needed clinical and microbiological investigations are thus needed.権利情報：© 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies
脂肪肝炎において、アンギオテンシンⅡ受容体の遮断はIGF-1を介した骨格筋ホメオスタシスを調整する
Full text linkSarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin Ⅱ receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived
skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine–choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and
skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a tran scriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1β) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the
hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.権利情報：© 2023 Elsevier B.V. All rights reserved
膵管腺癌における術前化学放射線療法に対する炭酸脱水酵素 9 発現の臨床的影響
Full text linkBackground: PDAC cells upregulate carbonic anhydrase 9 (CA9) expression in order to survive in hypoxic tumor environments, which plays a key role in tumor progression. However, the relationship between CA9 expression and preoperative treatment has not been clarified. We evaluated the clinical impact of CA9 expression on the efficacy of neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal
adenocarcinoma (PDAC).
Methods: We investigated CA9 expression in 273 surgical specimens and 20 serum samples obtained from patients with PDAC and evaluated their clinical outcomes. We analyzed the function of CA9 using human pancreatic cancer cell lines.
Results: CA9 was positively expressed in 36.2% of patients who underwent NACRT, which was significantly lower than those who underwent upfront surgery (US) (58.9%, p<0.001). Interestingly, patients who were CA9-positive in the US group had a significantly poorer prognosis than that of those in the NACRT group (median survival time [MST], 21.5 months vs.4 9.2 months, p<0.001), while there was no significant difference between patients who were CA9-negative in the US and NACRT groups (MST, 45.8 months vs. 46.3 months, p=0.357). Moreover, serum CA9 levels tended to correlate positively with CA9 expression in cancer tissues. In-vitro experiments demonstrated that CA9 expression was reduced after treatments with radiation and chemoradiation therapy (RT/CRT), and that CA9 knockdown suppressed
the impacto fR T/ CRT on cancer cell proliferation.
Conclusions: CA9 may act as a target molecule for RT/CRT, highlighting its clinical importance as a valuable biomarker for more stringent in dications for NACRT.権利情報：© 2024 IAP and EPC. Pubilshed byE lsevier B.V. All rightsa re reserved,including those for text and data mining, AI training, and similar technologies
MgO添加β-TCPはin vitroおよびin vivoのラットモデルにおいて骨形成を促進する
Full text linkAllogeneic bone grafts are used to treat bone defects in orthopedic surgery, but the osteogenic potential of artificial bones remains a challenge. In this study, we developed a β-tricalcium phosphate
(β-TCP) formulation containing MgO, ZnO, SrO, and SiO2 and compared its bone-forming ability
with that of β-TCP without biological elements. We prepared β-TCP discs with 60% porosity containing 1.0 wt% of these biological elements. β-TCP scaffolds were loaded with bone marrow-derived mesenchymal stem cells (BMSC) from 7-week-old male rats and cultured for 2 weeks. ALP activity and mRNA expression of osteogenic markers were evaluated. In addition, scaffolds were
implanted subcutaneously in rats and analyzed after 7 weeks. In vitro, the MgO group showed lower Ca concentrations and higher osteogenic marker expression compared to controls. In vivo, the MgO group showed higher ALP activity compared to controls, and RT-qPCR analysis showed significant expression of BMP2 and VEGF. Histopathology, fluorescent immunostaining, and micro-CT also showed relatively better bone formation in the MgO group. β-TCP with MgO may enhance bone morphology in vitro and in vivo and improve the prognosis of patients with substantial and refractory bone defects.権利情報：© The Author(s) 2024. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 licence, and indicate if you modified the licensed material. You do not have
permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/
アルツハイマー病における視空間認知障害と右中側頭回および右楔前部の脱髄との関連
Full text linkBackground: Alzheimer’s disease (AD) is associated with impairments in not only memory but also visuospatial cognitive function. Despite its
adverse effects on the quality of life, patients with early-stage AD are often neglected. Emerging evidence suggests that patients with AD exhibit
increased vulnerability of myelin, a crucial component for neuronal conduction and survival. To test our hypothesis that myelin damage was associated with cognitive deficits in AD, we examined correlations of myelin integrity, quantified by T1-weighted/T2-weighted (T1w/T2w) ratios, with visuospatial cognitive abilities and compared them between patients with AD and cognitively normal (CN) individuals.
Methods: Fifty-seven patients with AD and 22 CN subjects were enrolled in this study. To assess subjects’ visuo-constructive abilities, we employed
the Rey–Osterrieth Complex Figure Copy Test (ROCFT-c) paired with analysis of T1- and T2-weighted magnetic resonance imaging brain images. Voxel-based associations between T1w/T2w ratios and ROCFT-c scores in the AD group were assessed, controlling for age and handedness (voxel threshold uncorrected P < 0.001, cluster threshold uncorrected P < 0.05).
Additionally, we compared the T1w/T2w ratios of these identified brain regions between the AD and CN groups.
Results: The voxel-based analysis demonstrated positive correlations between T1w/T2w ratios and ROCFT-c scores in the right middle temporal gyrus and right praecuneus in patients with AD who exhibited significantly lower T1w/T2w ratios in the right middle temporal gyrus (P = 0.038) and a trend toward lower T1w/T2w ratios in the right praecuneus (P = 0.055).
Conclusions: Our results demonstrated a strong association between reduced myelin integrity in the right middle temporal gyrus and right praecuneus and visuospatial cognitive dysfunction in patients with
AD. These findings are believed to shed light on the neural basis of visuospatial processing in patients with AD, underlining the necessity for developing
objective biomarkers for assessing patients’ visuospatial cognitive function.権利情報：© 2024 Japanese Psychogeriatric Society
メニエール病におけるストレスレベルと内リンパ腔容積の関係
Full text linkObjectives: Since the first report by Hallpike and Yamakawa in 1938, many more patients with Meniere's disease (MD) with endolymphatic hydrops (EHs) have been described. Mental/physical stress and a subsequent increase in the release of the anti-diuretic hormone (ADH) supposedly triggers MD. In the present study, to assess the relationship between stress and EHs, we conducted a series of stress-related questionnaires as well as a 3D endolymphatic space (ELS) analysis in patients with unilateral MD. Methods: We enrolled 76 patients with unilateral MD (uMD) as the active group and 75 patients with unilateral benign paroxysmal positional vertigo (uBPPV) as the control group; both underwent examinations between June 2014 and November 2019. All patients underwent 3-T magnetic resonance imaging (MR1) 4 h after intravenous gadolinium injection. We used the total fluid space (TFS), ELS, and ELS rate (ELS/TFSxl00), which is the percentage of the volume of the ELS relative to that of the TFS, for a precise evaluation of the ELS and EHs in MD. Stress was evaluated using the SelfRating Depression Scale (SDS), the psychological Stress Response Scale (SRS), and the modified Dizziness Handicap Inventory (mDHI). Stress scores and blood ADH levels were compared across patient groups. Results: In patients with uMD, ELS rates significantly correlated with SRS scores on both the affected and the healthy side and with mDHI scores on the affected side, while the SDS and ADH showed no significant correlation with the ELS rates. Correlations were much stronger in the group with severe SDS and one with low ADH levels. Conclusions: The present results indicate that stress may be involved in EHs development in uMD, not only in the ipsilateral but also the contralateral ear. They also suggest that patients with neuropsychiatric tendencies may develop EHs and MD in response to a stressful lifestyle.権利情報：©2023 Japanese Society of Otorhinolaryngology-Head and Neck Surgery, Inc. Published by Elsevier B.V. All rights reserved
ブタ第VIII因子相同配列に組み換えたヒト-ブタハイブリッド第VIII因子はA2およびC2ドメイン特異的なインヒビターの阻害作用を部分的に回避する
Full text linkIntroduction: Porcine factor (pF)VIII has low cross-reactivity with anti-human (h)FVIII inhibitor alloantibodies. Clinical trials of pFVIII in congenital hemophilia A patients with inhibitor (PwHA-I) are in progress. Most FVIII inhibitors recognize the A2 and/or C2 domain(s), and recombinant human-porcine hybrid (hp)FVIII containing mutations within these domains may escape the neutralizing effects of these inhibitors. Aim: To evaluate the ability of hpFVIII to limit the anti-FVIII activity of inhibitor alloantibodies. Methods: Three hybrid mutants were created by substituting the A2, C2 domain or both in human hFVIII, with the corresponding domain of pFVIII (termed hp(A2), hp(C2), and hp(A2/C2), respectively). The reactivity of these mutants was assessed by one-stage clotting assays (OSA), thrombin generation assays (TGA), and rotational thromboelastometry (ROTEM) using FVIII-deficient samples. Results: OSA demonstrated that mutation restricted the inhibitory effects of both anti-FVIII A2 or C2 monoclonal antibodies (mAb) and polyclonal inhibitor-antibodies (polyAb) from PwHA-I. TGA indicated that peak thrombin with hp(A2) and hp(A2/C2) was not attenuated in the presence of anti-A2 polyAb, but that with hFVIII and hp(C2) was suppressed to levels equivalent to those of FVIII-deficient plasma. With anti-A2/C2 polyAb, the activity of hp(A2/C2) was unaffected. ROTEM demonstrated that the addition of hp(A2) or hp(A2/C2) to anti-A2 polyAb shortened clot times/clot formation times, whilst hFVIII or hp(C2) were ineffective. Similarly with anti-A2/C2 polyAb, hp(A2/C2) restored coagulation potential to a greater extent than hp(A2) and hp(C2). Conclusion: Hybrid FVIII mutations within the porcine A2 and/or C2 domain corresponding to respective inhibitor-epitopes could support effective therapy in PwHAI.権利情報：© 2023 JohnWiley & Sons Ltd. This is the peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/10.1111/hae.14911], which has been published in final form at [https://doi.org/10.1111/hae.14911]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
ミクログリアが分泌する脳由来神経栄養因子は内側前頭皮質の神経発達と社会性行動を制御する
Full text linkMicroglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45-p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.権利情報：© The Author(s) 2024. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/