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Four subtypes of ovarian high-grade serous carcinoma (HGSC) have previously been identified, each with different prognoses and drug sensitivities. However, the accuracy of classification depended on the assessor's experience. This study aimed to develop a universal algorithm for HGSC-subtype classification using deep learning techniques. An artificial intelligence (AI)-based classification algorithm, which replicates the consensus diagnosis of pathologists, was formulated to analyze the morphological patterns and tumor-infiltrating lymphocyte counts for each tile extracted from whole slide images of ovarian HGSC available in The Cancer Genome Atlas (TCGA) data set. The accuracy of the algorithm was determined using the validation set from the Japanese Gynecologic Oncology Group 3022A1 (JGOG3022A1) and Kindai and Kyoto University (Kindai/Kyoto) cohorts. The algorithm classified the four HGSC-subtypes with mean accuracies of 0.933, 0.910, and 0.862 for the TCGA, JGOG3022A1, and Kindai/Kyoto cohorts, respectively. To compare mesenchymal transition (MT) with non-MT groups, overall survival analysis was performed in the TCGA data set. The AI-based prediction of HGSC-subtype classification in TCGA cases showed that the MT group had a worse prognosis than the non-MT group (P = 0.017). Furthermore, Cox proportional hazard regression analysis identified AI-based MT subtype classification prediction as a contributing factor along with residual disease after surgery, stage, and age. In conclusion, a robust AI-based HGSC-subtype classification algorithm was established using virtual slides of ovarian HGSC., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Limited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not., Objectives: The study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population., Methods: This open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome., Results: Out of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group ( n  = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group ( n  = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%)., Conclusion: Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events., (© 2024 The Authors.)

Objective: It is well known that power morcellation of unexpected uterine sarcoma affects prognosis. There are few reports on the effects of scalpel morcellation or myomectomy of uterine sarcoma on prognosis, which is not well understood. This study investigated the effect on recurrence and prognosis when tumors of uterine sarcoma undergo scalpel morcellation or myomectomy., Methods: We performed a retrospective, observational study by collecting data from the medical records of patients who were histologically diagnosed with uterine sarcoma at our hospital between 2005 and 2017. All patients with unexpected uterine sarcoma were diagnosed after laparoscopic hysterectomy with scalpel morcellation or myomectomy (abdominal and laparoscopic) for presumed myoma. We evaluated recurrence rate, recurrence site, progression-free survival (PFS), and overall survival (OS)., Results: A total of 15 patients were examined in this study. Twelve patients underwent myomectomy (7 patients with open surgery, 5 patients with laparoscopic surgery), and 3 patients underwent total laparoscopic hysterectomy with transvaginal scalpel morcellation. There were 11 cases of recurrence, and the recurrence rate was 78 %. The recurrence site was peritoneal dissemination in 10 cases (91 %) and lymph node metastasis in 1 case (9 %). The median PFS was 32 months [95 % confidence interval (CI) = 6.5-NA], and the median OS was 95.5 months [95 % CI = 55.8-NA]., Conclusion: Power morcellation, scalpel morcellation, and myomectomy may affect recurrence and prognosis. Further studies are needed in the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Inc.)

Background: Although serum uric acid (UA) is considered as a risk factor for cardiovascular disease, few data exist regarding the relationship between hyperuricemia, coronary blood flow, and subsequent outcome in patients with acute myocardial infarction (AMI). The purpose of our study is to assess whether hyperuricemia is associated with suboptimal coronary flow and increased risk of mortality in patients with AMI after percutaneous coronary intervention (PCI)., Methods: Using the Rural AMI registry data, 989 consecutive patients with AMI who underwent emergent PCI and had UA measurement at admission were analyzed. We defined hyperuricemia as serum UA ≥7.0 mg/dL in men and ≥ 6.0 mg/dL in women. The primary endpoint was suboptimal coronary flow, defined as post PCI Thrombosis In Myocardial Infarction flow grade ≤ 2. The secondary outcome was in-hospital mortality., Results: Hyperuricemia was found in 249 (25.2%) patients. Patients with hyperuricemia were more often complicated with cardiogenic shock compared with those without (16.9% vs. 7.4%, p < 0.001). In addition, the median high-sensitivity C-reactive protein was significantly higher in patients with hyperuricemia (0.18 mg/dL; IQR, 0.09-0.71 mg/dL) than in those without (0.14 mg/dL; IQR, 0.07-0.41 mg/dL, p < 0.05). Under these conditions, the prevalence of suboptimal coronary flow after PCI (17.3% vs. 10.1%, p < 0.05) and in-hospital mortality (10.8% vs. 3.6%, p < 0.001) were significantly higher in patients with hyperuricemia compared with those without. Multivariable logistic regression analysis revealed that hyperuricemia was significantly associated with suboptimal coronary flow [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.02-2.49; p < 0.05] and in-hospital mortality (OR, 2.08; 95% CI, 1.05-4.12; p < 0.05)., Conclusions: Assessment of serum UA upon admission provides useful information for predicting suboptimal coronary flow and in-hospital mortality in patients with AMI undergoing PCI., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic has shaped the dynamics of many diseases. This study aims to assess how the pandemic affected community-acquired pneumonia admission of all age groups among Japanese hospitals with various size and availability of COVID-19 wards. Our findings revealed a 44%-53% reduction in community-acquired pneumonia admission among 82 hospitals in Japan, from April through September of 2020, compared to the same period of 2019. Decreases were consistently found among hospitals with and without COVID-19 wards. The most significant decrease was found in the age group <20 years old. COVID-19 preventive measures and personal hygiene are considered to be effective measures to prevent the spreading of this disease. As vaccination progresses and the public gradually become less attentive to infection countermeasures, incidence of community-acquired pneumonia may increase in the coming season. Continued monitoring is required., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aims: Radiation-induced esophagitis, experienced during radiation therapy for lung cancer and head and neck cancer, is a major dose-limiting side effect of the treatment. This study aimed to elucidate the role of interferon-α (IFN-α) in radiation-induced esophagitis., Main Methods: C57BL/6 mice were exposed to 10 and 25Gy of single thoracic irradiation. Esophageal mucosal damage and inflammatory reactions were assessed for 5 days after irradiation., Key Findings: Irradiation induced esophagitis, characterized by reduction in the thickness of epithelial layer, upregulation of proinflammatory cytokines and chemokines, infiltration of inflammatory cells into the esophageal mucosa, and apoptosis of epithelial cells. Irradiation upregulated the level of gene expression for IFN-α in the esophageal tissue, and the neutralizing antibody against IFN-α ameliorated radiation-induced esophageal mucosal damage, while administration of IFN-α receptor agonist (RO8191) had an inverse effect. Depletion of plasmacytoid dendritic cells (pDCs) by anti-CD317 antibody or pharmacological inactivation with bortezomib suppressed radiation-induced mucosal inflammation and damage, accompanied by decrease in IFN-α expression level., Significance: These findings suggest that IFN-α and pDCs exert proinflammatory properties in the pathophysiology of radiation-induced esophagitis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The prevalence of sleep disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared in order to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Because sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021., Competing Interests: Conflict of Interest Yuichi Inoue is receiving daily allowances (lecture fees, etc.) from Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Takeda Pharmaceutical Company Limited, along with research expenses from Astellas Pharma Corporation, Eisai Corporation, Takeda Pharmaceutical Company Limited, and Jassen Pharmaceutical K,K. He is also affiliated with the donated courses provided by Astellas Pharma Corporation, Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Otsuka Pharmaceutical Co., Ltd., Koike Medical Co., Ltd., Takeda Pharmaceutical Company Limited, and Philips Japan, Ltd. Naohisa Uchimura is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Electric Co., Ltd., and Meiji Seika Furuma Co., Ltd.; manuscript fees from Eisai Co., Ltd., MSD Co., Ltd. and Otsuka Pharmaceutical Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Takatoshi Kasai is receiving research funding from Asahi Kasei Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Paramount Bed Co., Ltd., and ResMed Co., Ltd., along with scholarship (incentives) donations from Philips Japan Co., Ltd. He is also affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Fusae Kawana is an officer of the Japan Sleep Comprehensive Examination Association, and is affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Shigeru Sakurai is receiving scholarship (incentives) donations from Philips Japan, Ltd. and Kitara Co., Ltd. Takeshi Tanigawa is receiving research funding from Tokyo Electric Power Company Holdings, Inc. Kazuo Chin is receiving daily allowances (lecture fees, etc.) from Philips Japan, Ltd. and Teijin Home Medical Care, and is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Morio Tonogi is receiving research funding from GC Ortholy Corporation. Takeo Nakayama is receiving daily allowances (lecture fees, etc.) from Nippon Boehringer Ingelheim Co., Ltd., Pfizer Co., Ltd., and Janssen Pharmaceutical K.K., as well as receiving scholarship (incentives) donations from JMDC Co., Ltd. Motoo Yamauchi is receiving research funding from Koike Medical Co., Ltd. Toru Oga is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and Fukuda Lifetech Keiji Co., Ltd. Yasuhiro Tomita is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Satoshi Hamada is affiliated with a donated course provided by Teijin Pharma Limited. Kimihiko Murase is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., Fukuda Lifetech Keiji Co., Ltd., and ResMed Co., Ltd. Makoto Uchiyama is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited, along with scholarship (incentives) donations from Eisai Co., Ltd. and Meiji Seika Pharma Co., Ltd. Hiromasa Ogawa is affiliated with a donated course provided by Fukuda Lifetech Co., Ltd. Kazuo Mishima is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited; research funds from Taisho Pharmaceutical Co., Ltd. and Nobelpharma Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd. and Takeda Pharmaceutical Company Limited. Tsuneto Akashiba, Motoharu Ohi, Misa Takegami, Ryo Tachikawa, Shintaro Chiba, Satoru Tsuiki, Hiroshi Nakamura, Koji Narii, Asako Yagi, Yoshihiro Yamashiro, Masahiro Yoshida, Hiroyuki Mori, Hiroo Wada, Kazumichi Sato, Seiichi Nakata, and Shinichi Momomura have no COIs to declare., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The social motivation hypothesis posits that people with autism spectrum disorder (ASD) find social stimuli less rewarding and are therefore less motivated towards social interaction than people with neuro-typical development (TD). However, the less rewarding social stimuli characteristics during social interaction for people with ASD are largely unknown. The contingent positive responsiveness of others relevant to self-action motivates the early development of social interaction, thus representing a social reward. As individuals with ASD often exhibit atypical responses to self-relevant stimuli in their early life, we hypothesized that the self-relevant responses of others are less rewarding for individuals with ASD. To test this hypothesis, we conducted a functional magnetic resonance imaging study using a social contingency task. During the task, the participants attempted to make the audience laugh by telling funny jokes and thus activating the anterior rostral medial prefrontal cortex (arMPFC) of TD individuals (Sumiya et al., 2017). We explicitly predicted that the atypical activation of the arMPFC is related to the reduced reward value of self-relevant responses to others in individuals with ASD. Thirty-one adults with ASD and 24 age- and intelligence quotient-matched TD adults participated in the study. Participants with ASD reported significantly lower pleasure after the audience's responses to their own actions than those in the TD group. Correspondingly, the self-related activation of the arMPFC, defined by the results of our previous study, was attenuated in the ASD group compared to the TD group. The present findings indicate that weak self-relevant outcome processing mediated by the arMPFC of individuals with ASD dampens the rewarding nature of social interaction., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: To compare 3 laparoscopic contained morcellation techniques in terms of feasibility and safety., Design: Pilot study in an animal model (Canadian Task Force classification II-1)., Setting: Gynecologic oncology department at a cancer institute in Japan., Patients: Porcine model., Interventions: Three contained morcellation techniques were tested, each multiple times in 1 of 3 anesthetized female pigs: manual morcellation (8 times), dual-site power morcellation (8 times), and single-site power morcellation (6 times). All were tested on beef tongue introduced abdominally., Measurements and Main Results: The following variables were compared: bag insertion time, morcellation time, bag removal time, total in-bag morcellation time, and the volume of pneumoperitoneum CO 2 consumed. Bag rupture was evaluated ex vivo on completion of the procedure. Bag insertion time (in minutes) was significantly greater for dual-site morcellation (10.91 ± 3.38) than for manual (4.58 ± 2.47, p = .003) or single-site power (7.25 ± .77, p = .014) morcellation. Bag removal time (in minutes) was also significantly greater for dual-site morcellation (.85 ± .11 vs .27 ± .14, p<.001, vs .33 ± .59, p = .001). Total in-bag morcellation time, although greatest for manual morcellation at 21.4 ± 10.2 minutes, did not differ significantly between techniques. CO 2 consumption was significantly low for manual morcellation. Visual inspection revealed no bag damage when manual morcellation was performed, but bag damage occurred in 3 dual-site cases and in 1 single-site case., Conclusion: Considering preventing specimen leakage as the main aim of contained morcellation, the bag used for power morcellation needs improvement. Although manual morcellation requires an umbilical wound of about 25 mm, the absence of bag damage, acceptable total morcellation time, relatively low CO 2 consumption, and nonuse of a power device, which translate to an economic benefit, lead us to conclude that manual morcellation will remain advantageous into the future., (Copyright © 2019. Published by Elsevier Inc.)

Background: Obesity is associated with increased morbidity and mortality. However, obesity paradox has been discussed in some patients with cardiovascular disease., Objectives: We investigated the mechanisms of the obesity paradox in acute myocardial infarction (AMI) patients., Methods: We evaluated 1634 AMI patients with primary percutaneous coronary intervention (PCI). Patients were divided into 6 subgroups according to baseline body mass index (BMI) (low BMI: <20 kg/m 2 , normal BMI: 20-24.9 kg/m 2 , high BMI: ≥25 kg/m 2 ) and age (the younger and elderly groups consisting of patients <70 and ≥70 years old). The primary outcome was defined as all-cause mortality., Results: During the follow-up periods (median, 620 days; range, 344 to 730 days), 8.7% of patients experienced all-cause death. According to the Kaplan-Meier survival analysis, the patients in the younger age group with high BMI demonstrated significantly higher all-cause mortality compared to the other patients in the same age group (P = 0.012). In contrast, patients in the elderly age group with low BMI demonstrated significantly higher all-cause mortality compared to the others in the same age group (P < 0.001). Multivariate cox regression analyses showed that low BMI in the elderly age group (HR 1.69, 95% CI 1.12 to 2.55, P = 0.012) and high BMI in the younger age group (HR 2.77, 95% CI 1.19 to 6.45, P = 0.018) were independent predictors of all-cause mortality., Conclusions: The obesity paradox was recognized only in patients in the elderly age group and not in the younger age group. The prognostic impact of BMI may differ by age in AMI patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To investigate the effect of non-surgical periodontal therapy on insulin resistance and sensitivity among individuals with borderline diabetes not receiving medications., Methods: A crossover, randomized controlled trial was conducted among participants with borderline diabetes diagnosed by a 75-g oral glucose tolerance test. Participants were randomly assigned to either an early or later intervention group. The early intervention group underwent non-surgical periodontal therapy of scaling and root planing during the first 6 months, followed by a 6-month non-intervention period. The order was reversed in the later intervention group. Primary outcomes included: fasting or post-load serum glucose and insulin, body mass index (BMI), HOMA-IR, HOMA-β, and Matsuda Index., Results: Seventy-four participants were randomized, and 71 participants completed the trial. There were no significant differences between groups in glucose and insulin concentrations during the intervention and non-intervention periods. When analyzed within groups by median-split of bleeding on probing (BOP) levels before intervention, the lower BOP group showed improved changes in BMI, HOMA-IR, HOMA-β, and Matsuda Index (P < 0.05). Further, we observed a positive correlation between baseline BOP and change in BMI (P = 0.06). Change in BMI was positively correlated with changes in HbA 1c , HOMA-IR, and HOMA-β (P < 0.05), and inversely correlated with change in Matsuda Index (P = 0.001)., Conclusions: Periodontal therapy had no significant effect on markers related to insulin and glucose metabolism among individuals with borderline diabetes. However, participants with a lower BOP (%) showed significant improvements in BMI, fasting serum insulin, HOMA-IR, HOMA-β and Matsuda Index., Clinical Significance: Among individuals diagnosed with borderline diabetes, those who had <37% of a lower BOP (%) showed potential improvements in BMI, fasting serum insulin, HOMA-IR, HOMA-β and Matsuda Index following non-surgical periodontal therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Study Objective: To show a novel combination laparoscopic and open perineal approach to complete resection of aggressive angiomyxoma., Design: Step-by-step video demonstration of the combination approach (Canadian Task Force classification III)., Setting: Combined laparoscopic and open perineal approach was performed in the tertiary center., Patient: A 46-year-old woman presented with an 8-cm vulvar mass, diagnosed as an aggressive angiomyxoma. The patient, who strongly desired to preserve her uterus and ovaries, provided informed consent for resection of the tumor by our combination approach, also approved by our Institutional Review Board., Intervention: Combined laparoscopic and open perineal approach., Measurements and Main Results: Aggressive angiomyxoma is a rare mesenchymal neoplasm that occurs most often in the female pelviperineal region [1]. Aggressive angiomyxoma is locally infiltrative, and high postoperative local recurrence rates (36%-72%) due to incomplete resection have been reported [2]. Therefore, until recently, wide surgical excision with tumor-free margins have been the most commonly accepted treatment. However, aggressive angiomyxoma is a benign, slow-growing tumor, and because extensive surgical resection, which is associated with high operative morbidity rates, has not been shown to have a significant effect on prognosis, a more conservative procedure may be preferable [3]. The mass was located mainly at the left ischiorectal fossa, but it extended above the pelvic diaphragm and was attached to internal obturator muscle, vagina, bladder, urethra, and rectum. We excised the tumor completely and without complications by a combined laparoscopic and open perineal approach. Twelve months have passed since the surgery, and there has been no adjuvant treatment and no sign of recurrence., Conclusion: Our combination approach to aggressive angiomyxoma in the pelviperineal region is technically feasible, and the good visualization and meticulous dissection provided during the laparoscopic portion of the surgery contribute to complete resection., (Copyright © 2018 AAGL. Published by Elsevier Inc. All rights reserved.)

Study Objective: To show total laparoscopic complete resection of a recurrent low-grade endometrial sarcoma., Design: Step-by-step demonstration of the technique of laparoscopic anterior pelvic exenteration with super radical parametrectomy, including the explanation of detailed pelvic anatomy (Canadian Task Force classification III)., Setting: Low-grade endometrial stromal sarcoma (LGESS) is a rare malignancy that makes up around 0.2% of all uterine malignancies [1]. Total abdominal hysterectomy and bilateral salpingo-oophorectomy is a standard treatment; however, the recurrence risk is quite high [2]. For a recurrent LGESS that is resistant to hormone therapy and chemotherapy, complete resection with negative surgical margins (R0 resection) can be the most promising method [3]., Patient: The patient had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy because of a LGESS. Almost 20 years later, a recurrent LGESS was detected at the vaginal stump, and the patient underwent several rounds of chemotherapy and hormonal therapy. These treatments were inefficacious, and the recurrent tumor progressed. An abdominal computed tomographic scan revealed that the recurrent tumor occupied the vaginal stump, involved the bladder and the left ureter, and extended to the left pelvic sidewall., Interventions: Anterior pelvic exenteration with super radical parametrectomy was performed laparoscopically with no blood transfusion. R0 resection could be achieved without any intraoperative and postoperative complications. Without any adjuvant treatment, there has been no sign of recurrence during the 12 months that have passed since the surgery. This video obtained institutional review board approval through our local ethics committee in the Cancer Institutional Hospital (institutional review board number 2016-1007)., Conclusion: The good visualization and meticulous dissection provided during laparoscopic surgery can make the approach advantageous and may contribute to R0 achievement., (Copyright © 2018 American Association of Gynecologic Laparoscopists. Published by Elsevier Inc. All rights reserved.)

The objective of this open-label, randomised (i.e. 2:1 ratio), Phase 3 study was to compare the efficacy and safety of tedizolid phosphate 200 mg, once-daily treatment with that of linezolid 600 mg, twice-daily treatment for 7-14 days in Japanese adult patients (N = 125) with skin and soft tissue infections (SSTIs) and/or for 7-21 days for those with SSTI-related bacteraemia, caused by confirmed or highly suspected methicillin-resistant Staphylococcus aureus (MRSA). Primary outcome was clinical cure rate at test-of-cure (TOC, in SSTI: 7-14 days, in bacteraemia: 4-6 weeks after end-of-therapy [EOT]) time point in the microbiologically evaluable MRSA (ME-MRSA) population (N = 39). Secondary endpoints were clinical and microbiological response rates at EOT. Safety parameters were evaluated in the safety analysis population up to follow up. Data analysis was descriptive in nature. Baseline characteristics of patients were similar between treatment groups. At TOC in the ME-MRSA population, clinical cure rate was similar in tedizolid phosphate (92.6%) and linezolid (88.9%) groups. At EOT, clinical cure (tedizolid phosphate: 93.1%, linezolid: 90.0%) and microbiological success (tedizolid phosphate: 93.1%, linezolid: 100.0%) rates were similar in the ME-MRSA population. Both treatments were well tolerated; overall treatment-emergent adverse events (TEAEs) in tedizolid phosphate (79.5%) and linezolid (75.6%) treatment groups were similar. Drug-related TEAEs were numerically lower with tedizolid phosphate versus linezolid (30.1%; 39.0%, respectively), as well as gastrointestinal (21.7%; 26.8%) and myelosuppression-related (2.4%; 22.0%) TEAEs. One death occurred in the linezolid group. Tedizolid phosphate may be an appropriate antibiotic for the treatment of SSTIs in Japanese adult patients. International clinical trial registration number: NCT01967225. Japanese clinical trial registration number: JapicCTI-132308., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Limited evidence is available on the association between markers of arterial stiffness and the prevalence of atrial fibrillation among Asian populations. Therefore, we examined those associations in the Japanese population., Methods: We conducted a cross-sectional population-based study of 4264 men and women aged 40-79 years. The augmentation index (AI), a marker of arterial stiffness, was calculated as the ratio of central pulse pressure/brachial pulse pressure, where the AI and central aortic pressure were measured by an automated tonometer: the HEM-9000AI device (Omron Healthcare co., Kyoto, Japan). Atrial fibrillation was estimated by the Minnesota codes using resting electrocardiograph (ECG)., Results: The prevalence of atrial fibrillation and total arrhythmia were higher with larger AI values. These associations did not change after adjustment for known cardiovascular risk factors. The multivariable odd ratios (95% confidence intervals) in the highest versus lowest tertiles of AI were 3.4 (1.4-8.6, p for trend = 0.008) for atrial fibrillation and 1.8 (1.2-2.7, p for trend = 0.004) for total arrhythmia. There was no association of central or brachial pulse pressure levels with the prevalence of atrial fibrillation or total arrhythmia., Conclusions: AI values, but not brachial or central pulse pressures, were positively associated with the prevalence of atrial fibrillation and total arrhythmia, independent of cardiovascular risk factors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background & Aims: It has been hypothesized that ω-3 polyunsaturated fatty acids have anti-atherosclerotic and neuronal protective functions and may benefit prevention of dementia, but the epidemiological evidence, especially for α-linolenic acid, is quite limited. The aim of this study was to examine whether serum ω-3 polyunsaturated fatty acids are associated with risk of dementia., Methods: We performed an intracohort case-control study nested in a community-based cohort, the Circulatory Risk in Communities Study, involving 7586 Japanese individuals aged 40-74 years at the baseline period of 1984-1994. Omega-3 polyunsaturated fatty acid constituents (α-linolenic, eicosapentaenoic, and docosahexaenoic acids) in serum total lipid were measured in 315 cases of incident disabling dementia in the above-mentioned cohort between 1999 and 2004, and in 630 controls whose age, sex, area, and baseline year were matched with the cases., Results: As we had postulated, serum α-linolenic acid was inversely associated with risk of disabling dementia: the multivariate odds ratios (95% confidence intervals) were 0.57 (0.39-0.85), 0.51 (0.34-0.76), and 0.61 (0.41-0.90) for persons with the second, third, and highest quartiles of serum α-linolenic acid, respectively, as compared with the lowest quartile (P for trend = 0.01). Associations of other ω-3 fatty acids with disabling dementia were not statistically significant., Conclusions: Serum α-linolenic acid was inversely associated with risk of disabling dementia. Although the causality needs to be confirmed by randomized control trials, we identified serum α-linolenic acid as a biomarker that predicts future dementia., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Endoscopic submucosal dissection (ESD) is a widely accepted procedure for superficial esophageal squamous cell neoplasia (ESCN) because of a high complete resection rate. However, there were a few reports about the long-term outcomes of these patients due to short follow-up periods., Aims: We aimed to evaluate the 5-year survival after ESD for superficial ESCN., Methods: This was a retrospective cohort study performed at a single institution. Between 2006 and 2009, 94 patients with superficial ESCN underwent ESD. Eighty-three patients (93.3%) who had completed an extended period of observation of at least 5 years were enrolled. The main outcomes were the 5-year survival rates. The secondary outcomes were the cumulative incidence rate of metachronous ESCN, and the clinical outcomes., Results: The 5-year relative overall survival rate was 99.0%, whereas the cause specific survival rate was 100% during 72.9 months of median follow up period. Subgroup analysis showed that the 5year survival of patients with EP/LPM and MM/SM1 (submucosal invasion ≤200μm) were 100% and 89.0%, respectively. The cumulative incidence rate of metachronous ESCN at 5 years was 16.8%., Conclusion: ESD for superficial ESCN is a curative treatment with a favorable 5-year survival rate., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce cytokines, including tumor necrosis factor-α and interleukins (ILs), in the small intestine via a Toll-like receptor 4 (TLR4)-dependent pathway, leading to intestinal ulceration. Activation of the inflammasome promotes pro-caspase-1 cleavage, leading to pro-IL-1β maturation. We examined the role of NLRP3 inflammasome in NSAID-induced enteropathy. Small intestinal damage developed 3 h after indomethacin administration, accompanied by increases in IL-1β and NLRP3 mRNA expression and mature caspase-1 and IL-1β levels. In vivo blocking of IL-1β using neutralizing antibodies attenuated indomethacin-induced damage, whereas exogenous IL-1β aggravated it. NLRP3(-/-) and caspase-1(-/-) mice exhibited resistance to the damage with reduction of mature IL-1β production. This resistance was abolished by exogenous IL-1β. TLR4 deficiency prevented intestinal damage and inhibited upregulation of NLRP3 and IL-1β mRNAs and maturation of pro-caspase-1 and pro-IL-1β, whereas TLR4 activation by its agonists exerted opposite effects. Apyrase, an adenosine triphosphate (ATP) scavenger, or Brilliant Blue G, a purinergic P2X7 receptor antagonist, inhibited the damage as well as caspase-1 activation and IL-1β processing, despite there being sufficient amounts of pro-IL-1β and NLRP3. These results suggest that NLRP3 inflammasome-derived IL-1β plays a crucial role in NSAID-induced enteropathy and that both TLR4- and P2X7-dependent pathways are required for NLRP3 inflammasome activation.

Aim: Enteric glial cells (EGCs) modulate colonic motility in a maternal separation model. We aimed to investigate structural changes in gastric EGC and gastric emptying as responses to maternal separation and acute adulthood stress in rats to elucidate the pathophysiological roles of gastric EGC., Main Methods: As a chronic stress, we subjected male Wistar rats to 3h of maternal separation during postnatal days 2-14. As an acute adulthood stress (7weeks of age), we used the 8-h water-immersion method. We morphologically evaluated gastric EGCs using whole-mount longitudinal muscle-myenteric plexus preparations. We analyzed gastric emptying by the phenol red method., Key Finding: The area of EGC processes that apparently overlapped with neurons increased according to stress intensity (acute stress, 10.4%; maternal separation, 10.2%; maternal separation plus acute stress, 26.6%; control, 5.0%). Ratios of morphologically changed leaf-like processes to the total processes were 8.1%, acute stress; 10.3%, maternal separation; 4.0%, control. Ratio dramatically increased in the combined stress group (20.5%, p=0.026 vs. control). The mean bulging head area of leaf-like processes in the combined stress group was greater by 6.4μm(2) (control, 2.4μm(2); p=0.042). Gastric emptying in the maternal separation group was gradually delayed (104.1% at 7weeks, 66.7% at 17weeks, and 48.5% at 48weeks; p<0.05, respectively). Gastric emptying in the combined stress group tended to be delayed at 17weeks (45.7% vs. 81% in controls, p=0.066)., Significance: Gastric EGCs exhibited structural changes according to stress intensity, which may be associated with stress-induced dysfunction of the stomach., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Lower heart rate variability (HRV) is associated with the inflammation that is linked with the progression of atherosclerosis. We examined this association, taking insulin sensitivity into consideration, as it is related to both HRV and inflammation., Methods: Subjects were 1728 individuals ages 30-79 years who did not smoke between 2009 and 2012. C-reactive protein (CRP) concentrations and white blood cell (WBC) counts were assessed as markers of inflammation. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. Pulse was recorded for 5 min, and time-domain HRV indices of standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) were calculated. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power and LF/HF., Results: Sex and age-adjusted logistic models presented quartiles of SDNN, RMSSD, LF, and HF significantly associated with the highest quartile of CRP or WBC. After adjustment for body mass index and ISI, the associations were attenuated for WBC; however, even after further adjustment for several variables, SDNN, RMSSD, LF, and HF remained significantly associated with elevated CRP concentrations. When results were stratified by weight, the associations appeared more evident among non-overweight individuals., Conclusion: Lowered HRV, primarily due to parasympathetic dysfunction, was associated with elevated inflammation, independent of weight, insulin sensitivity, and other related factors., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: To elucidate the role of cerebral serotonin neurotransmission in visceral perception in functional dyspepsia (FD), we observationally examined the regional expression level of the serotonin transporter (SERT) and its correlation with clinical symptoms., Main Methods: FD patients (Rome III criteria; N=9, age range: 36-76years) and healthy controls (N=8, age range: 25-61years) participated in this study. Positron emission tomography scanning with [(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB), which binds specifically to SERT, was used to quantify the binding potential (BPND) of [(11)C]DASB in the midbrain, thalamus, caudate, putamen, amygdala, and hippocampus with reference to co-registered magnetic resonance images. Clinical symptoms were assessed using the Gastrointestinal Symptoms Rating Scale (GSRS). Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI)., Key Findings: BPND of the midbrain (P=0.041) and thalamus (P=0.031) was higher in FD patients than in controls. The BPND values in the midbrain correlated with total GSRS (r=0.663, P=0.004) and abdominal pain (r=0.419, P=0.047) scores. Its values in the thalamus correlated with total GSRS (r=0.423, P=0.044), abdominal pain (r=0.502, P=0.022), and indigestion (r=0.476, P=0.028) scores. Its value in the hippocampus correlated with abdominal pain and state-STAI scores (r=0.528, P=0.017; r=0.428, P=0.043)., Significance: Up-regulation of the SERT level in the midbrain and thalamus may underlie the pathogenesis of FD such as abdominal and psychological symptoms via a brain-gut interaction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Despite wide use, high initial success, and acceptable durability of endovascular therapy (EVT) for femoropopliteal (FP) lesions, the frequency of 30-day perioperative complications (POCs) and their effect on clinical outcomes have not been systematically evaluated, which is the subject of this study., Methods: We used a multicenter database of 2145 consecutive patients (70% male; overall mean age, 73 ± 9 years) who successfully underwent EVT for FP lesions to investigate independent predictors of POCs (logistic regression analysis) and effect of POCs on prognostic outcomes (Cox proportional regression)., Results: POCs were observed in 209 patients (10%). In multivariate logistic regression analysis, body mass index <18.5 kg/m(2), critical limb ischemia, and TransAtlanic Inter-Society Consensus for the Management of Peripheral Arterial Disease class D lesions were independently associated with POCs (adjusted odds ratios [95% confidence intervals], 2.0 [1.3-2.9], 2.5 [1.9-3.3], and 1.6 [1.2-2.1], respectively). After risk stratification of POCs according to the number of these risk factors, the incidence of POCs was higher in the groups with higher scores. Follow-up for >30 days (mean, 2.3 ± 1.8 years) was available for 2079 of 2145 patients. A Cox hazard regression model adjusted for baseline clinical characteristics showed POCs were negatively and independently associated with future occurrence of major adverse limb events (defined as major amputation and major reintervention) or death (hazard ratio [95% confidence interval], 1.6 [1.2-2.1]; P < .05)., Conclusions: Body mass index <18.5 kg/m(2), critical limb ischemia, and TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease class D lesion were positively associated with POCs after EVT for FP lesions. The occurrence of POCs may adversely affect clinical outcomes in the chronic phase., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Glucagon-like peptide (GLP)-2, secreted by L cells in the small intestine, has anti-inflammatory effects in the gastrointestinal tract. A GLP-2 analogue has been an effective treatment for Crohn disease (CD). G-protein-coupled receptor (GPR) 40 and GPR120 are probably involved in GLP-2 production, the mechanisms of which remain unclear. In our experiments, normal ileal mucosa expressed GPR40, but rarely expressed GPR120. However, both GPRs were overexpressed in the L cells of the inflamed ileal mucosa of CD patients. Mucosal inflammation induced the overexpression of GPR40, GPR120, and several inflammatory cytokines, with correlations between ileal concentrations of tumor necrosis factor (TNF)-α and GPR expression levels; however, inflammation did not induce the expression of proglucagon, a precursor of GLP-2 in CD patients. In rat L cells and GLUTag cells, TNF-α treatment increased GPR120 mRNA expression without affecting GPR40 mRNA expression. Dual agonists of GPR40 and GPR120, GW9508 and linoleic acid, respectively, increased GLP-2 production from L cells, but these agonists decreased it in the presence of TNF-α. The GPR40 antagonist, GW1100, inhibited the GW9508-induced increase in GLP-2 production, and silencing GPR120 resulted in further elevation of GLP-2 production. Thus, GPR120-dependent signaling inhibited the stimulatory effects of GPR40 on GLP-2 expression, and TNF-α treatment decreased GLP-2 expression by up-regulating GPR120 expression in L cells., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Non-fasting triglycerides were reported to have a greater impact on risk of ischemic cardiovascular events than fasting triglycerides. However, evidence from Asia, where the prevalence of dyslipidemia is generally lower, has been limited., Methods: We used 1975-1986 baseline surveys to investigate cohort data of 10,659 (4264 men and 6395 women) residents aged 40-69 years, initially free from ischemic heart disease and stroke, in four Japanese communities. Serum triglyceride concentrations at baseline were obtained for 2424 fasting (≥8 h after meal) and 8235 non-fasting (<8 h after meal) participants., Results: During the 22-year follow-up, 284 (165 men and 119 women) developed ischemic heart disease and 666 (349 men and 317 women) ischemic stroke. After adjustment for age, sex and known cardiovascular risk factors, multivariable hazard ratios (95%CI) of ischemic cardiovascular disease (ischemic heart disease and ischemic stroke) for the highest versus lowest quartiles of triglycerides were 1.71 (1.14-2.59), P for trend = 0.013, for fasting participants and 1.60 (1.25-2.05), P for trend <0.001, for non-fasting participants. The positive associations did not differ between fasting and non-fasting men, while they were strong for non-fasting women. They were stronger for ischemic heart disease than for ischemic stroke. After further adjustment for HDL-cholesterol, these associations were slightly attenuated, but remained statistically significant., Conclusion: Non-fasting as well as fasting triglycerides are predictive of risk of ischemic cardiovascular disease for Japanese men, as are non-fasting triglycerides for women., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background: Adipose-derived regenerative cells (ADRCs) are a promising source of autologous stem cells for regeneration and repair of damaged tissue. Herein, we investigated the therapeutic potential of ADRC sheets created by a magnetite tissue engineering technology (Mag-TE) for myocardial infarction., Methods and Results: Adipose tissue was obtained from wild-type (WT) mice and ADRCs were isolated. ADRCs incubated with magnetic nanoparticle-containing liposomes (MCLs) were cultured. MCL-labeled ADRCs were mixed with a diluted extracellular matrix (ECM) precursor, and a magnet was placed on the reverse side. Magnetized ADRCs formed multilayered cell sheets after a 24-h incubation. WT mice were subjected to myocardial infarction by permanent ligation of the left anterior descending artery. We then transplanted the constructed ADRC sheet or a cell-free collagen gel sheet, as a control, onto the infarcted myocardium using an Alnico magnet before skin closure. Cardiac parameters were measured by echocardiogram, and angiogenesis was determined by tissue capillary density. ADRC sheet-treated mice showed significant improvements in systolic function, infarct wall thinning, and fibrotic length after myocardial infarction. ADRC sheet implantation also promoted angiogenesis in both the infarct area and the border zone in WT mice after myocardial infarction. The angiogenic effects of ADRC sheets were attributed to an increased expression of VEGF and bFGF mRNA in ischemic hearts., Conclusions: ADRC sheets created by this Mag-TE method protect the heart against pathological cardiac remodeling. Our ADRC sheets have the potential to be a novel regenerative strategy for ischemic heart disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: There are few comprehensive reports detailing the prevalence of major adverse events associated with a double-balloon enteroscopy procedure., Methods: We retrospectively investigated the prevalence of major adverse events in 538 patients (262 males and 276 females; median age, 65 years; age range, 12-95 years) who underwent double-balloon enteroscopy at our Institution between April 2008 and October 2011., Results: Of the 17 adverse events recorded (3.2%), acute pancreatitis (n=5; 0.9%) occurred during both diagnostic (n=3) and therapeutic (n=2) anterograde double-balloon enteroscopy, and all of them were treated conservatively. For these cases, the average duration of the examination was 135 min, which was longer than for the other patients (97 min) (P=0.046). Intestinal bleeding (1.3%) was observed in 6 cases after endoscopic polypectomy and in 1 case following a biopsy procedure during a diagnostic double-balloon enteroscopy. The prevalence rates of intestinal perforation and other complications were 0.2% and 0.7%, respectively., Conclusions: The rate of adverse events associated with double-balloon enteroscopy was high compared to that associated with conventional upper/lower gastrointestinal endoscopy (0.042%/0.078%). The occurrence of acute pancreatitis may be significantly dependent on the duration of double-balloon enteroscopy examination., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: This study aimed to investigate associations between central aortic pressure (CAP) and subclinical organ damage of the heart amongst the general population., Methods: We conducted a cross-sectional study in a community-based population, consisting of 3002 men and women aged between 40 and 79 years. The CAP was measured using the HEM-9000AI device, an automated tonometer. Electrocardiograms (ECG) were read according to the Minnesota Code. Subclinical organ damage in the heart was defined as measurable left high amplitude R waves (LHAR), major and minor ST-T abnormalities, and left ventricular hypertrophy (LVH)., Results: Age- and sex-adjusted prevalence of LHAR, major and minor ST-T abnormalities, and LVH was higher for subjects in the highest tertile of CAP levels than those in the lowest tertile. After further adjustments for other cardiovascular risk factors, these associations did not change substantially. The multivariable odds ratios (ORs) (95% CI) of LHAR, major and minor ST-T abnormalities, and LVH for the highest tertile of CAP levels compared to the lowest tertile were 2.7(1.9-3.9), 1.8(1.1-2.9), 1.7(1.3-2.3) and 3.2(1.3-8.1), respectively. The positive associations with LHAR and minor ST-T abnormalities were observed primarily among non-hypertensive subjects. The respective corresponding ORs were 2.8(1.7-4.6) and 1.7(1.2-2.4) for non-hypertensive subjects, and 1.7(0.9-3.3) and 1.1(0.7-1.8) for hypertensive subjects., Conclusion: CAP levels were associated with subclinical organ damage of the heart independent of cardiovascular risk factors, and these associations were primarily seen in non-hypertensive subjects., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Sarcopenia, the age-dependent loss of skeletal muscle mass, is highly prevalent among older adults in many countries; however, the prevalence of sarcopenia in healthy Japanese community-dwelling older adults is not well characterized., Objective: The aim of this study was to evaluate the prevalence of sarcopenia and to examine the association of sarcopenia with falls and fear of falling in community-dwelling Japanese older adults., Design: This is a cross-sectional study., Setting and Subjects: Healthy men (568) and women (1314) aged 65 to 89 years participated in this research., Measurements: For all participants, 3 measurements were taken: skeletal muscle mass measurement using bioelectrical impedance, 10 m at a usual walking speed, and handgrip strength. Sarcopenia was defined as the presence of both poor muscle function (low physical performance or low muscle strength) and low muscle mass., Results: The prevalence of sarcopenia, determined using the European Working Group on Sarcopenia in Older People-suggested algorithm, in men and women aged 65 to 89 years was 21.8% and 22.1%, respectively. The prevalence of sarcopenia increased age-dependently, especially in those older than 75 years in both genders. In the young old, the prevalence of sarcopenia was higher in women than in men; however, in those older than 85 years, the prevalence of sarcopenia was lower in women than in men (P < .05). In addition, fall incidents and fear of falling were more prevalent in sarcopenic older adults than in nonsarcopenic older adults (P < .05)., Conclusions: These results suggest that sarcopenia is highly prevalent in community-dwelling Japanese older adults and is related to falls and fear of falling., (Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: The association of adiponectin levels with cardiovascular disease (CVD) may vary by age and health condition. It is unknown whether adiponectin predicts CVD events among individuals with high blood glucose levels., Methods: We conducted a nested case-control study among 15,566 men and women aged 40-85 years from four communities, who were free of CVD at baseline. During 192,181 person-years of follow-up, 117 individuals subsequently developed coronary heart disease or ischemic stroke and had high plasma glucose concentrations (fasting/nonfasting ≥ 5.6/7.2 mmol/L or treated) at baseline. Controls were randomly selected at a 2:1 ratio and matched for sex, age, blood glucose, year of survey, fasting conditions, and community (n = 234). Baseline total and high molecular weight (HMW) adiponectin and their ratio were examined for total subjects and the association with CVD was compared between ages of 40-69 and 70-85 years., Results: After adjustment for matched variables and traditional risk factors, total and HMW adiponectin and their ratio were not associated with overall risk of CVD. However, significant interactions of the associations between the age groups were found. The highest quartile for HMW adiponectin and HMW/total adiponectin ratio decreased risk of CVD compared with the lowest quartile among middle-aged individuals (multivariable-adjusted odds ratio = 0.33 [95%CI, 0.13-0.83] and 0.47 [0.22-0.98], respectively), while this association was not seen among the elderly., Conclusions: High HMW adiponectin levels may decrease the risk of CVD in middle-aged adults with high blood glucose., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Few studies have assessed the risk factors associated with nonsteroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal damage., Aims: To evaluate the risk factors for NSAID-induced enteropathy in patients with rheumatoid arthritis., Methods: A cross-sectional study using capsule endoscopy was conducted. A total of 113 patients who took NSAIDs for over 3 months underwent capsule endoscopies. Endoscopic findings were scored as (0) normal, (1) red spots, (2) 1-4 erosions, (3) >4 erosions, or (4) large erosions/ulcers. Initial scores were grouped into 3 categories: No damage (0-1), mild damage (2), and severe damage (3-4), and the potential risk factors for damage development were assessed., Results: Five patients were excluded because of incomplete visualization of the entire small intestine. Fifty-two (47.2%) and 27 (25%) patients had no damage and mild damage, respectively, while the remaining 30 patients (27.8%) had severe damage and significantly decreased hemoglobin levels. In a multivariate logistic regression analysis, ages of 65 years or more (odds ratio [OR], 4.16; 95% confidence interval [CI], 1.51-11.47), proton pump inhibitor usage (OR, 5.22; 95% CI, 1.36-20.11), and histamine H2 receptor antagonist usage (OR, 3.95; 95% CI, 1.28-12.25) were independent risk factors for severe damage., Conclusions: Elderly patients and acid suppressant users are more likely to develop severe NSAID-induced enteropathy., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF.

This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one-compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective.

Helicobacter pylori (H. pylori)-induced immune responses in the gastric mucosa are skewed toward T helper (Th) 1 phenotype, which is characterized by predominant production of tumor necrosis factor (TNF)-α and interferon (IFN)-γ by helper T cells. Toll-like receptors (TLRs) play an essential role in mucosal defense against microbes through the recognition of bacterial molecules. Among the members of the TLR family, TLR9 recognizes bacterial unmethylated CpG DNA sites, and signal transduction of TLR9 induces production of a variety of cytokines, including type-I IFN (IFN-α/β). We investigated the expression and role of TLR9 in H. pylori-induced gastritis in mice. Expression of TLR9 mRNA in the gastric tissue increased after infection with H. pylori. TLR9 was mainly expressed in the macrophages, dendritic cells, and CD3(+) cells in the gastric mucosa. Neutrophil infiltration and the expression levels of TNF-α and IFN-γ mRNA were higher in TLR9 knockout (KO) mice than in wild-type mice at 2 and 4 months after H. pylori inoculation. These differences in inflammatory parameters between H. pylori-infected wild-type and TLR9 KO mice disappeared 6 months after H. pylori inoculation. Expression of interleukin-4 mRNA, typical Th2 cytokine, in the gastric tissue did not differ between H. pylori-infected wild-type and TLR9 KO mice. Expression level of IFN-α/β mRNA in the TLR9 KO mice was lower than that in wild-type mice by 4 months after inoculation. Administration of IFN-α reduced H. pylori infection-induced increase in neutrophil infiltration and the expression levels of TNF-α and IFN-γ mRNA in TLR9 KO mice. Our findings suggest that TLR9 signaling plays important roles in the suppression of H. pylori-induced gastritis in the early phase via downregulation of Th1-type cytokines modulated by IFN-α., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Release of high mobility group box 1 (HMGB1) from damaged cells, which is involved in many types of tissue injuries, activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor 2 (TLR2), TLR4, and receptor for advanced glycation end-products (RAGE). Our objective was to determine the role of HMGB1 in nonsteroidal anti-inflammatory drug (NSAID)-induced damage of the small intestine. Oral indomethacin (10 mg/kg) induced damage to the small intestine and was associated with increases in intestinal HMGB1 expression and serum HMGB1 levels. In wild-type mice, recombinant human HMGB1 aggravated indomethacin-induced small intestinal damage; enhanced the mRNA expression levels of tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1, and KC; activated nuclear factor kappa B; and stimulated phosphorylation of the mitogen-activated protein kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). In contrast, blocking HMGB1 action with neutralizing antibodies prevented damage and inhibited both inflammatory cytokine overexpression and activation of these intracellular signaling pathways. TLR2-knockout (KO) and RAGE-KO mice exhibited high sensitivities to indomethacin-induced damage, similar to wild-type mice, whereas TLR4-KO mice exhibited less severe intestinal damage and lower levels of TNF-α mRNA expression. Exogenous HMGB1 aggravated the damage in TLR2- and RAGE-KO mice but did not affect the damage in TLR4-KO mice. Thus, our results suggest that HMGB1 promotes NSAID-induced small intestinal damage through TLR4-dependent signaling pathways., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Fetal fibroblast cell culture from cotyledons of bovine placenta and animal experiments close to term were used to elucidate afterbirth release and factors missing in the signal transduction mechanism for retained fetal membranes (RFM) after delivery. In cell culture the addition of arachidonic acid (Ara) to the medium caused rapid release to free floating cell in the culture dish, accompanied by matrix metalloproteinase (MMP) activation, being consistent with previous in vivo observations, where a relation between MMP and fetal membrane release had been shown. Ara-induced cell floating was not inhibited by the addition of cyclooxygenase (COX) inhibitor, and not induced by the addition of PGF2α or PGE2 to replace Ara, while 12-lipoxygenase (12-LOX) metabolite of Ara, 12-oxo-eicosatetraenoic acid (12-oxoETE), strongly induced cell floating. In the animal experiments, 12-oxoETE injection to delivery-induced cows (n = 6) using prostaglandin (PG) and dexamethazone resulted in rapid release of fetal membranes. In cows with natural calf delivery, a 12-oxoETE peak (11.7-16.8 ng/ml) was observed in maternal blood plasma prior to release of fetal membranes. This investigation thus gives new indications for that the mediator for fetal membrane release is 12-oxoETE and not PG., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Epidemiological studies have shown high-sensitive C-reactive protein (hs-CRP) to predict cardiovascular disease. However, there are only limited studies on the effects of hs-CRP levels on risk of stroke especially stroke subtypes. We examined associations of hs-CRP levels with risks of total stroke and its subtypes., Methods: A prospective nested case-control study of Japanese 40-85 years of age was conducted using frozen serum samples collected from 13,521 men and women who participated in cardiovascular risk surveys from 1984 to 2001 for one community and 1989 to 1998 for the other two communities under the Circulatory Risk in Communities Study (CIRCS). Three control subjects per case were matched by sex, age, community, year of serum storage, and fasting status., Results: By the end of 2005, we identified 261 incident strokes (165 ischemic strokes and 96 hemorrhagic strokes). There was a positive association between hs-CRP and incidence of incidence of total stroke, ischemic stroke and lacunar infarction. After further adjustment for known cardiovascular risk factors, these relationships remained statistically significant. The multivariable conditional odds ratios associated with 1-SD increment of log-transformed hs-CRP were 1.17(1.01-1.35) for total stroke, 1.27(1.06-1.52) for ischemic stroke, and 1.24(1.00-1.55) for lacunar infarction. The association between hs-CRP levels and incidence of ischemic stroke did not vary by sex, age, body mass index and smoking. No associations were found between hs-CRP levels and risk of hemorrhagic stroke., Conclusions: hs-CRP predicts the incidence of total and ischemic strokes among middle-aged Japanese men and women., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The associations between alcohol consumption and sleep-disordered breathing in women are uncertain., Methods: We conducted a cross-sectional study of 3113 women aged 30-69 years. The 3% oxygen desaturation index (3% ODI), based on overnight pulse oximetry findings, was selected as an indicator of sleep-disordered breathing., Results: 3% ODI frequencies of ≥5 were higher for drinking women with ethanol intakes of ≥23.0 g/d than for never drinkers: the respective multivariable odds ratios and 95% confidence intervals was 1.8(1.0-3.4). The corresponding odds ratio was 3.0(1.6-5.8) for habitual snoring. The associations of ethanol intakes of ≥23.0 g/d with 3% ODI ≥ 5 was more evident among women with BMI <23.0 kg/m(2) (median) than those with higher BMI but did not vary by habitual snoring. The multivariable odds ratios of 3%ODI ≥ 5 for women with ethanol intakes of ≥23.0 g/d versus never drinkers were 2.7(1.0-6.7) for lower BMI and 1.5(0.6-3.3) for higher BMI and the corresponding odds ratio were 2.8(1.6-7.2) and 3.2(1.3-7.9) for habitual snoring, respectively., Conclusion: Alcohol consumption was associated with higher prevalence of sleep-disordered breathing among Japanese women., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Aging is associated with impaired angiogenesis (new blood vessels formation from the endothelial cells of pre-existing vessels) in a variety of tissues. The precise mechanisms of aging-related impairment of angiogenesis are not known. PTEN is a dual-specificity phosphatase that antagonizes in some cells the PI3K/Akt signaling pathway, important for cell survival, function and angiogenesis. PTEN's role in aging-related impairment of angiogenesis is not known. In this study, we investigated whether expression of PTEN in endothelial cells may play a mechanistic role in aging-related impairment of angiogenesis. We demonstrated that human microvascular endothelial cells (HMVEC) derived from aging individuals (Aged-HMVEC) have: (1) significantly increased PTEN mRNA and protein levels and (2) impaired in vitro angiogenesis vs. neonatal derived HMVEC (Neo-HMVEC), and that (3) downregulation of PTEN using specific siRNA restores angiogenesis in Aged-HMVEC to normal. This is the first demonstration of increased PTEN expression in human microvascular endothelial cells derived from aging tissues and that elevated PTEN is a major factor responsible for aging-related impairment of in vitro angiogenesis., (Published by Elsevier Inc.)

Purpose: Left ventricular (LV) mechanical dyssynchrony is an important codeterminant of cardiac dysfunction in heart failure (HF) patients exhibiting either a narrow or a wide QRS complex. We hypothesized that an angiotensin converting enzyme (ACE) inhibitor would prevent LV dyssynchrony during the progression of pacing-induced HF through its beneficial effects on hemodynamic change and myocardial fibrosis., Methods: Twenty-eight dogs were assigned to the following treatment groups; rapid ventricular pacing (HF group; n=10), concomitant ACE inhibitor and rapid pacing (enalapril 1.9 mg/kg/day: ACEI group; n=8), or sham-operated control (control group; n=10). After 4 weeks of pacing, cardiac function was evaluated using micromanometers and conductance catheters. We used indexes to quantify the temporal and spatial aspects of mechanical dyssynchrony derived from online segmental conductance catheter signals. At each time point, a segmental signal was defined as dyssynchronous if its change was opposite to the simultaneous change in the total LV volume. Mechanical dyssynchrony was calculated as the mean of the segmental dyssynchronies during systole, diastole, and throughout the cardiac cycle., Results: In the ACEI group, the LV ejection fraction was preserved, and total systemic resistance and end-diastolic volume were significantly decreased, while stroke volume was significantly increased compared to the HF group. The mechanical dyssynchrony index in the HF group was significantly higher compared to that of the control group, while it was significantly lower in the ACEI group. Thus, conventional therapy with an ACE inhibitor diminished LV dyssynchrony during the progression of pacing-induced HF., (Copyright 2008 Elsevier Ireland Ltd. All rights reserved.)

Background and Objectives: Sleep apnea is highly prevalent in patients with heart disease. However, the association between sleep apnea and ventricular arrhythmias is unclear. The aim of this study was to examine the relationship between sleep apnea and electrophysiologic characteristics and clinical outcome after catheter ablation in patients having ventricular arrhythmias., Methods and Results: Forty-four patients with ventricular tachycardia (VT) or premature ventricular complexes (PVCs) without structural heart diseases (57% men; mean age: 55 + or - 15 years) underwent a sleep study. Subjects with an apnea-hypopnea index (AHI) > or = 10/h were considered to have sleep apnea. Electrophysiologic studies were performed on all patients, and 35 patients underwent catheter ablation therapy. Seventeen patients (39%) had sleep apnea with an average AHI of 27 + or - 17/h. Electrophysiologic characteristics of ventricular arrhythmias showed that sites of VT/PVCs origin in the pulmonary artery and the aortic sinus of Valsalva were detected in 27% and 20% patients with sleep apnea, which was a relatively higher rate than that in patients without sleep apnea (8% and 0%, respectively). Successful catheter ablation was achieved in 11 patients (85%) with sleep apnea and 17 (77%) without sleep apnea. During a mean follow-up period of 13.5 + or - 7.3 months after catheter ablation, 5 patients (45%) with sleep apnea and 1 patient (6%) without sleep apnea experienced recurrent VT/PVCs. Comparing the outcome between the two groups, the VT/PVCs recurrence rate was significantly higher in patients with sleep apnea than in those without sleep apnea (p=0.02)., Conclusions: Ventricular arrhythmia patients with sleep apnea have a high recurrence of arrhythmias after successful catheter ablation. Patients with ventricular arrhythmias should be systematically assessed for sleep apnea owing to the potential detrimental effects of sleep apnea in the follow-up period., (Copyright 2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine the association between concentrations of serum vitamin C, a contributive factor to prevention of cardiovascular disease and levels of hs-CRP, a risk factor for cardiovascular disease, in population-based samples of middle-aged men and women., Design: A cross-sectional study., Methods and Results: The subjects were 778 men and 1404 women, aged 40-69 years, who participated in a cardiovascular risk survey in Kyowa, Ibaraki prefecture in 2002 as part of the Circulatory Risk in Communities Study (CIRCS). Inverse associations between serum vitamin C concentrations and hs-CRP levels were established for both men and women. Multivariable-adjusted mean values of hs-CRP for the lowest to highest quintiles of vitamin C levels were 0.75, 0.65, 0.61, 0.61 and 0.47 mg/L (P for trend <0.001) for men, and 0.56, 0.51, 0.49, 0.41 and 0.41 mg/L (P for trend <0.001) for women. The inverse association between vitamin C and hs-CRP was stronger for non-smoking men and women, non-overweight women and postmenopausal women., Conclusions: Serum vitamin C concentrations were found to be inversely associated with hs-CRP levels in both men and women, primarily among non-smokers, non-overweight women and postmenopausal women. The respective roles of serum vitamin C and hs-CRP levels in the development of cardiovascular disease thus warrant further investigation., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: An inverse association between protein intake and blood pressure has been reported in Western countries. However, the evidence is limited for Asians, whose protein sources are different from those in Western populations., Objectives: The objective was to examine the association between protein intake and blood pressure in Japanese adults., Methods: We conducted a population-based, cross-sectional study of 7585 subjects (3499 men and 4086 women) from 40 to 69 y of age living in 5 communities in Japan. Dietary intakes of total, animal, and plant protein were estimated by a single 24-h dietary recall. We then examined the associations between dietary intake of those proteins and blood pressure after adjustment for age, sex, community, body mass index, antihypertensive medication use, ethanol intake, smoking, and dietary intakes of sodium, potassium, and calcium., Results: After adjustment for cardiovascular disease risk factors, a 25.5-g/d increment in total protein intake was associated with a decrease in systolic blood pressure of 1.14 mm Hg (P < 0.001) and in diastolic blood pressure of 0.65 mm Hg (P < 0.001), and a 19.9-g/d increment in animal protein intake was associated with a decrease in systolic blood pressure of 1.09 mm Hg (P < 0.001) and in diastolic blood pressure of 0.41 mm Hg (P = 0.003). A 13.1-g/d increment in plant protein intake was associated with a decrease in diastolic blood pressure of 0.57 mm Hg (P < 0.001). Further adjustment for nutritional factors weakened these associations, but the inverse associations of total protein intake with diastolic blood pressure and of animal protein intake with systolic blood pressure remained statistically significant., Conclusion: Total and animal protein intakes were inversely associated with blood pressure in Japanese adults.

Helicobacter pylori-induced immune responses are skewed toward a T helper (Th) 1 phenotype. IL-17-producing Th17 cells have recently been discovered, and we examined the role of IL-17A in H. pylori-induced gastritis. Six months after inoculation with H. pylori, the mice received an intraperitoneal injection of recombinant IL-17A, anti-IL-17A antibody or irrelevant IgG(2a) for 3days. H. pylori infection markedly increased mRNA for IL-17A. Double immunofluorescence studies showed that IL-17A proteins were expressed on CD4(+) T cells, macrophages, and dendritic cells. H. pylori infection elevated mRNAs for IL-12, IFN-gamma, and TNF-alpha with increase in myeloperoxidase activity, whereas it did not affect mRNAs for IL-4 and IL-5. Neutralization of IL-17A elevated mRNAs for IFN-gamma and TNF-alpha, and myeloperoxidase activity, whereas recombinant IL-17A had a tendency to reduce these parameters. In conclusion, IL-17A exerts anti-inflammatory effects on H. pylori-induced gastritis through suppression of Th1 differentiation.

Objectives: Our aim was to investigate the frequency of left ventricular (LV) and right ventricular adipose tissue on multislice computed tomography (CT) in patients with a history of myocardial infarction (MI) and to determine correlations with infarct age., Background: Fat deposition in the ventricular wall has frequently been observed in post-infarct myocardial tissue. However, the in vivo relevance of adipose tissue in MI on CT and correlations with infarct age have not been determined., Methods: Fifty-three patients with a history of MI (mean age 66 +/- 10 years; 38 men, 15 women) and 63 subjects with no history of MI or coronary revascularization (mean age 65 +/- 12 years; 37 men, 26 women) were retrospectively studied for intramyocardial fat on 64-slice cardiac CT. Presence or absence, distribution, and correlations with infarct age of LV adipose tissue were evaluated., Results: Compared with noninfarct control subjects, the MI group showed a significantly higher prevalence of fat deposition within LV myocardium on CT (MI group, 62% [33 of 53] vs. control group, 3% [2 of 63]; p < 0.0001). In 32 of 33 patients (97%) with MI and LV fat deposition on CT, adipose tissue was observed in the region perfused by the infarct-related artery and was located in the subendocardium in 30 patients (94%), the middle layer in 1 patient (3%), and the subepicardium in 1 patient (3%). Mean infarct age was significantly higher in patients with LV adipose tissue (8.2 +/- 4.4 years) than in those without adipose tissue (2.2 +/- 2.6 years, p < 0.001). Thirty of 35 patients (89%) with infarct age >or=3 years showed adipose tissue in MI. Conversely, none of 9 patients with infarct age <10 months showed fatty replacement., Conclusions: Myocardial adipose tissue is common in patients with infarct age >or=3 years. CT evaluation of myocardial adipose tissue may be important for accurate interpretation of CT perfusion and infarct imaging of the heart.

Aims: Mesenchymal stem cells (MSCs) may modulate inflammatory responses resulting in improvement in inflammatory diseases, as well as tissue regeneration via cellular differentiation. We examined the therapeutic effects of exogenously administered MSCs in dextran sulfate sodium (DSS)-induced colitis in rats., Main Methods: Experimental colitis was produced in inbred male Lewis rats by administration of 4% DSS in drinking water for 7 days. MSCs (5x10(6) cells) which were isolated from whole marrow cells and cultured in an optimal medium for MSC outgrowth were administered to the treated rats via the tail vein on days 0, 2, and 4. On day 7, we evaluated colon length, histological changes, and colonic various mRNA expressions by RT-PCR. Localization of MSCs was evaluated using a green-fluorescent cell linker dye. To evaluate the anti-inflammatory action of MSCs, we assayed LPS-induced TNF-alpha secretion in a co-culture of MSCs and monocytes (THP-1 cells) using ELISA., Key Findings: MSCs reduced in bloody stools, weight loss, colon shortening, and microscopic injuries. In the rectum of MSCs-treated rats, mRNA expression of TNF-alpha, IL-1beta, and COX-2 decreased to 40, 15, and 15% of their respective control levels. MSCs significantly suppressed mRNA expression of VEGF, HGF, and b-FGF to 40, 25, and 25% of their respective control levels. Green-fluorescent-labeled MSCs were found only within the lamina propria in inflamed regions. LPS-induced TNF-alpha secretion by THP-1 cells was significantly suppressed by co-culture with MSCs dose-dependently., Significance: We conclude that exogenous MSCs accumulated in inflamed tissues and ameliorated DSS-induced colitis via a local anti-inflammatory action.