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Oltipraz, a synthetic dithiolethione, has chemopreventive effect through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Nrf2 is known to be involved in the development of experimental steatohepatitis in rodents. In this study, to evaluate the effect of oltipraz on lipid and bile acid metabolism, wild-type and Nrf2-null mice were fed the standard diet (containing 4% soybean oil) with or without oltipraz. Based on these results, we examined the effect of oltipraz on the experimental steatohepatitis in high-fat diet (containing 4% soybean oil and 20% lard) fed Nrf2-null mice. Oltipraz induced hepatic mRNA expression of peroxisome proliferator-activated receptor α, carnitine palmityl transferase 1, and bile salt export pump by Nrf2 independent mechanisms. In Nrf2-null mice fed a high-fat diet for 12 weeks, moderate to severe inflammation and fibrosis were observed. Oral administration of oltipraz suppressed the degree of inflammation and fibrosis in Nrf2-null mouse liver fed a high-fat diet. These histopathological findings approximately corresponded to the data of mRNA expression of tumor necrosis factor α, monocyte chemoattractant protein-1, Timp-1, and collagen type 1α1. These results indicated that oltipraz administration ameliorated liver injury by Nrf2 independent manner in a model of steatohepatitis generated by Nrf2-null mice with high-fat diet.

Several clinical studies have been conducted into the practicality and safety of regenerative therapy using hESC/iPSC-retinal pigment epithelium (RPE) as a treatment for the diseases including age-related macular degeneration. These studies used either suspensions of RPE cells or an RPE cell sheet. The cells can be injected using a minimally invasive procedure but the delivery of an intended number of cells at an exact target location is difficult; cell sheets take a longer time to prepare, and the surgical procedure is invasive but can be placed at the target area. In the research reported here, we combined the advantages of the two approaches by producing a quickly formed hiPSC-RPE strip in as short as 2 days. The strip readily expanded into a monolayer sheet on the plate, and after transplantation in nude rats, it showed a potency to partly expand with the correct apical/basal polarity in vivo, although limited in expansion area in the presence of healthy host RPE. The strip could be injected into a target area in animal eyes using a 24G canula tip.

Augmentative and alternative communication (AAC) requires on-going support but few studies describing AAC training for healthcare professionals were found.We developed a short-term education progra...

Definitive radiation therapy (RT), using external beam RT and/or brachytherapy, is a standard treatment option for primary vaginal carcinoma. However, this treatment has poor prognosis when applied to vaginal nonsquamous cell carcinoma (non-SCC). We aimed to clarify treatment outcome and surgical safety in early-stage primary vaginal non-SCC. After receiving approval from the institutional review board, we retrospectively reviewed the clinical records and pathological samples of patients treated at our hospital between 1991 and 2018. Among 49 patients with primary vaginal carcinoma, 12 with histologically confirmed early-stage primary vaginal non-SCC were included in this study. In total, 40% of patients with primary vaginal carcinoma treated at our hospital had primary vaginal non-SCC. The average observation time was 34 months (median 53.3 months). Three patients had local recurrence: 2 in pelvic lymph nodes and 1 in the vagina. Furthermore, 2 patients died of their disease. Five-year local control rate of stage I and stage II non-SCC was 75% and 100%, respectively. Disease-specific survival rate of stage I and stage II non-SCC was 81.8% and 100%, respectively. No major morbidity was observed. Three patients required allogeneic blood transfusion, whereas 1 underwent autotransfusion. None of the 12 patients were discharged with self-catheterization. Five-year local control and disease-specific survival rates of patients surgically treated for vaginal non-SCC were favorable. Therefore, surgery could be a safe and reasonable option for early-stage primary vaginal non-SCC.

Background We examined risk factors for development of ventricular tachycardia (VT) in pediatric patients with ventricular premature contractions (VPCs) and a structurally normal heart. Methods The subjects were 81 844 first graders and 88 244 seventh graders of Kagoshima City School‐based cardiovascular screening (SCV‐screening) between 2001 and 2015. We retrospectively reviewed the clinical data of students who were diagnosed as having VPC. Results Ventricular premature contractions were observed in 134 first graders (0.16%) and 270 seventh graders (0.31%). On the screening electrocardiograms (ECGs), 43 patients (11%) showed bi‐/trigemini, three patients (0.7%) showed a couplet, and one patient showed VT. We obtained 166 patients' follow‐up information and evaluated 59 patients (36%) as improved, 97 patients (58%) as no change, and 10 patients (6%) as worsened (couplets, five; triplets, two; VT, three). We assumed that these worsened patients have risk factors for development of VT. Comparing the findings of SCV‐screening ECGs of risk patients with the others, a significant difference was observed only in the number of VPCs (per 10 seconds) (mean ± SD; 4.3 ± 2.6 vs 1.8 ± 1.4, P, Patients with ventricular premature contraction and a structurally normal heart diagnosed through School‐based cardiovascular screening commonly showed improved or no changes in ECG during follow‐ups, but a few patients developed VT.

Background The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. Conclusions Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

BackgroundThe purpose of this study to compare glenohumeral joint motion during active shoulder axial rotation between subacromial impingement syndrome (SIS) shoulders and asymptomatic shoulders using cine-magnetic resonance imaging (cine-MRI). Measurement of glenohumeral joint motion via manual intervention does not assess the usual glenohumeral joint motion, and the glenoid surface cannot be confirmed manually. However, cine-MRI can produce clear images of glenohumeral joint rotation. Therefore, we sought to measure the active ROM of the glenohumeral rotation using cine-MRI.MethodsSeventy-three shoulders in 42 asymptomatic volunteers and 110 SIS shoulders in 103 consecutive patients were included in this study. We evaluated 36 matched pairs (72 shoulders in total) adjusting for baseline characteristics with propensity score matching method. The patients underwent cine-MRI during axial rotation of the adducted arm. During imaging, participants rotated their shoulder from the maximum internal rotation to the maximum external rotation over the first 10 s and then back to the maximum internal rotation over the subsequent 10 s. We assessed internal/external rotation, and compared the asymptomatic and SIS shoulders in this regard. Evaluation of rotation angles was performed on a series of axial images through the humeral head center.ResultsThe mean internal rotation angles of the asymptomatic and patient groups were 55° ± 10° and 41° ± 23°, respectively, (P = .002; 95% Confidence Interval [CI], 51–58 vs 33–49); the mean external rotation angles were 47° ± 15° and 21° ± 25°, respectively, (P ConclusionsCompared to asymptomatic shoulders, SIS shoulders showed significantly restricted glenohumeral rotation as determined by cine-MRI. Our results suggested that the significant limitation of active glenohumeral rotation might be associated with rotator cuff dysfunction.

Purpose This study aimed at evaluating the influence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. Methods We retrospectively analyzed the data of patients with stage I A endometrial cancer admitted in our hospital between 2005 and 2015. Results Among 989 patients with stage IA endometrial cancer who underwent peritoneal cytology, 135 (13.7 %) had PPC. In multivariate analysis, BMI ≥ 25 kg/m2, grade 2 cancer, type II cancer, muscle invasion, and PPC were extracted as independent risk factors for recurrence in stage IA patients. In addition, type II cancer was identified as an independent risk factor in stage IA patients with PPC. There was no significant difference in the 5-year relapse-free survival rate in stage IA patients with PPC who received adjuvant chemotherapy when compared those who did not receive chemotherapy (p = 0.78). Similarly, the difference in the 5–year recurrence free survival rate between the two groups was not significant in patients with type II cancers (p = 0.11). However, the baseline risk of 5-year relapse-free survival without chemotherapy in stage IA patients with PPC and type II was very low (66.7%). Conclusions PPC was an independent risk factor for recurrence in stage IA endometrial cancer. Adjuvant chemotherapy did not influence the relapse-free survival rate in patients with stage IA endometrial cancer with PPC. Therefore, it is necessary to investigate adjuvant chemotherapy for early endometrial cancer patients with risk factors for recurrence, especially those with multiple factors.

This study evaluated the influence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. We retrospectively analyzed the data of patients with stage IA endometrial cancer admitted in our hospital between 2005 and 2015. Among 989 patients who underwent peritoneal cytology, 135 (13.7%) had PPC. Multivariate analysis extracted several independent risk factors for recurrence in stage IA patients, including those with PPC. Adjuvant chemotherapy did not cause a significant difference in the 5-year relapse-free survival rate in patients with PPC (p = 0.78). Similarly, the 5-year recurrence-free survival rate with or without chemotherapy was not different among type II cancer patients (p = 0.11). However, the baseline risk of 5-year relapse-free survival without chemotherapy in patients with PPC and type II was very low (66.7%). While PPC was an independent risk factor for recurrence in stage IA endometrial cancer, adjuvant chemotherapy did not influence the survival rate in patients with PPC. While it is controversial whether adjuvant chemotherapy should be administered in stage IA uterine cancer with only PPC as a prognostic factor, it should be considered for early-stage patients who have multiple risk factors for recurrence.

Rationale: Syncope often occurs in patients with advanced head and neck cancers due to the stimulation of the autonomic nervous system by the tumor. Here, we describe a case of frequent syncopal episodes after laryngopharyngectomy for hypopharyngeal cancer. As all syncopal episodes were observed during the forenoon, we also evaluated the heart rate variability using ambulatory electrocardiography to determine why the syncopal episodes occurred during a specified period of the day. Patient concerns: A 73-year-old Japanese man who underwent laryngopharyngectomy for recurrent hypopharyngeal cancer started experiencing frequent episodes of loss of consciousness that occurred during the same time period (10:00–12:00). He had never experienced syncopal episodes before the operation. From 23 to 41 days postoperatively, he experienced 9 syncopal episodes that occurred regardless of his posture. Diagnoses: Pharyngo-esophagoscopy revealed an anastomotic stricture between the free jejunum graft and the upper esophagus. Swallowing videofluoroscopy confirmed the dilatation of the jejunal autograft and a foreign body stuck on the oral side of the anastomosis. Contrast-enhanced computed tomography revealed that the carotid artery was slightly compressed by the edematous free jejunum. The patient was diagnosed with carotid sinus syndrome (CSS) as the free jejunum was dilated when consuming breakfast, which may have caused carotid sinus hypersensitivity and induced a medullary reflex. Interventions: Administration of disopyramide was effective in preventing syncope. Heart rate variability analysis using ambulatory electrocardiography showed that parasympathetic dominancy shifted to sympathetic dominancy during 10:00 to 12:00. The significant time regularity of the syncopal episodes may have been affected by modified diurnal variation in autonomic tone activity. Outcomes: After the surgical release and re-anastomosis of the pharyngoesophageal stenosis via an open-neck approach, no recurrent episodes of syncope were reported. Lessons: We reported a case of frequent syncopal episodes limited to the forenoon due to CSS after surgery for hypopharyngeal carcinoma. The patient was treated with anticholinergics followed by the release and re-anastomosis of the pharyngoesophageal stenosis. When syncope occurs after surgery for head and neck lesions, CSS due to postoperative structural changes should be considered as a differential diagnosis of syncope.

Highlights • We report the first case of a paraurethral mixed Müllerian cystadenoma. • The cystic lesion was lined by a mixture of three different types of epithelium. • All epithelial cells were positive for estrogen receptor and PAX8.

After pelvic lymphadenectomy (PLA), pelvic vessels, nerve, and ureter are skeletonized. Internal hernias beneath the skeletonized pelvic structure following pelvic lymphadenectomy (IBSPP) are a rare complication following PLA. To the best of our knowledge, only 12 IBSPP cases have been reported and clinical details on such hernias remain unknown. The aim of the study was to investigate the incident and etiology of IBSPP. 1313 patients who underwent open or laparoscopic pelvic lymphadenectomy were identified from our database. A retrospective review was performed. Mean follow-up period was 33.9 months. A total of 12 patients had IBSPP. Multivariate analysis of laparoscopic surgeries group as compared to open surgeries group, para-aortic lymphadenectomy rate, number of dissected lymph nodes by PLA, antiadhesive material use rate, and blood loss were lower in laparoscopic surgeries group: odd ratio (OR) = 0.13 [95% confidence interval (CI) 0.08–0.19], and OR = 0.70 [95% CI 0.50–0.99], OR = 0.17 [95% CI 0.10–0.28], OR = 0.93 [95% CI 0.92–0.94]. However, no significant difference was observed in the incidence of IBSPP between laparoscopic surgery (1.0%) and open surgery (0.8%). All IBSPP occurred in the right pelvic space. These findings may contribute to the development of prevention methods for this disease.

In 2003, Hockel described the laterally extended endopelvic resection (LEER), which may be an effective surgical technique for patients with laterally recurrent cervical cancer ( Hockel, 2003 ). Super-radical hysterectomy, which was introduced by Ryukichi Mibayashi in 1941, is the traditional surgical approach for cervical cancer patients ( Kim et al., 2017 ). These two procedures are similar and belong to the same group (type D) in the Querleu-Morrow classification ( Querleu et al., 2017 ). Until now, no surgical video clearly demonstrated their differences, because technical complexities and concern for procedural safety are still being debated. The present video demonstrated total pelvic exenteration (TPE) for laterally recurrent, previously irradiated cervical cancer that involved both the bladder and rectum. In this case, the recurrent tumor infiltrated the parametrium, reached the left pelvic sidewall, and invaded the left piriform muscle, sacrospinous ligament, and spine segment S2. To completely clear the tumor, we used TPE with super-radical hysterectomy on the right side and LEER on the left. We performed this procedure laparoscopically because improved visualization allows for meticulous dissection and a higher possibility of achieving R0. Surgery time was 9 h 45 min including the time for creation of the ileal conduit and colostomy, and blood loss was 230 ml with no blood transfusion needed. Pathological R0 resection was achieved without any intraoperative and postoperative complications. Compared to super-radical hysterectomy, LEER ensured additional surgical margins. Without any adjuvant treatment, there has been no sign of recurrence during the 12 months that have passed since the surgery. Laparoscopic TPE with super-radical hysterectomy and LEER for laterally recurrent, previously irradiated cervical cancer is a technically feasible and safe surgical option. LEER can ensure more surgical margins than super-radical hysterectomy, and it may be a treatment of choice for more advanced lateral recurrence.

In recent years, attention has been drawn to wireless power transfer of an electric vehicle via magnetic resonance coupling as a transmission method. Although the wireless power transfer enables to reduce the risk of electric shock and the loss of time for connecting the power cable, there are problems that underlie in leakage of magnetic field generated along with the wireless power transfer, absorbed by surrounding objects. Therefore, in this paper, we investigated the number and allocation of the coils of the phased array coil which we believe to have the potential of suppressing the magnetic field absorption while maintaining the transmission efficiency. The optimization of the phased array coil arrangement and the phase and amplitude of the input voltage was done using the Particle Swarm Optimization (PSO). As a result, there were five variationsin the arrangement of the RX coil, and the most effectivemagnetic field suppression was achieved in the configurationwith two TX coils, and the magnetic field was suppressed by -83.4%, compared to the configuration of a general MRC-WPT.

Background Uterine adenosarcoma, a rare uterine tumor subtype, is a biphasic tumor consisting of epithelial and mesenchymal elements. To date, there is no research comparing the histopathological features and immunohistochemistry of primary and recurrent tumors; furthermore, the relationship between pathology and the clinical course remains unclear. We reviewed the pathology and immunohistochemical features of patients with adenosarcoma and investigated the relevance of the histomorphological features to the clinical course. We also compared the immunohistochemical features of the primary and recurrent tumors. Methods The data of seven patients with adenosarcoma who underwent surgery in our hospital were evaluated. We performed immunohistochemical staining for the progesterone receptor, estrogen receptor, p53, and two Switch/Sucrose Non-Fermentable chromatin remodeling proteins (SMARCA4, BCOR), which were recently developed for the undifferentiated sarcoma diagnosis in addition to conventional staining methods. Results All patients had International Federation of Gynecology and Obstetrics stage IB–IC diseases. All tumors were polypoid and every patient presented with abnormal uterine bleeding. Six patients aged over 50 years and were menopausal; one patient aged under 50 years and was non-menopausal (average age: 59.1 years). Histologically, the sarcomatous components were homologous and heterogenous in six and one patient, respectively. Four and three cases were recurrent and non-recurrent, respectively. The recurrent patients showed high-grade morphology with sarcomatous overgrowth and were negative for ER and PR. Three recurrences could be evaluated by imaging, showing recurrence only in a distant area; biopsy specimens from these tissues revealed the identical mesenchymal component found in the primary tumor without a benign epithelial component. Immunohistochemical staining results were also similar to the corresponding of the original tumor, except for the p53 expression in one patient. At the primary site, p53 was overexpressed in two recurrent patients and had a wild-type level in one recurrent patient; however, all three recurrent tissues showed p53 overexpression. None of our patients showed SMARCA4 loss, and BCOR expression was positive in one case. Conclusions Initial pathological adenosarcoma analysis with appropriate immunohistochemical staining is vital for prognostic assessment. p53 expression might increase at recurrence. SMARCA4 and BCOR might not be an index of malignancy.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Uterine tumors detected after pelvic radiation therapy are rare. We report a case in which an endometrial tumor developed after pelvic radiation therapy for cervical cancer. The patient was a 70-year-old female with a history of pelvic radiotherapy for locally advanced cervical cancer. After 12 months of radiation therapy, magnetic resonance imaging showed tumors in the uterine cavity, and positron emission tomography-computed tomography showed no tumors, except uterine tumors. Since radiation therapy-induced cervical stenosis was conducted, endometrial examination could not be performed without anesthesia. As these tumors were detected after radiation therapy for uterine cancer, malignancy was considered. A laparoscopic-assisted transcervical hysteroscopic resection was performed for the diagnosis and treatment of uterine tumors after radiation therapy. This operative method was useful and enabled us to perform complete resection, observe the abdominal cavity, prepare for the possibility of secondary hysterectomy, and improve safety.

This study was performed to investigate the effectiveness of dexamethasone in the management of postpartum women with class 1 haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. This retrospective study was conducted on 18 women with class 1 HELLP syndrome at the Shiga University of Medical Science. They were divided into two groups: Group A comprised participants who did not receive dexamethasone, and Group B comprised participants that intravenously received dexamethasone. The main outcomes were the serum laboratory values, mortality and morbidity. The only significant difference between the two groups in baseline characteristics was the aspartate aminotransferase levels. The linear regression analysis showed a significant difference between the two groups in the recovery of platelet counts (p = .046) and aspartate aminotransferase (p = .009). These findings support the use of high-dose dexamethasone to promote recovery of the platelet counts and aspartate aminotransferase levels in postpartum women with class 1 HELLP syndrome. Impact statement What is already known on this subject? Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is one of the most dangerous complications that can occur during pregnancy and is considered a particularly serious variant of severe preeclampsia. Several clinical trials have been performed since 1994 because it was expected that corticosteroid therapy, primarily with dexamethasone, accelerates recovery after delivery. However, the effect of dexamethasone therapy on class 1 HELLP syndrome is unclear. What do the results of this study add? In this retrospective study, we demonstrated that dexamethasone administration significantly improved the recovery of the platelet count in postpartum women with class 1 HELLP syndrome, and did not increase the rate of maternal postpartum complications. What are the implications of these findings for clinical practice and/or further research? The use of high-dose dexamethasone in postpartum women with class 1 HELLP syndrome might be effective to promote recovery of the platelet count, and contributes a shorter duration of hospitalisation. Because the number of patients with class 1 HELLP syndrome is small, it is important to confirm these findings with well-designed multicentre prospective studies.

We present two cases of biopsy‐proven hypertrophic cardiomyopathy (HCM). Both cases showed abnormal electrocardiographic (ECG) findings more than 8 years before diagnosis. A 16‐year‐old healthy male experienced a rescued cardiac arrest. Another male adolescent showed abnormal Q wave and thickened ventricular wall at 15 years old. Retrospective analyses of ECGs performed at 6 years old indicated abnormal ECG findings. However, the diagnosis was normal because no ventricular wall thickening was present in echocardiography. For early diagnosis of HCM to prevent sudden cardiac arrest or death, it is essential to establish ECG and echocardiographic criteria to screen HCM in the young.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Regeneration of the corneal epithelium and endothelium has been achieved, but regeneration of the corneal stroma has not, because it has several remarkable properties, including high tensile strength, thrust resistance, and high transparency. We introduce several biosynthetic approaches to creating stromal substitutes closely resembling the native human corneal stroma are currently being studied. Currently, there are five approaches to regenerate corneal stroma: (1) decellularization, (2) the use of human recombinant collagen (HRC), (3) optical clarification (and lamination), (4) cell-based regeneration, and (5) organoid generation with induced pluripotent stem (iPS) cells. Immediate next steps for this area of research include clinical trials of decellularized stromal scaffolds created from porcine corneas or RHC. While these methods have both advantages and disadvantages, their refinement and clinical use, as well as the use of other methods, promise to lead to the continuing development of new approaches.

Background: The use of coronary computed tomography angiography (CCTA) for noninvasive anatomic detection of coronary artery disease is increasing. Recently, fractional flow reserve (FFR) assessment using routinely acquired CCTA datasets (FFRCT) has been developed. However, there are no reports about changes in coronary atherosclerosis, composition, and FFRCT in patients with type 2 diabetes. Methods: This prospective, multicenter, observational trial evaluated changes in coronary atherosclerosis after alogliptin therapy in patients with type 2 diabetes. Fifty-one patients with type 2 diabetes who underwent CCTA examination and having intermediate coronary artery stenosis were treated with 25 mg of alogliptin. After 48 weeks, CCTA examination was repeated. The primary endpoint was changes in FFRCT, and the secondary endpoint was changes in total atheroma volume (TAV) from the baseline to the 48-week follow-up. Results: The FFRCT decreased from the baseline to follow-up, but not significantly. A significant increase in TAV (from 658.5 mm3 to 668.9 mm3, p = 0.048) was observed. Vessel volume tended to increase, whereas percentage atheroma volume and lumen volume did not change. A significant negative correlation was observed between percentage change in TAV and change in FFRCT (r = −0.185, p = 0.048). A significant increase in calcified plaques (p = 0.01) and a decrease in intermediate-attenuation plaques (p = 0.006) was observed. Conclusions: In Japanese patients with diabetes and intermediate coronary artery stenosis, alogliptin could not improve FFRCT or reduce atheroma volume, whereas the plaque composition changed. A progression of atheroma volume was associated with a reduction in FFRCT. Keywords: Alogliptin, Coronary atherosclerosis, Coronary computed tomography angiography (CCTA), Diabetes mellitus, Fractional flow reserve (FFR)

Maternal high-fat diet (HFD) consumption during pregnancy and lactation affects metabolic outcomes and lipid metabolism of offspring in later life in a gender-specific manner. However, it is not known whether maternal HFD alters bile acid metabolism in adult mice offspring. The purpose of this study was to elucidate the relationship between maternal HFD-induced metabolic diseases and bile acid metabolism in male and female adult mice offspring. Female mice were fed either standard chow (C) or HFD (H) for 10 weeks pre-pregnancy until lactation. After weaning, offspring were fed a chow diet until 11 weeks of age, then challenged with either C or H diet for 4 weeks, and divided into eight groups in accordance with mother’s and offspring’s diets: male(M) CC, MHC, MCH, MHH, female(F) CC, FHC, FCH, and FHH. MHH showed greater weight gain compared to FHH. Liver weight was higher in MHH than in FHH. Serum total cholesterol levels were higher in MHH than in MHC, and tended to be higher in MHH than in FHH. Serum glucose levels were higher in MHH than in MHC. Hepatic triglyceride levels were higher in MHH than in MHC. Hepatic mRNA expression of bile acid uptake transporters Oatp1a1 and Oatp1b2 was increased in MHH, compared to MCH. Hepatic mRNA expression of HMGCoAR, Cyp7a1, Sult2a1, and Oatp1a4 was increased in FHH, compared to FCH. In conclusion, maternal HFD consumption may promote bile acid synthesis, sulfation and excretion in female offspring fed a HFD, which may confer resistance to HFD-induced metabolic phenotypes.

Several species of harmful algal blooms (HAB) exert inimical effects on bivalve molluscs, with mass mortalities and pathologies reported worldwide. Information on the effects of HAB on the reproduction of bivalve molluscs, however, remains very limited. The Japanese pearl oyster Pinctada fucata martensii is an important economic species cultured in Japan. In previous studies, harmful dinoflagellates and raphidophytes were shown to affect embryos and larvae of Japanese pearl oyster. In the present study, quantitative deleterious effects of Alexandrium catenella, Alexandrium affine, Heterosigma akashiwo, and Chattonella marina on egg viability and spermatozoa swimming velocity are reported. All four HAB species significantly reduced the swimming velocity of spermatozoa. Egg viability was affected only after exposure to A. catenella and A. affine. An additional cytotoxicity test using Vero cells showed that bioactive exudates are associated with the deleterious effects and these effects are more prominent during the death phase of the algal culture. The results of the present study warrant further research on the effects of HAB species on gamete quality of bivalves, further characterization of bioactive compounds secreted by Alexadnrium spp., and highlight the role of physical activation of the toxic mechanism of harmful raphidophytes suggested in a previous study and confirmed in the present study.

Primordial follicles maintain dormancy in the ovary and only a small number of them are activated towards ovulation every day. Several signaling pathways in oocytes and the surrounding flattened pre-granulosa cells have been shown to play crucial roles in primordial follicle activations and sex steroid hormones are also known to affect it. Intrinsic estrogen, estradiol, has been reported to suppress primordial follicle formation and the later primordial follicle activation in rodent neonatal ovaries. Conversely, some phytoestrogens and endocrine disruptors which possess intrinsic estrogen-like biological activity with different binding affinities to estrogen receptors, can activate primordial follicles. Testosterone and dehydroepiandrosterone have been used in fertility treatments in the expectation that they would activate primordial follicle, although evidence of their efficacy is inconclusive. Progesterone suppresses primordial follicle formation and the later primordial follicle activation i...

Two of the Arabidopsis thaliana SEC23 homologs, AtSEC23A and AtSEC23D, are expressed in the tapetum and play essential roles in pollen wall formation, exine patterning, and tapetum development., The specialized multilayered pollen wall plays multiple roles to ensure normal microspore development. The major components of the pollen wall (e.g. sporopollenin and lipidic precursors) are provided from the tapetum. Material export from the endoplasmic reticulum (ER) is mediated by coat protein complex II (COPII) vesicles. The Arabidopsis thaliana genome encodes seven homologs of SEC23, a COPII component. However, the functional importance of this diversity remains elusive. Here, we analyzed knockout and knockdown lines for AtSEC23A and AtSEC23D, two of the A. thaliana SEC23 homologs, respectively. Single atsec23a and atsec23d mutant plants, despite normal fertility, showed an impaired exine pattern. Double atsec23ad mutant plants were semi-sterile and exhibited developmental defects in pollen and tapetal cells. Pollen grains of atsec23ad had defective exine and intine, and showed signs of cell degeneration. Moreover, the development of tapetal cells was altered, with structural abnormalities in organelles. AtSEC23A and AtSEC23D exhibited the characteristic localization pattern of COPII proteins and were highly expressed in the tapetum. Our work suggests that AtSEC23A and AtSEC23D may organize pollen wall development and exine patterning by regulating ER export of lipids and proteins necessary for pollen wall formation. Also, our results shed light on the functional heterogeneity of SEC23 homologs.

Objective The “dysconnection hypothesis” has been proposed as a core neural basis for schizophrenia. Although growing neuroimaging-based evidence suggests atypical functional connectivity in patients with schizophrenia, the results are inconsistent and the effects of antipsychotic treatment remain elusive. Methods We performed resting-state electroencephalography (EEG) in 21 drug-naive patients with schizophrenia (14 patients were re-evaluated after administration of antipsychotic treatment) and 31 age-matched healthy control subjects. We estimated functional connectivity, using the phase lag index (PLI), which captures the true synchronization of EEG signals. Results The patients had reduced functional connectivity of the beta band across frontal regions and of the gamma band throughout the scalp when compared to the control subjects. In the schizophrenia group, symptom severity did not seem associated with functional connectivity. Antipsychotic treatment led to no alterations in functional connectivity. Conclusions Synchronous activity within and across brain areas over multiple frequencies reflect the integration of various types of information processing. Our findings of abnormal frequency- and region-specific functional connectivity patterns may provide further insight into the “dysconnection hypothesis” of schizophrenia. Significance The PLI may serve as a useful measure for the characterization and understanding of the intrinsic pathophysiological mechanisms of schizophrenia, and as a reliable biomarker for this disease.

This study aimed to evaluate the protective effect of everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, on cisplatin chemotherapy-induced ovarian toxicity. Eighty sexually mature, virgin, female, 7-week-old C57BL/6J mice were divided into four groups: control, cisplatin (Cis), everolimus (mTORi), and everolimus plus cisplatin (mTORi+Cis). Mice in the Cis and mTORi+Cis groups were intraperitoneally injected with 2 mg/kg of cisplatin for 15 d. Mice in the mTORi and mTORi+Cis groups were orally administered 2.5 mg/kg of everolimus for 29 d, from one week before the first cisplatin injection to one week after the last cisplatin injection. Histological examinations were performed 24 h after the last everolimus administration. The primordial, primary, and antral follicles were significantly depleted in the Cis group compared with that in the control group, confirming the gonadotoxicity of cisplatin. The number of primordial, secondary, and antral follicles was significantly higher in the mTORi+Cis group than in the Cis group, thereby displaying the effect of mTORi-treatment on ovarian protection. Primordial, secondary, and antral follicle counts were similar in the mTORi+Cis and the control groups. The results of this study indicate a protective effect of an mTOR inhibitor against cisplatin chemotherapy-induced gonadotoxicity in the ovarian reserve in an in vivo mouse model.

Ezetimibe and pemafibrate are lipid-lowering drugs and promote reverse cholesterol transport. However, it is unknown whether cholesterol is mainly excreted by hepatobiliary excretion or by non-biliary transintestinal cholesterol efflux (TICE). We evaluated the effects of ezetimibe and pemafibrate on hepatic and intestinal cholesterol transporter regulation in Sham-operated rats, and examined the effects of these drugs on TICE in bile duct-ligated rats. Seven-week-old male Sprague-Dawley rats were treated as follows for two weeks: 1) Sham, Sham operation; 2) BDL, bile duct ligation; 3) E-Sham, Sham + ezetimibe; 4) E-BDL, BDL + ezetimibe; 5) P-Sham, Sham + pemafibrate; and 6) P-BDL, BDL + pemafibrate. Blood, liver, jejunum, and feces were collected 72 h post-surgery. Hepatic cholesterol levels were decreased in P-Sham and E-Sham, and were lower in E-BDL and P-BDL than in BDL. Fecal cholesterol levels increased in E-Sham and P-Sham compared with Sham, and were higher in E-BDL and P-BDL than in BDL. In liver, Abcg5 mRNA showed induction in E-Sham, Abcg5 and Abca1 mRNA were induced in P-Sham, Abcg5 mRNA was reduced in E-BDL, and Abca1 mRNA was increased in P-BDL. In jejunum, Abcg5 mRNA was induced in E-Sham. Abcg8 mRNA was induced in E-Sham and P-Sham. NPC1L1 mRNA showed reduced expression in P-Sham and P-BDL. SR-B1 mRNA was reduced in P-Sham, and the expression decreased in P-BDL. LDL receptor mRNA was induced in BDL and P-BDL. Ezetimibe and pemafibrate may promote TICE by increasing Abcg5/g8, while pemafibrate may inhibit intestinal cholesterol absorption by decreasing SR-B1 and NPC1L1.

Activated eosinophils can infiltrate various tissues and cause inflammatory tissue damage. Asthma is a typical type of eosinophilic inflammatory disease that occurs in the respiratory system. Eosinophilic sialodochitis and sialoadenitis of the salivary gland are rare diseases clinically characterized by painful swelling. In this report, we present a 68-year-old woman with asthma who presented to our hospital with mandibular swelling. Her asthma had been well controlled with an inhaled combination of a corticosteroid and a long-acting β2 agonist, although she reported a past history of frequent asthma attacks and hospitalization. Laboratory investigation on admission revealed blood eosinophilia (2,673/μL), high levels of total immunoglobulin E (390 U/mL) and immunoglobulin G4 (183 mg/dL). Bone marrow examination showed no evidence of eosinophilic neoplasia. Histological examination of her minor salivary glands disclosed an infiltration of mixed lymphocytes and eosinophils. Chromatolytic eosinophils with Charcot-Leyden crystals were also observed within the edematous dermis and fibrous tissues surrounding the minor salivary gland. The patient was diagnosed with eosinophilic sialoadenitis. Treatment with oral corticosteroids (0.5 mg/kg/day) was initiated. Thereafter, the mandibular swelling improved. This report describes a rare case of eosinophilic sialoadenitis in a patient with severe eosinophilic asthma, for which histopathological and immunefluorescence microscopic analyses were performed.

For endometrial cancer patients, lymphadenectomy is recommended to exclude rarely metastasized cancer cells. This procedure is performed even in patients with low risk of recurrence despite the risk of complications such as lymphedema. A method to accurately identify cases with no lymph node metastases (LN−) before lymphadenectomy is therefore highly required. We approached this clinical problem by examining primary lesions of endometrial cancers with CAGE (Cap Analysis Gene Expression), which quantifies promoter-level expression across the genome. Fourteen profiles delineated distinct transcriptional networks between LN + and LN− cases, within those classified as having the low or intermediate risk of recurrence. Subsequent quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses of 115 primary tumors showed SEMA3D mRNA and TACC2 isoforms expressed through a novel promoter as promising biomarkers with high accuracy (area under the receiver operating characteristic curve, 0.929) when used in combination. Our high-resolution transcriptome provided evidence of distinct molecular profiles underlying LN + /LN− status in endometrial cancers, raising the possibility of preoperative diagnosis to reduce unnecessary operations in patients with minimum recurrence risk.