Search

Background: Primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS) may reduce the risk of subsequent cardiovascular events but remains challenging. The study aim was to evaluate the clinical characteristics and long-term outcomes of patients undergoing primary PCI for STEMI with CS., Methods: We conducted an observational cohort study of patients with STEMI who underwent primary PCI between April 2004 and December 2017 at Juntendo University Shizuoka Hospital. The primary outcome was cardiovascular death (CVD) during the median 3-year follow-up. We performed a landmark analysis for the incidence of CVD from 0 day to 1 year and from 1 to 10 years., Results: Among the 1758 STEMI patients in the cohort, 212 (12.1 %) patients with CS showed significantly higher 30-day CVD rate on admission than those without (26.4 % vs 2.9 %). Landmark Kaplan-Meier analysis showed that CVD from day 0 to year 1 was significantly higher in the patients with CS (log-rank p < 0.0001). Multivariate Cox regression analysis showed that CS was significantly associated with higher cardiovascular mortality (adjusted hazard ratio, 11.8; 95%confidence intervals, 7.78-18.1; p < 0.0001), but the mortality rates from 1 to 10 years were comparable (log-rank p = 0.68)., Conclusion: The cardiovascular 1-year mortality rate for patients with STEMI was higher for those with CS on admission than without, but the mortality rates of >1 year were comparable. Surviving the early phase is essential for patients with STEMI and CS to improve long-term outcomes., Competing Interests: Disclosures None. Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study investigates computational models of electric field strength for transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) based on individual MRI data of patients with schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BP), and healthy controls (HC). In addition, it explores the association of electric field intensities with age, gender and intracranial volume. The subjects were 23 SZ (12 male, mean age = 45.30), 24 MDD (16 male, mean age = 43.57), 23 BP (16 male, mean age = 39.29), 23 HC (13 male, mean age = 40.91). Based on individual MRI sequences, electric fields were computationally modeled by two independent investigators using SimNIBS ver. 2.1.1. There was no significant difference in electric field strength between the groups (HC vs SZ, HC vs MDD, HC vs BP, SZ vs MDD, SZ vs BP, MDD vs BP). Female subjects showed higher electric field intensities in widespread areas than males, and age was positively significantly associated with electric field strength in the left parahippocampal area as observed. Our results suggest differences in electric field strength of left DLPFC TMS for gender and age. It may open future avenues for individually modeling TMS based on structural MRI data., Competing Interests: Declaration of competing interest FP is a member of the European Scientific Advisory Board of Brainsway Inc., Jerusalem, Israel, and the International Scientific Advisory Board of Sooma, Helsinki, Finland. He has received speaker's honoraria from Mag&More GmbH and the neuroCare Group. His lab has received support with equipment from neuroConn GmbH, Ilmenau, Germany, and Mag&More GmbH and Brainsway Inc., Jerusalem, Israel. YM receives remuneration from NeuroCare as an office worker. ST received speaker's honoraria from Teijin Pharma Ltd., Tokyo, Japan. The other authors declare no conflict of interest in relation to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Although the functions of progesterone in the myometrium are well-established, the nongenomic effects of progesterone in pregnant myometrial contractions are still unclear. Therefore, this study aimed to investigate changes in the nongenomic effects of progesterone during pregnancy., Main Methods: Myometrial strips were obtained from non-pregnant, pregnant, and postpartum rats, and the nongenomic effects of progesterone in the myometrium during pregnancy were examined. Additionally, the influence of actinomycin D and cycloheximide and the effects of Org OD-02-0 (a specific membrane progesterone receptor (mPR) agonist) in the myometrium were investigated. Moreover, DNA microarray and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to identify genes involved in progesterone-induced effects in the myometrium., Key Findings: Progesterone did not cause rhythmic contractions in non-pregnant myometrium but induced rhythmic contractions in pregnant myometrium, with the effects peaking at 20 d + 8 h of pregnancy. However, myometrial contractions decreased after delivery and were restored to non-pregnant levels at 7 d postpartum. Additionally, progesterone stably inhibited high KCl-induced myometrial contractions during pregnancy. Moreover, the nongenomic effects of progesterone were unaffected by actinomycin D or cycloheximide, and Org OD-02-0 effectively mimicked these effects. DNA microarray analysis and qRT-PCR revealed a significant increase in mPRβ gene expression during pregnancy. However, mPRα, mPRγ, mPRδ, and mPRε expression levels remained unchanged., Significance: The stimulatory nongenomic effect of progesterone, which was inducible and mPRβ-dependent during pregnancy, may be involved in parturition. The inhibitory effect, which was constitutive and depended on other mPRs, may be involved in pregnancy maintenance., Competing Interests: Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. The study design was approved by the appropriate ethics review board. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline., Methods: A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays., Results: Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1β. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation., Conclusions: These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation., Competing Interests: Declaration of competing interest 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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There is a lack of predictive biomarkers for the onset or activity of protein-losing enteropathy (PLE), a Fontan procedure-associated complication. Here, we aimed to identify the gut microbiota composition of patients with active PLE and investigate its relationship with PLE activity., Methods: This multicenter case-control study involved patients who developed PLE (n = 16) after the Fontan procedure and those who did not (non-PLE; n = 20). Patients with PLE who maintained a serum albumin level of ≥3 g/dL for >1 year were included in the remissive-stage-PLE group (n = 9) and those who did not maintain this level were included in the active-PLE group (n = 7). 16S rRNA gene sequencing analysis of fecal samples was performed using QIIME2 pipeline. Alpha (Shannon and Faith's phylogenetic diversity indices) and beta diversity was assessed using principal coordinate analysis based on unweighted UniFrac distances., Results: Shannon and Faith's phylogenetic diversity indices were lower in the active-PLE group than in the remissive-stage- (q = 0.028 and 0.025, respectively) and non-PLE (q = 0.028 and 0.017, respectively) groups. Analysis of beta diversity revealed a difference in the microbiota composition between the active-PLE and the other two groups. Linear discriminant effect size analysis demonstrated differences in the relative abundance of Bifidobacterium and Granulicatella spp., and Ruminococcus torques between patients with active- and those with remissive-stage-PLE., Conclusions: Gut microbiota dysbiosis was observed in patients with active PLE. Changes in the bacterial composition of the gut microbiota and decreased diversity may be associated with the severity of PLE., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The dynamics of large-scale networks, which are known as distributed sets of functionally synchronized brain regions and include the visual network (VIN), somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network (FPN), and default mode network (DMN), play important roles in emotional and cognitive processes in humans. Although disruptions in these large-scale networks are considered critical for the pathophysiological mechanisms of psychiatric disorders, their role in psychiatric disorders remains unknown. We aimed to elucidate the aberrant dynamics across large-scale networks in patients with schizophrenia (SZ) and mood disorders., Methods: We performed energy-landscape analysis to investigate the aberrant brain dynamics of seven large-scale networks across 50 healthy controls (HCs), 36 patients with SZ, and 42 patients with major depressive disorder (MDD) recruited at Wakayama Medical University. We identified major patterns of brain activity using energy-landscape analysis and estimated their duration, occurrence, and ease of transition., Results: We identified four major brain activity patterns that were characterized by the activation patterns of the DMN and VIN (state 1, DMN (-) VIN (-); state 2, DMN (+) VIN (+); state 3, DMN (-) VIN (+); and state 4, DMN (+) VIN (-)). The duration of state 1 and the occurrence of states 1 and 2 were shorter in the SZ group than in HCs and the MDD group, and the duration of state 3 was longer in the SZ group. The ease of transition between states 3 and 4 was larger in the SZ group than in the HCs and the MDD group. The ease of transition from state 3 to state 4 was negatively associated with verbal fluency in patients with SZ. The current study showed that the brain dynamics was more disrupted in SZ than in MDD., Conclusions: Energy-landscape analysis revealed aberrant brain dynamics across large-scale networks between SZ and MDD and their associations with cognitive abilities in SZ, which cannot be captured by conventional functional connectivity analyses. These results provide new insights into the pathophysiological mechanisms underlying SZ and mood disorders., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to identify factors deterring secondary household transmission of SARS-CoV-2 from SARS-CoV-2-positive cohabitants., Methods: A case-control study was conducted with 272 healthcare workers in close contact with SARS-CoV-2-positive cohabitants. Logistic regression modeling was employed to determine the factors independently associated with secondary household transmission., Results: A SARS-CoV-2 infection within the past 6 months was the most protective factor against secondary household transmission (adjusted odds ratio = 0.07, 95% CI: 0.01-0.61, P <0.05). Home isolation and older age of primary index case (7-12, ≥18 years) were also associated with a reduced risk. Both monovalent and bivalent messenger ribonucleic acid booster vaccinations exhibited potential protective tendencies but were not statistically significant. Additionally, bivalent vaccines did not demonstrate a clear advantage over monovalent vaccines., Conclusion: A recent history of SARS-CoV-2 infection, home isolation of positive cohabitants, and older age of primary index cases were positively associated with a reduced risk of secondary household transmission. Regarding booster vaccinations, data from a single center with a limited sample size may not capture all statistically significant differences, necessitating broader studies., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Recent clinical trials have shown that percutaneous coronary intervention (PCI) for non-culprit lesions (NCLs) reduces the risk of adverse events in patients with ST-segment elevation myocardial infarction (STEMI), but the effect on long-term outcomes remains unclear in acute coronary syndrome (ACS) patients and a real-world clinical setting., Methods: A retrospective observational cohort study of ACS patients who underwent primary PCI between April 2004 and December 2017 at Juntendo University Shizuoka Hospital, Japan, was performed. The primary endpoint was the composite of cardiovascular disease death (CVD death) and non-fatal myocardial infarction (MI) during the mean follow-up period of 2.7 years, and a landmark analysis for the incidence of the primary endpoint from 31 days to 5 years between the multivessel PCI group and the culprit only PCI group was performed. Multivessel PCI was defined as PCI including non-infarct-related coronary arteries within 30 days after the onset of ACS., Results: Of the 1109 ACS patients with multivessel coronary artery disease of the current cohort, multivessel PCI was performed in 364 (33.2 %) patients. The incidence of the primary endpoint from 31 days to 5 years was significantly lower in the multivessel PCI group (4.0 % vs. 9.6 %, log-rank p = 0.0008). Multivariate Cox regression analysis showed that multivessel PCI was significantly associated with fewer cardiovascular events (HR 0.37, 95 % CI 0.19-0.67, p = 0.0008)., Conclusion: In ACS patients with multivessel coronary artery disease, multivessel PCI may reduce the risk of CVD death and non-fatal MI compared to culprit-lesion-only PCI., Competing Interests: Declaration of competing interest 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients., Methods: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients)., Results: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online., Conclusions: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country., Impact and Implications: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Intravascular imaging (IVI), including intravascular ultrasound (IVUS) and optical coherence tomography (OCT), is clinically useful for assessing the luminal size, lesion length, and plaque characteristics, as well as for evaluating stent deployment; however, it is not designed to estimate myocardial ischemia accurately. Thus, several types of IVI-derived fractional flow reserve (FFR) (IVI-derived FFR) have been developed and reported. In general, the algorithms of virtual FFR are based on basic fluid dynamics equations (mainly Poiseuille and Borda-Carnot equations) and original microvascular models (fixed velocity or calculating coronary flow reserve). Although the models and assumptions used in the past reports were mostly based on the standard population (not independent patient data), the developed software calculated FFR with high accuracy (88% to 94%) with strong correlations between IVI-derived FFR and wire-based FFR (0.69 to 0.89). Given several other less invasive virtual FFR methods currently available for clinical use, IVI-derived FFR would be limited for the sole use of pre-percutaneous coronary intervention (PCI) physiological evaluation; however, it may play a unique role at PCI guidance and optimization, potentially allowing comprehensive and time/cost-saving assessment of both anatomical and physiological lesion properties using a single diagnostic device., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Interleukin-33 (IL-33) is involved in type 2 innate immunity by inducing type 2 cytokines, such as IL-5 and IL-13, through the activation of group 2 innate lymphoid cells (ILC2s) or T helper 2 (Th2) cells. We previously reported that mice overexpressing IL-33 (IL-33Tg) in the cornea and conjunctiva spontaneously develop atopic keratoconjunctivitis-like inflammation. Despite previous studies, it is not fully understood what types of immune cells contribute to the disease process of IL-33-induced keratoconjunctivitis., Methods: To defect Th2 cells, IL-33Tg mice were crossed with Rag2KO mice. To defect ILC2s, IL-33Tg mice received bone marrow transplantations from B6.C3(Cg)-Rorasg/J mice that lacked ILC2. Immunostaining techniques were used to determine where ILC2 is distributed in the cornea and conjunctiva. We analyzed the transcriptomes of ILC2 from the conjunctiva by using single-cell RNA-seq analysis. To investigate whether tacrolimus reduces type 2 cytokine production by ILC2, ILC2 was cultured with tacrolimus, and the percentage of cytokine-producing ILC2 was examined. To investigate whether tacrolimus can inhibit IL-33-induced keratoconjunctivitis in vivo, IL-33Tg mice were treated with tacrolimus eye drops., Results: ILC2 infiltrated the conjunctival epithelium and subepithelial tissue. Keratoconjunctivitis developed spontaneously in Rag2KO/IL-33Tg mice, but keratoconjunctivitis was abolished in IL-33Tg mice lacking ILC2. ILC2 was not a uniform cluster but a heterogeneous cluster. Tacrolimus inhibited cytokine production from ILC2s in vitro, and tacrolimus eye drops inhibited keratoconjunctivitis in IL-33Tg mice in vivo., Conclusions: ILC2 plays a pivotal role in IL-33-induced keratoconjunctivitis in mice., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

For many producers, introduction of improved animal welfare systems is a turning point in their future production strategies as it increases production costs. The increase in egg retail prices is of growing concern not only for producers, but also for retailers and consumers. However, no report has calculated the estimated production costs or retail prices associated with introducing practices that support improved animal welfare in poultry farms in Japan. Therefore, this study aimed to estimate the production costs and table egg prices of 6 types of laying hen systems: conventional cage (CC): 8- and 12-tiers (CC8, CC12), enriched cage (EC): 8- and 12-tiers (EC8, EC12), aviary (AV), and barn systems (BR). Production costs include land purchases, construction costs of facilities, equipment and machinery, quantity of feed provided, farming materials invested, and wages. As a result, farm gate prices were estimated as CC8 = 12.19, CC12 = 12.19, EC8 = 14.52, EC12 = 14.52, AV = 21.14, and BR = 28.74 [yen/egg], and the production cost, including building the new farm, increased by EC8 = 19.1%, EC12 = 19.1%, AV = 73.4%, and BR = 135.7%, respectively, referring to the value of CC. The results show that the prices increase in systems between CC and BN. The retail price or table egg price was estimated to be CC8 = 24.68, CC12 = 24.68, EC8 = 28.07, EC12 = 28.07, AV = 37.27, and BR = 48.53 [yen/egg]. The retail price of BR is approximately twice that of CC. In addition, assuming that all of Japan's eggs were produced in the BR system, the soaring cost of eggs would likely affect the prices of factory eggs, such as liquid eggs and other products, thus affecting the prices of various food products. Understanding the significant management costs that affect the retail price of eggs would facilitate improved policies and practical approaches to support poultry farms and sustainable farming activities while addressing public concerns., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

This cross-diagnostic study aims to computationally model electric field (efield) for prefrontal transcranial direct current stimulation in mood disorders and schizophrenia. Enrolled were patients with major depressive disorder (n = 23), bipolar disorder (n = 24), schizophrenia (n = 23), and healthy controls (n = 23). The efield was simulated using SimNIBS software (ver.2.1.1). Electrodes were placed at the left and right prefrontal areas and the current intensity was set to 2 mA intensity. Schizophrenia and major depressive disorder groups showed significantly lower 99.5th percentile efield strength than healthy controls. In voxel-wise analysis, patients with schizophrenia showed a significant reduction of simulated efield strength in the bilateral frontal lobe, cerebellum and brain stem compared with healthy controls. Among the patients with schizophrenia, reduction of simulated efield strength was not significantly correlated with psychiatric symptoms or global functioning. The patients with bipolar disorder showed no significant difference in simulated efield strength compared with healthy controls, and there was no significant difference between the clinical groups. Our results suggest attenuated electrophysiological response to transcranial direct current stimulation to the prefrontal cortex in patients with schizophrenia, and to some extent in patients with major depressive disorder., Competing Interests: Declaration of Competing Interest Author Padberg is a member of the European Scientific Advisory Board of Brainsway Inc., Jerusalem, Israel, and the International Scientific Advisory Board of Sooma, Helsinki, Finland. He has received speaker's honoraria from Mag&More GmbH, the neuroCare Group, Munich, Germany, and Brainsway Inc. His-lab has received support with equipment from neuroConn GmbH, Ilmenau, Germany, Mag&More GmbH and Brainsway Inc. Author Mizutani-Tiebel receives remuneration from neruoCare as an office worker. The other authors declare no conflict of interest in relation to this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In the field of drug development, technology for producing human metabolites at a low cost is required. In this study, we explored the possibility of using prokaryotic water-soluble cytochrome P450 (CYP) to produce human metabolites. Streptomyces griseolus CYP105A1 metabolizes various non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, meclofenamic acid, and ibuprofen. CYP105A1 showed 4'-hydroxylation activity towards diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, and meclofenamic acid. It should be noted that this reaction specificity was similar to that of human CYP2C9. In the case of mefenamic acid, another metabolite, 3'-hydroxymethyl mefenamic acid, was detected as a major metabolite. Substitution of Arg at position 73 with Ala in CYP105A1 dramatically reduced the hydroxylation activity toward diclofenac, flufenamic acid, and ibuprofen, indicating that Arg73 is essential for the hydroxylation of these substrates. In contrast, substitution of Arg84 with Ala remarkably increased the hydroxylation activity towards diclofenac, mefenamic acid, and flufenamic acid. Recombinant Rhodococcus erythrocyte cells expressing the CYP105A1 variant R84A/M239A showed complete conversion of diclofenac into 4'-hydroxydiclofenac. These results suggest the usefulness of recombinant R. erythropolis cells expressing actinomycete CYP, such as CYP105A1, for the production of human drug metabolites., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease characterized by high IgE levels; however, the physiological significance of elevated IgE levels in patients with IgG4-RD is unclear. Previously, we reported the formation of IgG4-IgE complex in IgG4-RD patients with elevated IgE levels. In this study, we examined the frequency of this complex formation and its relationship with the clinical features in IgG4-RD patients., Methods: The IgG4-IgE complex was evaluated in 33 and 17 patients with and without IgG4-RD, respectively. The IgG4-IgE complex was evaluated by performing the immunoadsorption of IgG4 using anti-IgG4 antibody-conjugated matrices., Results: The frequency of IgG4-IgE complex formation in patients with IgG4-RD was significantly higher than that in those without IgG4-RD (21.2% vs. 0%). No significant differences were observed between the groups in terms of clinical characteristics and laboratory data. However, the IgG4-IgE complex-positive group had a significantly higher frequency of pancreatic lesions (85.7% vs. 42.3%) and a significantly lower rate of retroperitoneal fiber/periarterial lesions (0% vs. 38.5%) than the IgG4-IgE complex-negative group., Conclusion: The IgG4-IgE complex was found only in patients with IgG4-RD which may provide some clues to the pathogenesis and etiology of IgG4-RD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

N-methyl-D-aspartate receptor (NMDAR) dysfunction is an attractive hypothesis regarding the etiology of schizophrenia. We present the unprecedented case of a woman diagnosed with schizophrenia without anti-NMDAR antibodies after history of NMDAR encephalitis. A first episode of psychosis was antibody-positive and was improved with steroid and immunoglobulin treatment. Second and third episodes were antibody-negative, each about three months postpartum (different pregnancies) and were improved with antipsychotics. Without NMDAR encephalitis-related findings, we diagnosed schizophrenia. After anti-NMDAR encephalitis, NMDAR dysfunction may decrease the threshold for the onset of psychosis. This case provides insight into NMDAR dysfunction on etiology of schizophrenia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Post-pulmonary embolism (PE) syndrome is an important clinical condition that can affect the long-term prognosis after acute PE., Objective: We aimed to evaluate the prevalence of residual pulmonary thrombi and the thrombotic burden 1 year after acute PE, by using our refined computed tomography (CT) imaging method., Patients/methods: In this prospective study, patients diagnosed with acute PE were recruited and examinations were conducted at 1 month, 6 months, and 1 year. Especially at 1 year, patients were evaluated multifacetedly, including by laboratory tests, quality-of-life, 6-min walking test, and enhanced CT., Results: Fifty-two patients were enrolled. Two patients (3.8%) developed chronic thromboembolic pulmonary hypertension. A total of 43 patients completed evaluation at 1 year, among whom (74%) had residual thrombi, with a median modified CT obstruction index (mCTOI) of 10.7%. In multivariate analysis, residual thrombi at 1 month was the only factor significantly related to residual thrombi at 1 year (odds ratio, 103.4; 95% confidence interval, 4.2-2542.1). The tricuspid regurgitation pressure gradient ≥60 mmHg and left ventricular end-diastolic dimension at diagnosis were significantly related to mCTOI at 1 year (β = 0.367, P = .003; and β = -0.435, P = .001, respectively)., Conclusions: Using our improved CT imaging protocol, we found a high prevalence of residual thrombi 1 year after acute PE. Furthermore, right ventricular overload was related to the thrombotic burden. The long-term treatment strategy of acute PE could be modified to include precise CT imaging., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: IgE concentrations are occasionally elevated in patients with IgG4-related disease (IgG4-RD). In this report, we describe a novel case of IgG4-RD in which IgE concentrations were discordant between measuring reagents., Case: An 81-year-old man was diagnosed with IgG4-RD and histological autoimmune pancreatitis, which ensued without treatment. The IgE concentrations measured using Elecsys IgE II Immunoassay and Iatroace IgE were 1287.0 IU/mL and 60.9 IU/mL, respectively. IgG4 concentration was 675 mg/dL., Methods: To identify IgG and IgG4 directly bound to IgE, purification using protein G and anti-IgG4 antibody-conjugated matrixes and size-exclusion high-performance liquid chromatography (HPLC) were performed., Results: In purification analysis, the IgE concentration of the flow-through and bound fractions were 6.8 IU/mL (10.8%) and 56.2 IU/mL (89.2%) for IgG purification and 6.8 IU/mL (12.2%) and 49.0 IU/mL (87.8%) for IgG4 purification. IgE was eluted as a single peak (640 kDa) using size-exclusion HPLC. In the elution pattern of IgG4, a minor peak (640 kDa) and a major peak (170 kDa) were observed. These results indicate that IgG4 binds to IgE and forms a complex, resulting in a discrepancy between reagents., Conclusions: In this report, we present an IgG4-IgE complex in a patient with IgG4-RD, which affected the discrepancy in IgE concentrations between IgE reagents. This report points to the significance of increased IgE production in IgG4-RD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Research Question: What is the proportion of infants born as a result of assisted reproductive technology ART across different types of neonatal critical congenital heart disease (CCHD) in a Japanese population?, Design: A retrospective analysis of 418 consecutive infants with CCHD that required catheter treatment or surgery within the first 28 days of life or ductal-dependent lesions, in two paediatric centres in Japan, between January 2014 and December 2019. The proportion of ART in infants with each type of CCHD was evaluated. The proportion of ART in infants with univentricular heart defect (UVH) compared with those with biventricular heart defect (BVH) was evaluated., Results: The study group included 229 boys and 189 girls, with a gestational age of 38 ± 2 weeks. Overall, 61 infants (14.6%) were conceived by fertility treatment with 46 (11.0%) conceived by ART. Univentricular heart defect and BVH were identified in 111 infants (26.6%) and 307 infants (73.4%), respectively. The proportion of infants conceived by ART was significantly higher in UVH (16.2%) than in BVH (9.1%) (OR 2.28, 95% CI 1.11 to 4.68, P = 0.025), regardless of maternal age and maternal history of miscarriage., Conclusions: The proportion of ART in infants with CCHD, especially UVH, was high. These findings could form the basis of a rationale for carrying out fetal echocardiography in fetuses conceived by ART., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Recently, in addition to carboxylesterases (CESs), we found that arylacetamide deacetylase (AADAC) plays an important role in the metabolism of some clinical drugs. In this study, we screened for food-related natural compounds that could specifically inhibit human AADAC, CES1, or CES2. AADAC, CES1, and CES2 activities in human liver microsomes were measured using phenacetin, fenofibrate, and procaine as specific substrates, respectively. In total, 43 natural compounds were screened for their inhibitory effects on each of these enzymes. Curcumin and quercetin showed strong inhibitory effects against all three enzymes, whereas epicatechin, epicatechin gallate (ECg), and epigallocatechin gallate (EGCg) specifically inhibited AADAC. In particular, ECg and EGCg showed strong inhibitory effects on AADAC (IC 50 values: 3.0 ± 0.5 and 2.2 ± 0.2 μM, respectively). ECg and EGCg also strongly inhibited AADAC-mediated rifampicin hydrolase activity in human liver microsomes with IC 50 values of 2.2 ± 1.4 and 1.7 ± 0.4 μM, respectively, whereas it weakly inhibited p-nitrophenyl acetate hydrolase activity, which is catalyzed by AADAC, CES1, and CES2. Our results indicate that ECg and EGCg are potent inhibitors of AADAC., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Cancer cell count in the blood of cancer patients is extremely low. If these cells are easily detectable, cancer diagnosis may be possible by simply using a blood test, thus reducing patient burden. This study aimed to develop a cancer detection device by combining a microfilter that can be dynamically deformed and a nucleic acid aptamer that has a specific binding ability to cancer cells for easy detection. The cancer detection device was fabricated by photolithography, electroforming, and three-dimensional printing. The cancer cell detection ability of the fabricated device was evaluated using 1 mL of blood samples spiked with different concentrations of cancer cells. The lowest concentration of cancer cells in the blood was 5 cancer cells/1 mL blood. The fabricated microfilters specifically detected cancer cells in the blood successfully at exceedingly low concentrations. Moreover, the cancer detection experiment results using human whole blood revealed that cancer detection could be performed with higher accuracy using the fabricated cancer detection device compared to pre-existing cancer detection equipment (e.g., CellSearch system, Veridex). These findings provide important insights into the use of cancer cells in the blood as a diagnostic approach for cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

When animals are infected with helminthic parasites, resistant hosts mount type II helper T (Th2) immune responses to expel worms. Recent studies have clearly shown that epithelial cell-derived cytokines contribute to the induction of Th2 immune responses. Here we demonstrate the role of endogenous thymic stromal lymphopoietin (TSLP) for protection against Strongyloides venezuelensis (S. venezuelensis) infection, utilizing TSLP receptor-deficient Crlf2 -/- mice. The number of eggs per gram of feces (EPG) and worm burden were significantly higher in Crlf2 -/- mice than in wild type (WT) mice. S. venezuelensis infection induced Tslp mRNA expression in the skin, lung, and intestine and also facilitated the accumulation of mast cells in the intestine in a TSLP-dependent manner. Furthermore, CD4 + T cells from S. venezuelensis-infected Crlf2 -/- mice showed diminished capacity to produce Th2 cytokines in the early stage of infection. Finally, CD4 + cell-depleted Crlf2 -/- mice still showed higher EPG counts and worm burden than CD4 + cell-depleted WT mice, indicating that TSLP contributes to protecting mice against S. venezuelensis infection in both CD4 + T cell-dependent and -independent manners., Competing Interests: Declaration of competing interest The authors declare no financial or commercial conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Myocarditis is an inflammatory disease of the myocardium, which leads to cardiac dysfunction and heart failure. Previous studies have suggested that complex cross-talk between innate and adaptive immune responses is involved in the pathogenesis of acute myocarditis. Immunohistochemistry is the current standard method for the evaluation of infiltrating immune cells, however, it is difficult to investigate and quantify many immune cell populations using this technique., Methods: Endomyocardial biopsy samples of five pediatric patients with myocarditis were analyzed by cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT), a computational method for quantifying cell fractions from tissue gene expression profiles. CIBERSORT results were then compared with immunohistochemistry analyses., Results: Significant results of immune infiltrate deconvolution were obtained in four patients with fulminant myocarditis by CIBERSORT analysis. Among 22 immune cell types, 19 cell types were detected in one or more patients. Activated NK cells were the most prevalent population in two patients, whereas activated memory CD4 + T cells and M2 macrophages were the most prevalent population in one patient each. Overall CIBERSORT results were consistent with those of immunohistochemistry, although some discrepancies were observed., Conclusions: Infiltrating immune cell subsets detected by CIBERSORT analysis can reflect the time course of innate and adaptive immune responses in acute myocarditis. CIBERSORT may have the potential to characterize the detail of infiltrating immune cells in myocardial tissues and provide novel insights into the pathogenesis of acute myocarditis., (Copyright © 2020. Published by Elsevier Ltd.)

Background: T-wave inversion (TWI) is not considered useful for diagnosing pediatric arrhythmogenic right ventricular cardiomyopathy (ARVC), because right precordial TWI in ARVC resembles a normal juvenile pattern., Objectives: The aims of this study were to clarify the electrocardiographic (ECG) characteristics of pediatric ARVC to distinguish those patients from healthy children., Methods: Between 1979 and 2017, 11 ARVC patients under 18 years old were registered and compared with school screening ECGs from 48,401 healthy children., Results: The mean age at the first arrhythmic event or diagnosis was 13.3 ± 4.7 years. Nine patients were asymptomatic initially and were found by ECG screening, but 6 developed severe symptoms during the follow-up. Healthy children had a normal juvenile pattern, while ARVC children, especially symptomatic patients, had a significant tendency to have inferior and anterior TWI. The phenomenon of T-wave discontinuity (TWD) in which the TWI became deeper from V1 to V3 and suddenly turned positive in V5 was significantly more frequent in ARVC (60%) than healthy children (0.55%). Anterior TWI and TWD were also significantly more frequent in those who developed severe symptoms. The sensitivity and specificity of TWD were 60% (95% CI, 31-83%), and 99% (95% CI, 99-99%) to distinguish ARVC from healthy children, as well as 100% (95% CI, 71-100%) and 80% (95% CI, 51-80%), respectively, to predict severe symptoms in the future., Conclusions: The ECG is useful to distinguish ARVC children, even in the early phase. Anterior TWI and TWD could detect ARVC children and to predict the possible serious conditions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of this description is to report an "acute oblique osteotomy and ligation" (AOOL) procedure to shorten the fibula in high tibial osteotomy (HTO). A 4-cm longitudinal skin incision is made at the lateral aspect of the leg. After the central portion of the fibula is circumferentially isolated from all the periosteal tissues, a simple osteotomy is performed at the mid-portion of the fibular diaphysis in the quasi-frontal plane, which is inclined by 25 to 30° to the long axis of the fibula. Two thin holes are created beside the osteotomy line on the lateral surface of the fibula. A polyester thread is passed through the 2 holes. After the HTO is completed, the surgeon easily reduces the displaced fibular ends using this thread. This thread is securely tied to keep the contact between the 2 osteotomized surfaces. The AOOL procedure is technically easy and safely performed. We believe that the AOOL procedure is clinically useful to shorten the fibular shaft in HTO., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

A recent report demonstrated that sesamin strongly and non-competitively inhibits S-warfarin 7-hydroxylation activity in human liver microsomes with a K i value of 0.2 μM. This finding suggests that sesamin predominantly binds to CYP2C9 at another site for which it has a higher affinity than its affinity for the active site, thereby inhibiting the activity of CYP2C9 non-competitively. In this study, we found that sesamin competitively inhibited the 7-hydroxylation activity of S-warfarin in human liver microsomes with a K i value of 15.7 μM. In addition, the recombinant CYP2C9-dependent 7-hydroxylation activity of S-warfarin was competitively inhibited by sesamin with a Ki value of 13.1 μM. These results are consistent with the fact that sesamin is a good substrate of CYP2C9, and its activity follows Michaelis-Menten kinetics. As the plasma concentration of sesamin after its administration is usually lower than 0.01 μM, the inhibition of S-warfarin metabolism by sesamin does not appear to be severe., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Negatively charged synthetic hydrogels have been known to facilitate various cellular responses including cell adhesion, proliferation, and differentiation; however, the molecular mechanism of hydrogel-dependent control of cell behavior remains unclear. Recently, we reported that negatively charged poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) gel induces chondrogenic differentiation of ATDC5 cells via novel protein reservoir function. In this study, we identified the cell adhesion molecules binding to PAMPS gels that act as mechanoreceptors. First, we performed a pull-down assay by particle gels using cell membrane proteins of ATDC5, and found that multiple membrane proteins bound to the PAMPS gel, whereas the uncharged poly(N,N'-dimethylacrylamide) gel as control did not bind to any membrane proteins. Western blot analysis indicated differential binding of integrin (ITG) isoforms to the PAMPS gel, in which the α4 isoform, but not α5 and αv, efficiently bound to the PAMPS gel. ITG α4 knockdown decreased cell spreading of ATDC5 on PAMPS gels, whereas the enhanced expression increased the behavior. Furthermore, ITG α4 depletion suppressed PAMPS gel-induced expression of bone morphogenic protein (BMP) 4 contributing to chondrogenic differentiation, in concordance with the reduction of ERK activation. These results demonstrated that membrane protein binding to PAMPS gels occurred in a charge-dependent manner, and that ITG α4 plays a crucial role in cell spreading on PAMPS gels and acts as a mechanoreceptor triggering cellular signaling leads to chondrogenic differentiation., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The susceptibility to neurological and psychiatric disorders reveals sexual dimorphism in the structure and function of human brains. Recent evidence has also demonstrated the sex-related differences in cellular components of the brain, including neurons, microglia, astrocytes, and endothelial cells. Oligodendrocyte precursor cells (OPCs) regulate the neuronal system in various ways and play crucial roles in brain homeostasis beyond their well-known role as a reservoir for mature oligodendrocytes. Although recent studies have shown regional diversities and heterogeneities of OPCs, sex-related differences in OPCs are largely unknown. Here, we revealed transcriptomic differences in OPCs isolated from male and female neonatal rat brains. Furthermore, we demonstrated sex-dependent differences in OPCs regarding proliferation, migration, differentiation, tolerance against ischemic stress, energy metabolism, and the ability to regulate the blood-brain barrier integrity., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Orthotopic liver transplantation (OLT) is the only curative treatment for refractory chronic liver failure in liver cirrhosis. However, the supply of donated livers does not meet the demand for OLT due to donor organ shortage. Cell therapy using hepatocyte-like cells derived from human induced pluripotent stem cells (hiPSC-HLCs) is expected to mitigate the severity of liver failure, postpone OLT and ameliorate the insufficient liver supply. For the successful clinical translation of hiPSC-based cell therapy against liver cirrhosis, realistic animal models are required. In this study, we created a nonhuman primate (NHP) liver fibrosis model by repeated administrations of thioacetamide (TAA) and evaluated the short-term engraftment of hiPSC-HLCs in the fibrotic liver. The NHP liver fibrosis model reproduced well the pathophysiology of human liver cirrhosis including portal hypertension. Under immunosuppressive treatment, we transplanted ALBUMIN-GFP reporter hiPSC-HLC aggregates into the fibrotic livers of the NHP model via the portal vein. Fourteen days after the transplantation, GFP-expressing hiPSC-HLC clusters were detected in the portal areas of the fibrotic livers. These results will facilitate preclinical studies using the NHP liver fibrosis model and help establish iPSC-based cell therapies against liver cirrhosis., Competing Interests: Declaration of competing interest Kenji Osafune is a founder and member without salary of the scientific advisory boards of iPS Portal Japan., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Flavin containing monooxygenases (FMOs) represent one of the predominant types of phase I drug metabolizing enzymes (DMEs), and thus play an important role in the metabolism of xeno- and endobiotics for the generation of their corresponding oxides. These oxides often display biological activities, however they are difficult to study since their chemical or biological synthesis is generally challenging even though only small amounts are required to evaluate their efficacy and safety. Previously, we constructed a DME expression system for cytochrome P450, UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) using yeast cells, and successfully produced xenobiotic metabolites in a whole-cell dependent manner. In this study, we developed a heterologous expression system for human FMOs, including FMO1-FMO5, in Saccharomyces cerevisiae and examined its N- and S-oxide productivity. The recombinant yeast cells expressed each of the FMO successfully, and the FMO4 transformant produced N- and S-oxide metabolites at several milligrams per liter within 24 h. This whole-cell dependent biosynthesis enabled the production of N- and S-oxides without the use of the expensive cofactor NADPH. Such novel yeast expression system could be a powerful tool for the production of oxide metabolites., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: Periostin is a matricellular protein belonging to the fasciclin family, playing a role for the pathogenesis of allergic diseases by binding to integrins on cell surfaces. Serum periostin is elevated in various allergic diseases reflecting type 2 inflammation and tissue remodeling so that for allergic diseases, periostin is expected to be a novel biomarker for diagnosis, assessing severity or prognosis, and predicting responsiveness to treatments. We have previously shown that most serum periostin exists in the oligomeric form by intermolecular disulfide bonds., Methods: In this study, we examined how periostin forms a complex in serum, whether the periostin complex in serum is functional, and whether the complex formation interferes with reactivity to anti-periostin Abs., Results: We found that periostin formed a complex with IgA1 at a 1:1 ratio. The periostin in the serum complex contained at least five different isoforms. However, IgA was not essential for the oligomeric formation of periostin in mouse serum or in IgA-lacking serum. The periostin-IgA complex in human serum was functional, sustaining the ability to bind to α V β 3 integrin on cell surfaces. Moreover, periostin formed the complex with IgA broadly, which interferes the binding of the Abs recognizing all of the domains except the R4 domain to periostin., Conclusions: Periostin is a novel member of the IgA-associated molecules. These results are of great potential use to understand the pathological roles of periostin in allergic diseases and, from a practical standpoint, to develop diagnostics or therapeutic agents against periostin., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Pluripotency of mouse embryonic stem cells is regulated by transcription factor regulatory networks as well as mechanical stimuli sensed by the cells. It has been unclear how the mechanical strain applied to the plasma membrane is transferred to the nucleus in mouse embryonic stem cells (mESCs). We here investigated the machinery of the mechanotransduction based on the finding that spontaneous differentiation of mESCs was inhibited with the downregulation of ROCK2 in cells attached to soft substrates. On examining the effects of actin bindings to both focal adhesions and cell junctions in cells on soft substrates, co-localization of actin filaments and α-catenin, which links actin to E-cadherin, decreased after differentiation induction. Also, disrupting actin-nucleus mechanical link through dominant negative assay of Nesprins helps to sustain the pluripotency genes; thus, revealing that mechanical strain relayed by actin-Nesprin connection is required for the initiation of the differentiation process., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Membrane fusion under mildly acidic pH occurs naturally during viral infection in cells and has been exploited in the field of nanoparticle-mediated drug delivery to circumvent endosomal entrapment of the cargo. Herein, we aimed to confer virus-like fusogenic activity to HDL in the form of a ca. 10-nm disc comprising a discoidal lipid bilayer and two copies of a lipid-binding protein at the edge. A series of HDL mutants were prepared with a mixture of three lipids and a cell-penetrating peptide (TAT, penetratin, or Arg8) fused to the protein. In a lipid-mixing assay with anionic liposomes at pH 5.5, one HDL mutant showed the fusogenic activity higher than known fusogenic liposomes. In live mammalian cells, this HDL mutant showed high plasma membrane-binding activity in the presence of serum independent of pH. In the absence of serum, a mildly acidic pH dependency for binding to the plasma membrane and the subsequent lipid mixing between them was observed for this mutant. We propose a novel strategy to develop HDL-based drug carriers by taking advantage of the HDL lipid/protein composite structure., (Copyright © 2019. Published by Elsevier B.V.)

IL-33 is a proinflammatory cytokine that plays a pivotal role in allergic disorders. In a transgenic mouse expressing IL-33 driven by a keratin-14 promoter (IL33tg), atopic dermatitis (AD)-like inflammation develops spontaneously with the activation of group 2 innate lymphoid cells (ILC2s). However, it remains unknown how effector cells, such as T helper type 2 cells, ILC2s, and basophils, contribute to the inflammatory process induced by IL-33. To address the question, we examined the phenotype of IL33tg mice lacking each of these cells. AD-like inflammation still developed in Rag2KO IL33tg mice lacking T and B cells; in contrast, when ILC2s were depleted in IL33tg mice via bone marrow transplantation from ILC2-lacking, RAR-related orphan receptor alpha-deficient mice, the development of AD-like inflammation was almost completely suppressed. Basophils were accumulated in the inflamed skin of IL33tg mice, and AD-like inflammation was alleviated by the conditional depletion of basophils using anti-FcεRIα antibodies or a Bas-TRECK transgenic mouse system. In these basophil-depleted IL33tg skins, ILC2s were decreased, and cytokines and chemokines such as IL-5, IL-13, and CCL5 were reduced. From these results, we suggest that IL-33-induced AD-like inflammation is dependent on innate immune responses that are mediated by ILC2s in concert with basophils., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Electroconvulsive therapy (ECT) is indicated for critical psychiatric conditions, which themselves constitute a risk for deep venous thrombosis (DVT) owing to prolonged immobility, dehydration, and venous stasis., Objective: We describe challenging instances of ECT implementation while taking direct oral anticoagulants (DOACs)., Method: We report on 8 patients receiving DOACs for DVT who were successfully treated with ECT at the University of Yamanashi Hospital. We also provide a literature review on this topic., Results: There were 6 female patients (the average age was 60.9+/-13.4 y.o.) and diagnoses included major depression, bipolar depression and schizophrenia. DOACs were edoxaban for 4 patients, rivaroxaban for 2, and apixaban for 2. A total of 92 ECT sessions were cautiously and safely completed in collaboration with multidisciplinary medical professionals without problematic adverse events, such as bleeding. A literature search found one case series of warfarin but currently available evidence is confined to sporadic case reports regarding ECT and DOACs for DVT. These reports were represented by successful implementation of ECT to patients receiving treatment with anticoagulants for DVT or thromboembolism. Ours is the first of a successful treatment with ECT while taking apixaban or edoxaban., Conclusion: A clinical dilemma is that ECT is indicated for critical conditions that are likely to predispose patients to developing DVT. Paucity of data clearly highlights the need for more studies to support a contention that ECT, when carefully performed in consultation with other medical experts, is a viable treatment for those with DVT receiving oral anticoagulants., (Copyright © 2018 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Sesamin is known to have various biological effects. Although several metabolites of sesamin have been identified, its metabolism by phase II enzymes remains unclear, because usually its sulfo- and glucurono-conjugates in plasma and urine are analyzed after sulfatase/β-glucuronidase treatment. In this study, the metabolites of sesamin in rats administrated with sesamin (100 mg/kg b.w.) were analyzed without sulfatase/β-glucuronidase treatment. Two sulfate conjugates of sesamin monocatechol (SC-1) were detected in the liver and plasma. Their C max values were 5- and 10-times higher than that of sesamin itself. The V max /K m values for sulfate conjugation in the cytosol fraction of human liver were 1.7-times larger than that in the cytosol fraction of rat liver, suggesting that sulfate conjugation also occurs in human liver. The recombinant human proteins SULT1A1, 1A3, 1B1, and 1E1 expressed in Saccharomyces cerevisiae cells produced sulfate conjugates effectively. Our results could help revealing the mechanism of physiological effects of sesamin., (Copyright © 2018. Published by Elsevier Ltd.)

Cholangiocytes are the epithelial cells that line bile ducts, and ductal plate malformation is a developmental anomaly of bile ducts that causes severe congenital biliary disorders. However, because of a lack of specific marker genes, methods for the stepwise differentiation and isolation of human induced pluripotent stem cell (hiPSC)-derived cholangiocyte progenitors at ductal plate stages have not been established. We herein generated an AQP1-GFP reporter hiPSC line and developed a combination treatment with transforming growth factor (TGF) β2 and epidermal growth factor (EGF) to induce hiPSC-derived hepatoblasts into AQP1 + cells in vitro. By confirming that the isolated AQP1 + cells showed similar gene expression patterns to cholangiocyte progenitors at the remodeling ductal plate stage around gestational week (GW) 20, we established a differentiation protocol from hiPSCs through SOX9 + CK19 + AQP1 - ductal plate-like cells into SOX9 + CK19 + AQP1 + remodeling ductal plate-like cells. We further generated 3D bile duct-like structures from the induced ductal plate-like cells. These results suggest that AQP1 is a useful marker for the generation of remodeling ductal plate cells from hiPSCs. Our methods may contribute to elucidating the differentiation mechanisms of ductal plate cells and the pathogenesis of ductal plate malformation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)