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Abstract Human cytochrome P450 3A4 (CYP3A4) is a drug‐metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human‐like regulation of the coding genes. A normal diet (ND, CE‐2), CE‐2 with 1% cholesterol and 0.5% cholic acid (HCD) or CE‐2 with 0.5% cholic acid was given to the mice. The plasma concentrations of cholesterol, cholic acid and its metabolites in HCD mice were higher than those in ND mice. In this condition, the expression levels of hepatic CYP3A4 and the hydroxylation activities of triazolam, a typical CYP3A4 substrate, in liver microsomes of HCD mice were higher than those in liver microsomes of ND mice. Furthermore, plasma concentrations of triazolam in HCD mice were lower than those in ND mice. In conclusion, our study suggested that hepatic CYP3A4 expression and activity are influenced by the combination of cholesterol and cholic acid in vivo.

Abstract Background We report two cases of biceps brachii and brachialis paralysis due to musculocutaneous nerve injury in which elbow joint flexion was reconstructed using rotational transfer of the latissimus dorsi muscle with sutures to the radial and ulnar tuberosities, thereby enabling flexion by simultaneous activation of the humeroradial and humeroulnar joints. In cases of associated brachialis paralysis, weaker flexion strength can be expected when the forearm is in a pronated position than when it is in a supinated state. To the best of our knowledge, no previous study has reported the rotational position of the forearm during elbow joint flexion reconstruction. Case presentation Case 1 involved a 30-year-old Asian male who presented with a rupture of the musculocutaneous, median, radial, and ulnar nerves. Reconstruction was performed by rotational transfer of the latissimus dorsi muscle. In this case, the supination and pronation flexion forces were equal. Case 2 involved a 50-year-old Asian man who presented with partial loss of the musculocutaneous nerve, biceps brachii, and pectoralis major due to debridement. Reconstruction was performed by rotational transfer of the latissimus dorsi muscle. In this case, supination and pronation flexion strengths were demonstrated to be equal. Our reconstruction method used the rotational transfer of the latissimus dorsi muscle; the distal muscle flap was divided into radial and ulnar sides to allow elbow joint flexion by simultaneously activating the humeroradial and humeroulnar joints. These sides were then fixed to the anchors at the radial and ulnar tuberosities. Finally, they were wrapped around the myotendinous junction of the biceps brachii or brachialis and secured using sutures. Conclusions Although larger studies are required to verify these methods, this case study successfully demonstrates the following: (1) the flexion strength in the supinated position was equal to that in the pronated position; (2) the stability of the humeroradial and humeroulnar joints was unaffected by the forearm's rotational position; and (3) a satisfactory range of motion of the elbow joint was obtained, with no complications.

Inflammatory response induces phenotypic modulation of fibroblasts into myofibroblasts. Although transforming growth factor-βs (TGF-βs) evoke such transition, the details of the mechanism are still unknown. Here, we report that a LIM domain protein, cysteine-and glycine-rich protein 2 (CSRP2 [CRP2]) plays a vital role in the functional expression profile in myofibroblasts and cancer-associated fibroblasts (CAFs). Knock-down of CRP2 severely inhibits the expression of smooth muscle cell (SMC) genes, cell motility, and CAF-mediated collective invasion of epidermoid carcinoma. We elucidate the following molecular bases: CRP2 directly binds to myocardin-related transcription factors (MRTF-A/B [MRTFs]) and serum response factor (SRF) and stabilizes the MRTF/SRF/CArG-box complex to activate SMC gene expression. Furthermore, a three-dimensional structural analysis of CRP2 identifies the amino acids required for the CRP2-MRTF-A interaction. Polar amino acids in the C-terminal half (serine-152, glutamate-154, serine-155, threonine-156, threonine-157, and threonine-159 in human CRP2) are responsible for direct binding to MRTF-A. On the other hand, hydrophobic amino acids outside the consensus sequence of the LIM domain (tryptophan-139, phenylalanine-144, leucine-153, and leucine-158 in human CRP2) play a role in stabilizing the unique structure of the LIM domain. Key words: CRP2, 3D structure, myocardin-related transcription factor, myofibroblast, cancer-associated fibroblasts

Rationale. The progressive decline in lung function observed in asthma is attributed to persistent type 2 airway inflammation and associated airway remodeling. While various immune cells are involved in localized type 2 airway inflammation, whether these reflect the presence of airway obstruction due to persistent type 2 airway inflammation remains unclear. This study aimed to explore whether the proportions of immune cells in peripheral blood indicate the presence of type 2 inflammation and airway obstruction in asthmatics. Materials and Methods. Using flow cytometry, we identified and quantified Group 2 innate lymphocytes, T helper 2 cells, follicular helper T cells, and T helper 17 cells in peripheral blood samples from 49 individuals with asthma. We then conducted cross-sectional analyses to assess relationships between levels of these immune cells and lung function parameters, including the percentage predicted forced expiratory volume in 1 s (%FEV1). We also examined correlations between the proportions of immune cells and type 2 biomarkers. Results. Proportions of CXCR5+ follicular helper T cells in human peripheral blood, as opposed to Group 2 innate lymphoid cells (ILC2) or T helper 2 cells, were significantly higher in cases with %FEV1

Spatial transcriptomics reveal how distant cancer affect gene expression and zonation in mouse liver in a manner that differs between biological pathways.

Article Summary Strength and limitations of this study • This systematic review and a meta-analysis will investigate the associations between psychosocial factors at work and menstrual abnormalities or fertility. • This review will include only the literature that has utilized a longitudinal design. • Various outcomes related to reproductive health in female workers will be examined (e.g., fertility, premenstrual symptoms, cycle disorders, menopausal symptoms).

Abstract Background and Aim Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan–Meier analysis with propensity score matching and logistic progression analysis. Results The cumulative risk of developing a new symptom after 10 and 20 years of follow‐up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033–1.165; P = 0.002), the serum D‐Bil level (HR, 6.262; 95% CI, 2.522–15.553, P

Abstract We evaluated the early effects of pars plana vitrectomy (PPV) on corneal biomechanics by comparing corneal hysteresis (CH) after cataract surgery (phacoemulsification and aspiration with intraocular lens implantation; PEA + IOL) alone and PPV combined with cataract surgery. This study included 20 eyes (18 patients), who underwent cataract surgery alone (PEA + IOL group), and 28 eyes (27 patients) who underwent PPV combined with cataract surgery (PPV triple group). The CH was 11.1 ± 1.1, 10.4 ± 1.1, and 11.0 ± 1.0 mmHg in the PEA + IOL group and 11.0 ± 1.4, 9.8 ± 1.4, and 10.6 ± 1.6 mmHg in the PPV triple group, preoperatively, at 2 weeks, and 3 months after surgery, respectively. The CH was not significantly different after surgery in the PEA + IOL group, but decreased significantly in the PPV triple group 2 weeks following surgery (p

Plants retain the ability to generate a pluripotent tissue called callus by dedifferentiating somatic cells. A pluripotent callus can also be artificially induced by culturing explants with hormone mixtures of auxin and cytokinin, and an entire body can then be regenerated from the callus. Here we identified a pluripotency-inducing small compound, PLU, that induces the formation of callus with tissue regeneration potency without the external application of either auxin or cytokinin. The PLU-induced callus expressed several marker genes related to pluripotency acquisition via lateral root initiation processes. PLU-induced callus formation required activation of the auxin signaling pathway though the amount of active auxin was reduced by PLU treatment. RNA-seq analysis and subsequent experiments revealed that Heat Shock Protein 90 (HSP90) mediates a significant part of the PLU-initiated early events. We also showed that HSP90-dependent induction of TRANSPORT INHIBITOR RESPONSE 1, an auxin receptor gene, is required for the callus formation by PLU. Collectively, this study provides a new tool for manipulating and investigating the induction of plant pluripotency from a different angle from the conventional method with the external application of hormone mixtures.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly, affecting the macula of the retina and resulting in vision loss. There are two types of AMD, wet and dry, both of which cause visual impairment. Wet AMD is called neovascular AMD (nAMD) and is characterized by the formation of choroidal neovascular vessels (CNVs) in the macula. nAMD can be treated with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors, which help improve vision. However, approximately half the patients do not achieve satisfactory results. Subretinal fibrosis often develops late in nAMD, leading to irreversible photoreceptor degeneration and contributing to visual loss. Currently, no treatment exists for subretinal fibrosis, and the molecular mechanisms of fibrous tissue formation following neovascular lesions remain unclear. In this review, we describe the clinical features and molecular mechanisms of macular fibrosis secondary to nAMD. Myofibroblasts play an essential role in the development of fibrosis. This review summarizes the latest findings on the clinical features and cellular and molecular mechanisms of the pathogenesis of subretinal fibrosis in nAMD and discusses the potential therapeutic strategies to control subretinal fibrosis in the future.

Menstrual management (MM) facilities in schools are neglected in low- and middle-income countries. We examined the existing MM facilities, identified the deficient, and collected students' ideas in peri-urban schools of Nepal. The schools had basic MM facilities including water sanitation and hygiene (WASH) infrastructures, gender-segregated toilet facilities with taps, dustbins and running water, provision of emergency sanitary pads, etc. Out of 71 students who reported soiling of dresses with menstrual blood as a common problem, 27% went home and did not return in such situation instead of washing off at school. Forty-six per cent of students used washable absorbents, but washing and drying facilities were lacking, and students adapted by using disposable pads at school and washable at home. Out of 126 students, 106 took days off during menstruation in the past three months with an average of 2.6 days by one student. Sixty-one per cent gave the reason as pain and 39% tiredness for taking days off. Healthcare facilities were lacking in schools, hence, lack of these facilities in schools might be contributing to absenteeism. The traditionally advocated list of MM facilities for schools, largely involving WASH facilities, should be updated, including newly identified factors which were also suggested by students. HIGHLIGHTS WASH infrastructures were available, but water supply and soap were less frequently managed.; Reusable pads were advocated but lack of washing and drying space in schools made it less applicable; Students developed coping strategy to use disposable pads at school and washables at home.; A student skipped 2.6 school days in 3 months during menstruation due to health problems, but healthcare facilities were lacking.;

Abstract Purpose Spermatogenesis is a complex process orchestrated by several essential genes. Prominin‐1 (Prom1/PROM1) is a gene that is expressed in the testis but with a poorly understood role in spermatogenesis. Methods We used Prom1 knockout (Prom1 KO) mice to assess the role of Prom1 in spermatogenesis. To this end, we performed immunohistochemistry, immunofluorescence, western blotting, β‐galactosidase staining, and apoptosis assay. Additionally, we analyzed the morphology of sperm and assessed litter sizes. Results We observed that PROM1 is localized to the dividing spermatocytes in seminiferous epithelial cells, sperm, and columnar epithelium in the epididymis. In the Prom1 KO testis, an aberrant increase in apoptotic cells and a decrease in proliferating seminiferous epithelial cells were observed. Cellular FLICE‐like inhibitory protein (c‐FLIP) and extracellular signal‐regulated kinase 1/2 (ERK1/2) expression were also significantly decreased in Prom1 KO testis. In addition, a significantly increased number of epididymal spermatozoa with abnormal morphology and less motility was found in Prom1 KO mice. Conclusions PROM1 maintains spermatogenic cell proliferation and survival via c‐FLIP expression in the testis. It is also involved in sperm motility and fertilization potential. The mechanism underlying the effect of Prom1 on sperm morphology and motility remains to be identified.

Peripheral nerves conducting motor and somatosensory signals in vertebrate consist of myelinated and unmyelinated axons. In vitro myelination culture, generated by co-culturing Schwann cells (SCs) and dorsal root ganglion (DRG) neurons, is an indispensable tool for modeling physiological and pathological conditions of the peripheral nervous system (PNS). This technique allows researchers to overexpress or downregulate molecules investigated in neurons or SCs to evaluate the effect of such molecules on myelination. In vitro myelination experiments are usually time-consuming and labor-intensive to perform. Here we report an optimized protocol for in vitro myelination using DRG explant culture. We found that our in vitro myelination using DRG explant (IVMDE) culture not only achieves myelination with higher efficiency than conventional in vitro myelination methods, but also can be used to observe Remak bundle and non-myelinating SCs, which were unrecognizable in conventional methods. Because of these characteristics, IVMDE may be useful in modeling PNS diseases, including Charcot Marie Tooth disease (CMT), in vitro. These results suggest that IVMDE may achieve a condition more similar to peripheral nerve myelination observed during physiological development.

Diabetic macular edema (DME) is the main cause of visual loss in patients with diabetic retinopathy. DME has been treated using intravitreal anti-vascular endothelial growth factor (VEGF) drugs, steroids, laser photocoagulation, vitreoretinal surgery, and their combinations. These modalities are generally effective in preserving vision, but they sometimes produce only limited responses in patients with persistent or refractory DME. The levels of various inflammatory factors, including cytokines, chemokines, and extracellular matrices, as well as VEGF in the vitreous fluid, are increased in patients with DME. Excessive fibrinogen/fibrin levels in the vitreous fluid or fibrin deposition in the retina also contribute to DME pathogenesis. Tissue plasminogen activator (t-PA) promotes the degradation of fibrinogen or fibrin. Intravitreal t-PA injection is a commonly used treatment for subretinal hemorrhage secondary to age-related macular degeneration. Intravitreal t-PA injections have previously been used to restore vision by inducing posterior vitreous detachment in patients with DME. Herein, we describe the visual outcomes of intravitreal t-PA injection in a 78-year-old woman with treatment-resistant DME in her vitrectomized eye after several previous treatments. Before the injection, her best-corrected visual acuity (BCVA) was 0.7 logMAR and central foveal retinal thickness (CRT) was 735 μm. At 1 month after the injection, her BCVA was 0.8 logMAR and CRT was 558 μm, and 3 months later, her BCVA was 0.8 logMAR and CRT was 207 μm. Her BCVA was sustained, and CRT showed gradual improvements. These findings suggested the effectiveness of intravitreal t-PA injections for DME in the vitrectomized eye.

Abstract Background Currently, in Japan, shifting tasks from physician to hospital pharmacist is being developed to reduce physician workload and improve the quality of pharmacotherapy. This study aimed to investigate the effects of pharmacist involvement in the choice of inhaler as the task on the clinical outcomes of patients with chronic obstructive pulmonary disease (COPD). Methods This prospective, single-center, single-arm study included 36 outpatients with newly diagnosed COPD indicating inhaler therapy. Eligible patients were immediately interviewed by pharmacist. Then, pharmacist assessed patient’s inhalation flow rate, physical function to handle an inhaler, comprehension, and value, and finally recommended a personalized inhaler based on originally developed inhaler choice protocol, and pulmonologist prescribed a pharmacist-selected inhaler. The primary endpoint was the improvement in trough forced expiratory volume in 1 s (FEV1) between baseline and week 26. The secondary endpoints were safety, and improvements at week 26 in scores for the COPD Assessment Test (CAT), modified British Medical Research Council Dyspnea Scale (mMRC), and Adherence Starts with Knowledge-20 (ASK-20). Results The pneumonologists completely agreed with the pharmacist-recommended inhaler. Mean FEV1 significantly increased from baseline to week 26 (1.60, SD 0.54 L vs. 1.98, SD 0.56 L; p

Abstract Aims/Introduction The aim of the present study was to clarify the pathophysiologies of hyperglycemic crises in Japanese patients. Materials and Methods This was a retrospective study of patients with hyperglycemic crises admitted to Kumamoto Medical Center, Kumamoto, Japan, between 2012 and 2019. Patients were classified as having diabetic ketoacidosis (DKA), hyperglycemic hyperosmotic syndrome (HHS) or a mixed state of the two conditions (MIX), and laboratory data and levels of consciousness at hospital admission, as well as the rates of mortality and coagulation disorders, were compared. Results The diagnostic criteria for hyperglycemic crisis were met in 144 cases, comprising 87 (60.4%), 38 (26.4%) and 19 (13.2%) cases of DKA, HHS and MIX, respectively. Type 1 diabetes was noted in 46.0 and 26.3% of patients in the DKA and MIX groups, respectively. Fibrin degradation product and D‐dimer levels were significantly higher in the HHS group than in the DKA group (DKA and HHS groups: fibrin degradation product 7.94 ± 8.43 and 35.54 ± 51.80 μg/mL, respectively, P

Abstract Benzalkonium chloride (BAC) is used as a preservative in eyedrops but induces subconjunctival fibrosis that can result in failure of glaucoma surgery. Tenon’s capsule fibroblasts in subconjunctival tissue interact with the corneal epithelium through tear fluid. With the use of a coculture system, we have now investigated the effect of human corneal epithelial (HCE) cells on myofibroblastic transdifferentiation of human Tenon fibroblasts (HTFs) induced by BAC (5 × 10−6%). Immunofluorescence and immunoblot analyses revealed that the BAC-induced expression of α smooth muscle actin (αSMA) in HTFs was suppressed by coculture of these cells with HCE cells (p

Abstract Epithelial–mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a key role in proliferative retinal diseases such as age-related macular degeneration by contributing to subretinal fibrosis. To investigate the potential role of retinoic acid receptor-α (RAR-α) signaling in this process, we have now examined the effects of the RAR-α agonist Am580 on EMT induced by transforming growth factor-β2 (TGF-β2) in primary mouse RPE cells cultured in a three-dimensional type I collagen gel as well as on subretinal fibrosis in a mouse model. We found that Am580 inhibited TGF-β2-induced collagen gel contraction mediated by RPE cells. It also attenuated the TGF-β2-induced expression of the mesenchymal markers α-smooth muscle actin, fibronectin, and collagen type I; production of pro-matrix metalloproteinase 2 and interleukin-6; expression of the focal adhesion protein paxillin; and phosphorylation of SMAD2 in the cultured RPE cells. Finally, immunofluorescence analysis showed that Am580 suppressed both the TGF-β2-induced translocation of myocardin-related transcription factor-A (MRTF-A) from the cytoplasm to the nucleus of cultured RPE cells as well as subretinal fibrosis triggered by laser-induced photocoagulation in a mouse model. Our observations thus suggest that RAR-α signaling inhibits EMT in RPE cells and might attenuate the development of fibrosis associated with proliferative retinal diseases.

Abstract Background Open fractures are among the most severe injuries observed in orthopedic patients. Treating open fractures is difficult because such patients with infections may require multiple operations and amputations. Furthermore, only a few studies have focused on antibiotic prophylaxis in open fractures and evaluated how to cover lost soft tissue to increase the success rate of reconstruction. We evaluated the risk factors for deep infection in lower limb Gustilo–Anderson (G–A) type III fractures. Materials and methods This retrospective study investigated patients who underwent surgical procedures for lower limb G–A type III fractures between January 2007 and January 2017 at our institution. We enrolled 110 patients with 114 lower limb G–A type III fractures (77 G–A type IIIA fractures and 37 G–A type IIIB fractures) who were followed up for at least 2 years. We compared patients presenting infections with those without infections by assessing the following factors: severe contamination, diabetes, smoking, Injury Severity Scale, segmental fracture, location of fracture, G–A classification, damage control surgery, methods of surgery, timing of fixation, combination of antibiotics used, duration of antibiotic prophylaxis, timing of wound closure, and soft-tissue reconstruction failure. Results Eighteen fractures presented deep infections. Compared with patients without infections, patients developing infections differed significantly in terms of severe contamination (P

Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

Retinitis pigmentosa (RP) and macular dystrophy (MD) are characterized by gradual photoreceptor death in the retina and are often associated with genetic mutations, including those in the prominin-1 (Prom1) gene. Prom1-knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and constriction of retinal blood vessels. The mechanisms underlying such degeneration have remained unclear, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. Whereas gene expression was not affected at 2 weeks, the expression of several genes was altered at 3 weeks in the Prom1-KO retina, with the expression of that for endothelin-2 (Edn2) being markedly upregulated. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice reared in the dark. Treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis and retinal vessel stenosis in Prom1-KO mice. Our findings thus reveal early manifestations of retinal degeneration in a model of RP/MD and suggest potential therapeutic agents for these diseases. This article has an associated First Person interview with the first author of the paper.

Study region: Kathmandu Valley, Nepal. Study focus: Water scarcity affects more than 40 % of the global population. Households in low- and middle-income countries typically use alternative water sources to piped water such as groundwater, tanker water and jar water and various coping strategies to deal with water scarcity. This study quantitatively examines the association between using multiple water sources and individual water consumption. In addition, we investigated the relationship between individual water consumption and physical (i.e. water source, supply time) and non-physical (wealth status, education for household head, house ownership, participation in local community, water treatment) factors before and after the 2015 Gorkha earthquake. A survey about socio-demographics, domestic water use behavior, and community involvement was conducted three times and the data collected from 992 households were used for analysis. New hydrological insights for the region: It was confirmed that use of additional water sources is associated with greater individual water consumption. This was especially the case in households using both groundwater and tanker water. In addition, wealth status, education for household head, and house ownership were associated with increased individual water consumption but this association was not apparent after the earthquake. Participation in the local community was also associated with increased individual water consumption except for the period impacted by the earthquake. Households using treated water consumed less water across all periods surveyed.

Abstract Postoperative adhesion and occlusion remain a serious issue associated with various surgeries, including endoscopic surgery, in which proliferated fibrous tissues stick to adjacent tissues and often cause severe complications. Cell sheet engineering has emerged as an effective approach not only for cell transplantation but also for the treatment of postoperative adhesion and occlusion. However, as the tissues in the body, such as middle ear and small intestine, and typical operative sites are non-flat and spatially complicated, tailored cell sheets with three-dimensional (3D) configurations may lead to widespread use of this approach. In the present study, we used microstereolithography, biocompatible gold plating, and electrochemical cell detachment to achieve this purpose. Various objects with dimensions ranging from millimeter- to micrometer-scale were fabricated with photocurable resin using lab-made equipment for microstereolithography. To coat the fabricated objects with a thin gold layer, conventional cyanide-based gold plating was unusable because it severely damaged almost all cells. Electroless non-cyanide gold plating we prepared was cytocompatible and suitable for electrochemical cell detachment. Cell sheets on the gold-plated substrate could be directly transplanted into a mouse intraperitoneally using electrochemical cell detachment. We further demonstrated that cell sheets grown on gold-coated 3D objects were rapidly detached along with the desorption of electroactive-oligopeptide monolayer and transferred to a surrounding hydrogel. This approach may provide a promising strategy to prepare and directly transplant tailor-made cell sheets with suitable configurations.

Introduction This randomised controlled trial (RCT) aims to examine the effects of an internet-delivered acceptance and commitment therapy (iACT) programme (‘Happiness Mom’) on the psychological well-being of working mothers.Methods and analysis The target population of the RCT will be employed mothers with at least one preschool child. Participants who fulfil the study’s eligibility criteria will be randomly assigned either to an iACT intervention group (n=200) or to a wait-list control group (n=200). Participants in the intervention groups will be asked to complete the programme within 12 weeks of the baseline survey. The intervention programme contains eight modules based on ACT. Primary outcomes are six components of psychological well-being, based on Ryff’s theory. Secondary outcomes are intention to leave their job, work engagement, work performance, sick leave days, psychological distress, euthymia, positive emotions, job and life satisfaction, social support and parental burn-out.Ethics and dissemination Ethical approval for this study has been obtained from the Research Ethics Review Board of Graduate School of Medicine, the University of Tokyo (No. 2019134NI). If the intervention programmes are found to be significantly beneficial, the programmes can be made available for all working mothers with preschool children in Japan.Discussion This study will contribute to the development of an internet-based self-care programme that is effective, feasible, low cost and accessible to improve the well-being of working mothers.Trial registration number UMIN000039918.

Purpose To investigate the postoperative course of patients who explanted a diffractive bifocal intraocular lens (IOL) due to waxy vision and implanted with an extended depth of focus IOL. Methods This study evaluated 29 eyes of 25 patients who underwent diffractive bifocal IOL explantation followed by TECNIS Symfony® implantation because of dissatisfaction due to waxy vision at the Takabatake West Eye Clinic between January 2018 and November 2019. The indication criteria for this surgery were patients with uncorrected distance visual acuity of 0.05 logMAR or better, without eye diseases that may affect visual function, and no dissatisfactions about photic phenomena. We investigated patient demographics, uncorrected and corrected visual acuity, manifest refraction, contrast sensitivity, subjective symptoms, time to IOL explantation, explanted IOL type, and spectacle independence. Results The time to the IOL exchange after the initial IOL implantation was 55.3 ± 50.4 days (range: 14–196 days). The logMAR corrected distance visual acuity before and after IOL exchange were −0.13 ± 0.06 and −0.14 ± 0.06, respectively (p = 0.273). After IOL exchange surgery, the area under log contrast sensitivity function increased significantly from 1.07 ± 0.12 to 1.21 ± 0.12 (p < 0.001), and the waxy vision symptoms improved. The spectacle independence rate at the last visit was 88.0%. Conclusion For patients who complain of waxy vision despite good visual acuity after diffractive bifocal IOL implantation, exchange to extended depth of focus IOL was considered one of the useful surgical options.

Objectives: This study aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to improve subjective well-being (SWB), including evaluative, hedonic, and eudemonic well-being, and the mental component of quality of life (QOL) of working population.Methods: A literature search was conducted, using PubMed, Embase, PsycINFO, and PsycARTICLES. Eligible studies included those that were RCTs of any intervention, conducted among healthy workers, measured SWB as a primary outcome, and original articles in English. Study characteristics, intervention, outcomes, and results on SWB outcomes were extracted by the investigators independently. After a brief narrative summarizing and classifying the contents of the interventions, the included outcomes were categorized into each aspect of SWB (evaluative, hedonic, and eudemonic well-being, and the mental component of QOL). Finally, the characteristics of the effective interventions for increasing each aspect were summarized, and the pooled effect of interventions on SWB was investigated by a meta-analysis. Publication bias was investigated by drawing a funnel plot and conducting Egger's test.Results: From the 5,450 articles found, 39 met the inclusion criteria for the systematic review. The interventions included in this review were classified into six categories (physical activity, ergonomics, psychological, environmental, multicomponent intervention, and others). The meta-analysis from 31 studies showed that the pooled effect of included interventions on SWB was significantly positive (standardized mean difference (SMD) = 0.51; standard error (SE) = 0.10). A funnel plot showed there were extremely large or small SMDs, and Egger's test was significant. Thus, we conducted sensitivity analysis, excluding these extreme SMDs, and confirmed that the estimated pooled effect was also significantly positive. Subgroup analyses for separate types of interventions showed the effects of psychological interventions (e.g., mindfulness, cognitive behavioral based approach, and other psychological interventions) were also significantly positive.Conclusion: The current study revealed the effectiveness of interventions for increasing SWB. Specifically, psychological interventions (e.g., mindfulness, cognitive behavioral based approach, and other psychological interventions) may be useful for improving SWB.

PurposeThe purpose of this study is to develop and validate a Japanese version of the Servant Leadership Scale and to clarify the relationship between servant leadership (SL) and well-being among Japanese workers.MethodsAfter the Japanese version of the SLS (SLS-J) and of its short form (SLS-J-short) were developed in conformity with the guidelines (Wild et al., 2005), a web-based survey was administered to 516 Japanese employees (20 or older and have a supervisor). Confirmatory factor analysis (CFA) was conducted to evaluate a construct validation of the SLS-J and the SLS-J-short. Convergent validity was estimated with theoretically related constructs (e.g., transformational leadership, supervisory support, and interpersonal justice) and potential consequences of SL (e.g., affective commitment, work engagement, job satisfaction, organizational citizenship behavior (OCB), psychological distress, and work performance). Intraclass correlation coefficient (ICC) using the test-retest method was conducted with 104 of the initial respondents to assess internal consistency reliability. Additionally, the effects of SL on employees’ work engagement and the mediating role of employees’ affective commitment were estimated.ResultsCFA confirmed that an eight-factor model (SLS-J) and a five-factor model (SLS-J-short) had the most satisfactory fits for the two scales with Japanese workers. Tests of convergent validity and reliability showed sufficiency for each of the dimensions of SLS-J and SLS-J-short. Additionally, it was revealed that SL has an impact on employees’ work engagement through a mediation of affective commitment at a cross-sectional level, and the indirect association between SL and work engagement via affective commitment remained afterward.ConclusionSLS-J and SLS-J-short were confirmed to have good reliability and validity for Japanese workers. Also, this study found that SL has an important role in enhancing the engagement of workers.

Objective Persons with type 2 diabetes are often stigmatised for having what is considered a lifestyle-related disease. Accordingly, some blame themselves for their condition, resulting in feelings of low self-worth that ultimately impact their self-management behaviours. However, there are no studies examining why some do not blame themselves for their condition and manage to maintain their self-worth in relation to their illness. This study aimed to explore an understanding of how such persons experience the maintenance of self-worth in relation to their illness over the lifelong course of treatment.Design A cross-sectional qualitative study. Face-to-face semistructured interviews were conducted with a purposive sampling strategy. The data was analysed using a qualitative descriptive method that involved concurrent data collection and constant comparative analysis.Setting Two tertiary-level hospitals in Japan.Participants Thirty-three outpatients with type 2 diabetes who currently had good glycaemic control but had previously had poor glycaemic control.Results Three themes explaining the maintenance of self-worth were identified: (1) Participants gained ‘control’ over their illness by living a ‘normal life.’ They found a way to eat preferred foods, dine out with family and friends, travel and work as usual; (2) Participants discovered the positive aspects of type 2 diabetes, as they felt ‘healthier’ from the treatment and felt a sense of security and gratitude for the care they received from healthcare professionals; (3) Participants discovered a new sense of self-worth by moving towards goals for type 2 diabetes treatment and experienced inner growth through positive lifestyle choices.Conclusions The process of restoring and maintaining self-worth should be brought to the attention of healthcare professionals in diabetes care. These professionals could help patients discover positive self-representations through diabetes treatment (eg, a realisation that one does not lack self-control) and could aid in increasing patient engagement in diabetes self-management.

Albumin has an oxidized form, known as non-mercaptalbumin (HNA), which reflects systemic oxidative stress. The association between serum HNA levels and diabetic complications are yet to be reported. In this cross-sectional study, we investigated 164 diabetic subjects to assess the correlation between HNA% (the proportion in the total albumin) and various clinical parameters. HNA% was significantly associated with the severity of multiple complications including neuropathy (23.3 ± 4.1% vs 26.2 ± 5.1%) and nephropathy (24.1 ± 3.9%, 24.6 ± 4.2%, 28.5 ± 6.1%, 31.3 ± 5.7%, 37.8 ± 2.9%, stage 1/2/3/4/5, respectively). These findings highlight the universal importance of oxidative stress, indicating HNA% potential as a versatile marker of the severity of diabetic complications.

Summary: Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR α/β genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors. : Cellular Therapy; Immunological Methods; Cancer Subject Areas: Cellular Therapy, Immunological Methods, Cancer

[This corrects the article DOI: 10.1371/journal.pone.0219405.].

PurposeTo investigate the influence of EDOF IOLs, TECNIS Symfony® (Johnson & Johnson Surgical Vision, Inc.), on visual field sensitivity and to compare the IOLs with other kinds of IOLs.MethodsThe subjects included the normal fellow eyes of patients who underwent the Humphrey Field Analyzer (HFA) 30-2 with Swedish Interactive Threshold Algorithm Fast within 6 months after cataract due to glaucoma or suspected glaucoma. Each parameter of HFA was compared among eyes implanted with TENIS Symfony® (EDOF group), diffractive bifocal IOLs (bifocal group), and monofocal IOLs (monofocal group).ResultsThe total of 76 eyes, including 24 eyes in the EDOF group, 26 eyes in the bifocal group, and 26 eyes in the monofocal group, were included in this study. Mean deviation (MD) of HFA was -0.24±0.58 dB in the EDOF group, -1.38±0.58 dB in the bifocal group, and 0.02±0.44 dB in the monofocal group. Foveal threshold (FT) of HFA was 35.8±1.6 dB in the EDOF group, 33.6±1.7 dB in the bifocal group, and 36.6±1.4 dB in the monofocal group. In both MD and FT, there was significant difference between the bifocal group and the others (pConclusionTECNIS Symfony® may have little influence on visual field sensitivity, whereas diffractive bifocal IOLs decrease visual field sensitivity.

Abstract Background Chemotherapy-induced oral mucositis impairs the quality of life. The difference in severity of oral mucositis between different anti-epidermal growth factor receptor (EGFR) antibodies combined with cytotoxic drugs in colorectal cancer is unclear. The aim of this study was to investigate the differences in oral mucositis between panitumumab (Pmab) and cetuximab (Cmab) combined with 5-fluorouracil (5-FU). Methods We conducted a retrospective cohort study. A total of 75 colorectal cancer outpatients treated with an anti-EGFR antibody combined with FOLFOX, FOLFIRI, or 5-FU/leucovorin as the first- to third-line treatment were included. The primary endpoint was the incidence of grade 2–3 oral mucositis. The secondary endpoint was the time to onset of oral mucositis. We also compared the incidence of toxicities of interest, skin toxicity, hypomagnesaemia and neutropenia, and time to treatment failure (TTF) between the two groups. Results Thirty-two patients treated with Pmab and 43 patients treated with Cmab were evaluated. Patient characteristics were similar between the two groups. The incidence of grade 2–3 oral mucositis was significantly higher with Pmab than with Cmab (31.3% vs 9.3%, P

Background This study retrospectively evaluated the clinical outcomes of intramedullary nailing of femoral shaft fractures with third fragments and analyzed the risk factors for delayed union.Methods Retrospective analyses involving 51 patients who underwent intramedullary nailing of femoral shaft fractures with third fragments (AO classification type B, 35 cases; type C, 16 cases) were conducted. Delayed union was defined as either more than 10 months required for callus formation in more than three of the four cortical bone surfaces observed in the frontal and lateral radiographic views or the requirement for additional surgery such as nail conversion or bone transplantation. Seventeen patients developed delayed union (D group). Thirty-four patients achieved bony union within 9 months (U group). The following background variables were compared between groups: age at the time of the injury; AO classification; ratio of open fracture; waiting period before surgery; rate of the infraisthmal fracture; diameter of the intramedullary nail; ratio of the intramedullary nail to the femur; length and displacement of the third fragment; and use of open reduction, poller screws, or dynamization.Results Significant differences were found between the D and U groups for age (32.2±14.1 vs. 25.3±9.6 years), open fracture ratio (35.3% vs. 11.8%), and displacement of the third fragment (13.7±6.4 vs. 9±6.3 mm). Multiple logistic regression analysis only identified displacement of the third fragment as a risk factor for delayed union (p=0.03; OR 1.13; 95% CI 1.01 to 1.26).Discussion Delayed union was observed in 17 cases (33.3%) after intramedullary nailing of femoral shaft fractures with third fragments. Displacement of the third fragment influenced delayed union.Level of evidence Level III.

The electrophysiological properties underlying the automaticity of the guinea pig pulmonary vein myocardium were studied. About 30% of the isolated pulmonary vein tissue preparations showed spontaneous electrical activity, as shown by glass microelectrode recordings from their myocardial layer. The remaining quiescent preparations had a resting membrane potential less negative than that in the left atria. Blockade of the acetylcholine activated potassium current (IK-ACh) by tertiapin induced a depolarizing shift of the resting membrane potential and automatic electrical activity in the pulmonary vein, but not in the atria. The tertiapin-induced electrical activity, as well as the spontaneous activity, was inhibited by the application of carbachol or by chelation of intracellular Ca2+ by BAPTA. The isolated pulmonary vein cardiomyocytes had an IK-ACh density similar to that of the atrial cardiomyocytes, but a lower density of the inwardly-rectifying potassium current (IK1). Spontaneous Ca2+ transients were observed in about 30% of the isolated pulmonary vein cardiomyocytes, but not in atrial cardiomyocytes. The Ca2+ transients in the pulmonary vein cardiomyocytes were induced by tertiapin and inhibited by carbachol. These results indicate that the pulmonary vein cardiomyocytes have a reduced density of the inwardly-rectifying potassium current, which plays a permissive role in their intracellular Ca2+-dependent automaticity.

Necrosis is a form of cell death that results in rupture of the plasma membrane and the release of cellular contents, and it can give rise to sterile inflammation in the retina and other tissues. The secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells contributes to retinal homeostasis as well as to pathological angiogenesis. We have now examined the effect of a necrotic cell lysate prepared from human RPE cells (NLR) on the release of VEGF by healthy RPE cells. We found that NLR markedly increased the release of VEGF from RPE cells and that this effect was attenuated by nintedanib, a multiple receptor tyrosine kinase inhibitor, whereas it was unaffected by inhibitors of NF-κB signaling or of caspase-1. NLR also induced the phosphorylation of extracellular signal-regulated kinase (Erk) and signal transducer and activator of transcription 3 (Stat3) in a manner sensitive to inhibition by nintedanib, although inhibitors of Erk and Stat3 signaling pathways did not affect NLR-induced VEGF secretion. In addition, nintedanib attenuated the development of choroidal neovascularization in mice. Our results have thus shown that a necrotic lysate of RPE cells induced VEGF secretion from healthy RPE cells and that this effect was mediated by receptor tyrosine kinase signaling. They therefore suggest that VEGF secretion by healthy RPE cells is a potential therapeutic target for retinal diseases associated with sterile inflammation and pathological angiogenesis.

We previously showed that dietary omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) suppress inflammation in mice with experimental autoimmune uveitis (EAU). We have now investigated the role of antigen presenting cells (APCs) in this action of ω-3 LCPUFAs. C57BL/6 mice were fed a diet supplemented with ω-3 or ω-6 LCPUFAs for 2 weeks, after which splenocytes were isolated from the mice and cocultured with CD4+ T cells isolated from mice with EAU induced by injection of a human interphotoreceptor retinoid-binding protein peptide together with complete Freund's adjuvant. The proliferation of and production of interferon-γ and interleukin-17 by T cells from EAU mice in vitro were attenuated in the presence of splenocytes from ω-3 LCPUFA-fed mice as compared with those from mice fed ω-6 LCPUFAs. Splenocyte fractionation by magnetic-activated cell sorting revealed that, among APCs, dendritic cells (DCs) were the target of ω-3 LCPUFAs. Adoptive transfer of DCs from mice fed ω-3 LCPUFAs attenuated disease progression in EAU mice as well as the production of pro-inflammatory cytokines by T cells isolated from these latter animals. The proliferation of T cells from control Balb/c mice was also attenuated in the presence of DCs from ω-3 LCPUFA-fed mice as compared with those from ω-6 LCPUFA-fed mice. Furthermore, T cell proliferation in such a mixed lymphocyte reaction was inhibited by prior exposure of DCs from mice fed an ω-6 LCPUFA diet to ω-3 LCPUFAs in vitro. Our results thus suggest that DCs mediate the anti-inflammatory action of dietary ω-3 LCPUFAs in EAU.

The anti-inflammatory properties of TC-2559, an α4β2 nicotinic acetylcholine receptor (nAChR) agonist, on cultured murine macrophages was investigated. TC-2559 suppressed the upregulation of CC-chemokine ligand 3 (CCL3) and interleukin-1β (IL-1β) following lipopolysaccharide (LPS) treatment in J774A.1 cells. TC-2559 inhibited the phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) but not nuclear factor-κB p65 after LPS. Blockade of pSTAT3 by AG490 inhibited the upregulation of CCL3 and IL-1β after LPS. In conclusion, TC-2559-driven α4β2 nAChR signaling suppressed the upregulation of CCL3 and IL-1β by inhibiting pSTAT3 in inflammatory macrophages, resulting in the suppression of neuropathic pain.

Abstract.: We previously reported that nicotine (NIC)-induced analgesia was elicited in part by activation of the endogenous opioid system. Moreover, it is well known that NIC has physical-dependence liability, but its mechanism is unclear. Therefore, we examined whether physical dependence on NIC was mediated by activation of the endogenous opioid system in ICR mice. We evaluated increased serum corticosterone (SCS) as an indicator of NIC withdrawal, as it is a quantitative indicator of naloxone (opioid receptor antagonist, NLX)-precipitated morphine withdrawal in mice. In this study, NLX precipitated an SCS increase in mice receiving repeated NIC, by a dose-dependent mechanism, and correlated with the dose and number of days of repeated NIC administration. When an opioid receptor antagonist (naltrexone) was concomitantly administered with repeated NIC, the NLX-precipitated SCS increase was not elicited. Concomitant administration of the α7 nicotinic acetylcholine receptor (nAChR) antagonist (methyllycaconitine) with repeated NIC, but not the α4β2 nAChR antagonist (dihydro-β-erythroidine), did not elicit an SCS increase by NLX. Thus, a physical dependence on NIC was in part mediated by the activation of the endogenous opioid system, located downstream of α7 nAChR. Keywords:: nicotine, physical dependence, opioid system, corticosterone, α7 nicotinic acetylcholine receptor (nAChR)

Abstract.: Methamphetamine addiction is characterized by drug craving caused by stimulation of the reward system. Because neuroinflammation underlies several neurological disorders, we investigated whether CC-chemokine ligand 2 (CCL2) participates in the methamphetamine dependence using mice. Upregulation of CCL2 but not CC-chemokine receptor 2 (CCR2), a dominant receptor for CCL2, mRNA in both the prefrontal cortex (PFC) and nucleus accumbens (NAC) was observed after methamphetamine (3 mg/kg, s.c.) administration. Using immunohistochemistry, high CCL2 protein levels localized to neurons in the PFC and NAC. In the conditioned place preference (CPP) test, methamphetamine (0.3 – 3 mg/kg, s.c.) induced a CPP, reflecting psychic dependence on methamphetamine, in a dose-dependent manner. The CPP to methamphetamine was attenuated by RS504393 (1 mg/kg, s.c.), a CCR2 antagonist. Moreover, methamphetamine increased phosphorylated tyrosine hydroxylase (pTH) levels in the ventral tegmental area (VTA). Increased levels of pTH in the VTA by methamphetamine was also suppressed by RS504393. Furthermore, intracerebroventricular injection of recombinant CCL2 increased pTH levels in the VTA. Taken together, we demonstrate that activation of dopamine neurons, which enhances reward-system activity, via the CCL2-CCR2 axis plays a crucial role in psychic dependence on methamphetamine. Novel treatments targeting this machinery may be effective for drug addiction. Keywords:: CC-chemokine ligand 2 (CCL2), monocyte chemoattractant protein-1 (MCP-1), chemokine, inflammation, addiction

Abstract.: Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic–pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR. Keywords:: nicotine, antinociception, physical dependence, α7 nAChR, opioid system

Neuropathic pain, which is intolerable and persistent, arises as a direct consequence of a lesion or disease affecting the somatosensory system and can be debilitating for the affected patients. Accumulating evidence from animal studies has revealed the potential molecular basis for neuropathic pain, resulting in many promising therapeutic targets. While efforts at drug discovery have been made, conventional pharmacotherapy, including the use of opioid analgesics, is still insufficient for the relief of neuropathic pain. Therefore, novel target molecules that may lead to the development of promising analgesics are eagerly anticipated for improved treatment of neuropathic pain. In various insults such as sepsis and ischemia, high-mobility group box 1 (HMGB1) is released extracellularly to induce inflammation. HMGB1 was originally identified as a ubiquitous nuclear protein, but emerging evidence has suggested that HMGB1 also plays a role in neuroinflammation as a pro-inflammatory mediator. These findings suggest that HMGB1 may be involved in the pathology of neuropathic pain. In fact, some reports demonstrate an involvement of HMGB1 in the development and maintenance of neuropathic pain in experimental animals. Here, we overview the characteristics of HMGB1 as a pro-inflammatory mediator and show the promise of HMGB1 as a therapeutic target for neuropathic pain. Keywords:: HMGB1, neuropathic pain, neuroinflammation, pro-inflammatory cytokine, nucleokine

BACKGROUND:Middle gastrointestinal bleeding (MGIB) risk has not been fully investigated due to its extremely rare occurrence and the need for multiple endoscopies to exclude upper and lower gastrointestinal bleeding. This study investigated whether MGIB is associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), thienopyridines, anticoagulants, and proton-pump inhibitors (PPIs), and whether PPI use affects the interactions between MGIB and antithrombotic drugs. METHODS:In this multicenter, hospital-based, case-control study, 400 patients underwent upper and lower endoscopy, 80 had acute overt MGIB and 320 had no bleeding and were matched for age and sex as controls (1:4). MGIB was additionally evaluated by capsule and/or double-balloon endoscopy, after excluding upper and lower GI bleeding. Adjusted odds ratios (AOR) for MGIB risk were calculated using conditional logistic regression. To estimate the propensity score, we employed a logistic regression model for PPI use. RESULTS:In patients with MGIB, mean hemoglobin level was 9.4 g/dL, and 28 patients (35%) received blood transfusions. Factors significantly associated with MGIB were chronic kidney disease (p

We recorded the electrical activity from the myocardial layer of isolated mouse pulmonary veins with the glass microelectrode technique. Spontaneous electrical activity was observed in about half of the preparations, which appeared either as constant firing or as repetitive bursts. Noradrenaline enhanced, while acetylcholine reduced, automatic activity. The action potentials evoked in quiescent preparations showed a resting membrane potential less negative than the atria and an extremely rapid early repolarization followed by a late plateau. The present study revealed that the mouse pulmonary vein myocardium shows diverse electrical activity, which is influenced by autonomic neurotransmitters. Keywords:: pulmonary vein myocardium, automaticity, autonomic neurotransmitter

To clarify the role of peroxisome proliferator activated receptor γ (PPARγ) in neuropathic pain, we examined the effect of pioglitazone, a PPARγ agonist, on tactile allodynia and thermal hyperalgesia in a neuropathic pain model. Mice were subjected to partial sciatic nerve ligation (PSL) and given pioglitazone (1 – 25 mg/kg, p.o.) once daily. PPARγ was distributed in the neurons of the dorsal root ganglion and the dorsal horn of the spinal cord and in the adipocytes at the epineurium of the sciatic nerve in naive mice. PSL elicited tactile allodynia and thermal hyperalgesia for two weeks. Administration of pioglitazone for the first week after PSL attenuated thermal hyperalgesia and tactile allodynia, which was dose-dependent and blocked by GW9662 (2 mg/kg, i.p.), a PPARγ antagonist. Administration of pioglitazone for the second week also relieved tactile allodynia, but administration one week before PSL had no effect. A single administration of pioglitazone to mice on day 7 of PSL did not alter tactile allodynia and thermal hyperalgesia. PSL-induced upregulation of tumor necrosis factor-α and interleukin-6, which are essential for neuropathic pain, was suppressed by pioglitazone for the first week. This suggests that pioglitazone alleviates neuropathic pain through attenuation of proinflammatory cytokine upregulation by PPARγ stimulation. Keywords:: interleukin-6 (IL-6), neuropathic pain, partial sciatic nerve ligation, peroxisome proliferator activated receptor γ (PPARγ), tumor necrosis factor-α (TNF-α)

We present a case of carpal tunnel syndrome involving wrist trigger caused by a hypertrophied lumbrical muscle with flexor synovitis. The case was a 40-year-old male heavy manual worker complaining of numbness and pain in the median nerve area. On active flexion of the fingers, snapping was observed at the carpal area, and forceful full grip was impossible. Tinel’s sign was positive and an electromyographic study revealed conduction disturbance of the median nerve at the carpal tunnel. Magnetic resonance imaging revealed edematous lumbrical muscle with synovial proliferation around the flexor tendons. Open carpal tunnel release was performed under local anesthesia. Synovial proliferation of the flexor tendons was found and when flexing the index and middle fingers, the lumbrical muscle was drawn into the carpal tunnel with a triggering phenomenon. After releasing the carpal tunnel, the triggering phenomenon and painful numbness improved.

Dietary consumption has recently been identified as a major environmental source of pro-inflammatory advanced glycation end-products (AGEs) in humans. It is disputed whether dietary AGEs represent a risk to human health. Nε-(carboxymethyl)lysine (CML), a representative AGE compound found in food, has been suggested to make a significant contribution to circulating CML levels. However, recent studies have found that the dietary intake of AGEs is not associated with plasma CML concentrations. We have shown that the serum levels of glyceraldehyde-derived AGEs (Glycer-AGEs), but not hemoglobin A1c, glucose-derived AGEs (Glu-AGEs), or CML, could be used as biomarkers for predicting the progression of atherosclerosis and future cardiovascular events. We also detected the production/accumulation of Glycer-AGEs in normal rats administered Glu-AGE-rich beverages. Therefore, we assessed the concentrations of various AGEs in a total of 1,650 beverages and foods that are commonly consumed in Japan. The concentrations of four kinds of AGEs (Glu-AGEs, fructose-derived AGEs (Fru-AGEs), CML, and Glycer-AGEs) were measured with competitive enzyme-linked immunosorbent assays involving immunoaffinity-purified specific antibodies. The results of the latter assays indicated that Glu-AGEs and Fru-AGEs (especially Glu-AGEs), but not CML or Glycer-AGEs, are present at appreciable levels in beverages and foods that are commonly consumed by Japanese. Glu-AGEs, Fru-AGEs, CML, and Glycer-AGEs exhibited concentrations of ≥85%, 2-12%,

In this paper, we propose a blood pressure calculation and associated measurement method that by using a fiber Bragg grating (FBG) sensor. There are several points at which the pulse can be measured on the surface of the human body, and when a FBG sensor located at any of these points, the pulse wave signal can be measured. The measured waveform is similar to the acceleration pulse wave. The pulse wave signal changes depending on several factors, including whether or not the individual is healthy and/or elderly. The measured pulse wave signal can be used to calculate the blood pressure using a calibration curve, which is constructed by a partial least squares (PLS) regression analysis using a reference blood pressure and the pulse wave signal. In this paper, we focus on the influence of individual differences from calculated blood pressure based on each calibration curve. In our study, the calculated blood pressure from both the individual and overall calibration curves were compared, and our results show that the calculated blood pressure based on the overall calibration curve had a lower measurement accuracy than that based on an individual calibration curve. We also found that the influence of the individual differences on the calculated blood pressure when using the FBG sensor method were very low. Therefore, the FBG sensor method that we developed for measuring the blood pressure was found to be suitable for use by many people.