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Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α 1 adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α 1 adrenoceptors.

Crystalline microporous membranes are promising tools for gas separation because their molecular dimension pores allow us to accurately sieve molecules by size. Recently, microporous hexagonal WO 3 was reported as a new potential membrane material and its membrane was found to enable separation of water from water/acetic acid mixtures. Pore size of hexagonal WO 3 seemed to be also suitable for separation of small gasses; however, its gas permeation properties have not been reported. Additionally, densification of membranes by decreasing intercrystalline gaps are extremely important in gas separation. One effective method to densify polycrystalline membranes is to repeat membrane synthesis, namely multi-stage synthesis. Here, we attempt to prepare dense hexagonal WO 3 membranes on porous tubular supports by multi-stage synthesis and examined their densification and gas permeation properties. Densification was confirmed by permeation of SF 6 (gas molecule larger than pores of hexagonal WO 3 ), and its potential for separating small gasses was considered from single gas permeation of He and He/SF 6 permselectivity. The results indicated that the multi-stage synthesis is effective to densify the membranes and He/SF 6 permselectivity reached 42.8 for three-stage synthesis under modified conditions, implying hexagonal WO 3 is a potential membrane material for small gas separation.

Rationale 5F-AMB is one of the synthetic cannabinoids (SCs) designed to potentiate the ability to activate cannabinoid 1 (CB1) receptors and is abused worldwide. Although inhalation of 5F-AMB elicits serious adverse effects including impaired memory and consciousness, it is not known whether and how 5F-AMB affects the activity of pyramidal neurons in the medial prefrontal cortex (mPFC), a brain region associated with higher functions such as memory and cognition. Objectives In the present study, we examined the effects of 5F-AMB on mPFC layer V (L5) pyramidal neurons using in vitro whole-cell patch-clamp recordings. Results Bath application of 5F-AMB attenuated the frequency but not the amplitude of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs). The attenuating effects of 5F-AMB were abolished by the CB1 receptor antagonist AM251. 5F-AMB also attenuated the frequency of miniature EPSCs and IPSCs recorded in the presence of tetrodotoxin. Moreover, the extent of attenuating effects of 5F-AMB on stimulus-evoked EPSCs was significantly larger than that on evoked IPSCs. Conclusions These findings suggest that 5F-AMB attenuates both excitatory and inhibitory transmission in mPFC L5 pyramidal neurons via the activation of CB1 receptors located in presynaptic terminals. Further, the net impact of 5F-AMB on L5 pyramidal neurons is inhibition due to the change in balance between excitation and inhibition. This inhibitory effect might at least partly contribute to the expression of the adverse effects induced by 5F-AMB inhalation.

Hexagonal tungsten oxide (h-WO3) membrane is a novel candidate for dehydration of acetic acid (CH3COOH)/water mixtures owing to its molecular sieving property and acidic resistance. Meanwhile, c-plane orientation is an important factor for h-WO3 membranes because the pores of h-WO3 run along its c-axis. However, so far, high c-plane orientation has not been successful on tubular substrates. Here, the effect of synthesis conditions of h-WO3 membranes on tubular substrates against c-plane orientation and CH3COOH/water separation performance are investigated. The h-WO3 membranes were prepared by hydrothermal synthesis from a precursor sol containing various amounts of sodium tungstate (Na2WO4) in the presence of tubular substrates with seeds embedded on their outside surface. The seeding method and the amount of Na2WO4 in the precursor sol significantly affected both crystal orientation and densification of the membrane. A precursor sol with appropriate amounts of Na2WO4 was essential to simultaneously satisfy high c-plane orientation and densification of the membrane while excess Na2WO4 drastically decreased the degree of c-plane orientation. A highly c-plane oriented h-WO3 membrane was successfully obtained under the optimized condition, which exhibited a maximum separation factor of 40.0 and a water permeance of 1.53 × 10−7 mol·m−2·s−1·Pa−1 in a 90:10 wt % CH3COOH/water mixture. The water permeance approximately doubled compared to the previous report, possibly owing to the significantly higher degree of c-plane orientation. Furthermore, it was found that its separation ability can be maintained while stored in 90:10 wt % CH3COOH/water mixture with pH < 0 for more than 500 h.

Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α adrenoceptors.

Organic light-emitting diodes (OLEDs) using thermally activated delayed fluorescence (TADF) materials have advantages over OLEDs using conventional fluorescent materials or high-cost phosphorescent materials, including higher efficiency and lower cost. To attain further high device performance, clarifying internal charge states in OLEDs at a microscopic viewpoint is crucial; however, only a few such studies have been performed. Here, we report a microscopic investigation into internal charge states in OLEDs with a TADF material by electron spin resonance (ESR) at a molecular level. We observed operando ESR signals of the OLEDs and identified their origins due to a hole-transport material PEDOT:PSS, gap states at an electron-injection layer, and a host material CBP in the light-emitting layer by performing density functional theory calculation and studying thin films used in the OLEDs. The ESR intensity varied with increasing applied bias before and after the light emission. We find leakage electrons in the OLED at a molecular level, which is suppressed by a further electron-blocking layer MoO 3 between the PEDOT:PSS and light-emitting layer, resulting in the enhancement of luminance with a low-voltage drive. Such microscopic information and applying our method to other OLEDs will further improve the OLED performance from the microscopic viewpoint.

Background Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified. Methods A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline. Results Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p  < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p  = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period. Conclusions The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline. Trial registration UMIN000019024.

Anxiety and depression in rehabilitation patients can adversely impact clinical outcomes. They may have anxieties about the differences in their physical conditions and living environments compared to before hospitalization. Although medical staff address patients' anxieties, the content of anxieties and the type of intervention have not been clarified. This study aimed to highlight the contents of anxieties and interventions for patients undergoing rehabilitation, based on medical staff's perspectives. Seventeen medical staff were interviewed about the anxieties they perceived patients experience at the convalescent rehabilitation ward (early, middle, and late phases of hospitalization) and the corresponding interventions. Text mining and hierarchical cluster analysis were used to classify the contents of anxieties and interventions. This study was conducted based on the consolidated criteria for reporting qualitative research. Patients' anxieties were classified into six clusters. Among the clusters, prospects for rehabilitation plans, hospital life (e.g., unfamiliar hospital environment), and family situation (e.g., concerns about family life at home) were identified in the early to middle phases, and life at home after discharge was identified in the late phase. The prognosis of physical function and prospects of social life (e.g., return to work) were identified throughout all phases. The types of interventions for these anxieties were classified into eight clusters. The medical staff provided information about patients' prospects and helped them contact family members in the early phase. In the middle phase, feedback on patients' improvement in physical function was incorporated. In the late phase, information on social resources was provided to address anxieties about life after discharge. This study showed that patients' anxiety and interventions varied according to hospitalization phases. The findings underscore appropriate ways and the timing of interventions to keep patients in a better psychological state, potentially leading to better rehabilitation outcomes.

Acute leukemia is typically diagnosed from presenting features related to hematological symptoms, but certain patients present with prominent musculoskeletal pain without signs of hematological abnormality. We reviewed the medical records of 58 children diagnosed with acute lymphoblastic leukemia (ALL) at our hospital to evaluate initial features. Forty six of these patients had hematological symptoms, anemia, or hemorrhage (Group H), while 12 patients had prominent musculoskeletal pain without hematological symptoms (Group P). Diagnosis of leukemia took significantly more time for those 12 patients (Group H, 17.1 days; Group P, 48.5 days). In three of the 12 patients in Group P, localized abnormal imaging findings and unremarkable blood test results led to initial diagnoses of chronic recurrent multifocal osteomyelitis, bone fracture, and septic osteomyelitis. However, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) revealed multiple intense bone foci or systemic bone marrow uptake, leading to the diagnosis of ALL. A review of 18F-FDG-PET results from 23 patients with ALL who underwent a PET scan (Group H, n = 15; Group P, n = 8) showed multiple bone foci or systemic bone marrow uptake in all cases. In conclusion, lack of hematological symptoms in ALL patients can delay diagnosis, and 18F-FDG-PET is useful for diagnosing leukemia in such cases.

Aims/hypothesis Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. Methods Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. Results Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl 3 . Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. Conclusions/interpretation These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR. Graphical Abstract