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Reactive microglia are suggested to be involved in neurological disorders, and the mechanisms underlying microglial activity may provide insights into therapeutic strategies for neurological diseases. Microglia produce immunological responses to various stimuli, which include fractalkine (FKN or CX3CL1). CX3CR1, a FKN receptor, is present in microglial cells, and when FKN is applied before lipopolysaccharide (LPS) administration, LPS-induced inflammatory responses are inhibited, suggesting that the activation of the FKN signal is beneficial. Considering the practical administration for treatment, we investigated the influence of FKN on immunoreactive microglia using murine primary microglia and BV-2, a microglial cell line. The administration of LPS leads to nitric oxide (NO) production. NO was reduced when FKN was administered 4 h after LPS administration without a change in inducible nitric oxide synthase expression. In contrast, morphological changes, migratory activity, and proliferation were not altered by delayed FKN treatment. LPS decreases the CX3CR1 mRNA concentration, and the overexpression of CX3CR1 restores the FKN-mediated decrease in NO. CX3CR1 overexpression decreased the NO production that is mediated by LPS even without the application of FKN. ATP and ethanol also reduced CX3CR1 mRNA concentrations. In conclusion, the delayed FKN administration modified the LPS-induced microglial activation. The FKN signals were attenuated by a reduction in CX3CR1 by some inflammatory stimuli, and this modulated the inflammatory response of microglial cells, at least partially.

Low-voltage areas (LVAs) in the left atrium may promote atrial fibrillation (AF), but the efficacy of LVA ablation for preventing arrhythmia has not been determined. In the present study, we carried out a multicenter, randomized controlled trial (SUPPRESS-AF) to investigate the efficacy of LVA ablation in patients with persistent AF who had left atrial LVAs. Patients with persistent AF and left atrial LVAs that covered ≥5 cm 2 of the left atrial surface on a voltage map after pulmonary vein isolation (PVI) were randomized to undergo LVA ablation (PVI + LVA-ABL group) or not (PVI-alone group) in a 1:1 fashion. Recurrence of AF or atrial tachycardia (AT) was monitored using 24-h Holter electrocardiography (ECG) and twice-daily portable ECG recordings. The primary endpoint was freedom from AF or AT recurrence without antiarrhythmic drug use during 1 year of follow-up. Of 1,347 patients (1,003 males and 344 females) who underwent initial ablation for AF, patients with left atrial LVAs were assigned to the PVI + LVA-ABL ( n  = 170) or the PVI-alone group ( n  = 171). Although the PVI + LVA-ABL group demonstrated a numerically higher rate of freedom from AF or AT recurrence compared with the PVI-alone group (61% (95% confidence interval (CI) = 53–68%) versus 50% (95% CI = 42–57%)), this difference did not reach statistical significance ( P for log(rank) test = 0.127). There was no difference in the procedure-related serious adverse events between the two groups (1.7% versus 1.8%, P  < 0.0001). In conclusion, LVA ablation in addition to PVI did not significantly reduce 1-year AF or AT recurrence in patients with persistent AF with left atrial LVAs. Future studies are needed to identify patients who may receive greater benefit from LVA ablation. In view of previous work suggesting that low-voltage areas may promote atrial fibrillation, a multicenter, randomized controlled trial tested the hypothesis that ablation of low-voltage areas in addition to pulmonary vein isolation might reduce the recurrence of atrial arrhythmic events, but found no significant benefit to the combined procedure.

Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.

Perinatal mental health is a major public health concern. Epidemiological studies indicate that approximately 10–20% of women in the postpartum period experience clinically significant depressive or obsessive-compulsive symptoms. Many postpartum symptoms involve heightened vigilance and behaviors aimed at protecting the infant from possible harm, suggesting the presence of offspring-centered defensive processes. One offspring-centered defensive behavior described in wild rats is entrance-sealing, in which lactating females plug the entrance of their burrow to limit access by potential intruders. Although laboratory mice rarely exhibit such behavior spontaneously, similar bedding-plugging behavior has been occasionally observed, suggesting that mice retain the capacity for this response. However, no method has existed for reliably quantifying such behavior under controlled laboratory conditions. To address this gap, we developed the Tube-Plugging Test (TPT), an assay that measures bedding accumulated at tube-like openings attached to the home cage and enables repeated, non-invasive quantification of plugging behavior. Using this approach, we found that tube plugging occurred rarely in males, intermittently in virgin females, and most robustly in postpartum females. Notably, plugging behavior exhibited substantial inter-individual variability, but was more temporally stable across days in postpartum females than in virgin females. In postpartum females, exposure to a male intruder altered plugging behavior at the tube through which the intruder was introduced, suggesting that plugging is modulated by direct social context. Together, these findings establish the TPT as a simple and reproducible method for quantifying plugging behavior and identify tube plugging as a measurable component of offspring-centered defensive behavior.

Thrombus formation is a troublesome and sometimes lethal complication occurring in patients with severe heart failure and supported by a left ventricular assist device (LVAD). Appropriate treatment for pump thrombosis especially in emergency cases with severe pump failure is difficult to choose. Herein, we present important findings of a case of unexpected LVAD pump thrombosis that rapidly developed into serious pump failure and circulatory arrest due to total obstruction of the LVAD inflow tract by a huge thrombus.

Modern western dietary habits and low physical activity cause metabolic abnormalities and abnormally elevated levels of metabolites such as low-density lipoprotein, which can lead to immune cell activation, and inflammatory reactions, and atherosclerosis. Appropriate stimulation of vascular endothelial cells can confer protective responses against inflammatory reactions and atherosclerotic conditions. This study aims to determine whether a designed optogenetic approach is capable of affecting functional changes in vascular endothelial cells and to evaluate its potential for therapeutic regulation of vascular inflammatory responses in vitro . We employed a genetically engineered, blue light-activated Ca 2+ channel switch molecule that utilizes an endogenous store-operated calcium entry system and induces intracellular Ca 2+ influx through blue light irradiation and observed an increase in intracellular Ca 2+ in vascular endothelial cells. Ca 2+ -dependent activation of the nuclear factor of activated T cells and nitric oxide production were also detected. Microarray analysis of Ca 2+ -induced changes in vascular endothelial cells explored several genes involved in cellular contractility and inflammatory responses. Indeed, there was an increase in the gene expression of molecules related to anti-inflammatory and vasorelaxant effects. Thus, a combination of human blue light-activated Ca 2+ channel switch 2 (hBACCS2) and blue light possibly attenuates TNFα-induced inflammatory NF-κB activity. We propose that extrinsic cellular Ca 2+ regulation could be a novel approach against vascular inflammation.

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na+-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity.

SummaryBackground This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW.Trial registration: NCT02836600 (ClinicalTrials.gov) registered on July 19, 2016.

Chronic stress can impair the health of human brains. An important strategy that may prevent the accumulation of stress may be the consumption of functional foods. When senescence-accelerated mice prone 10 (SAMP10), a stress-sensitive strain, were loaded with stress using imposed male mouse territoriality, brain volume decreased. However, in mice that ingested theanine (6 mg/kg), the main amino acid in tea leaves, brain atrophy was suppressed, even under stress. On the other hand, brain atrophy was not clearly observed in a mouse strain that aged normally (Slc:ddY). The expression level of the transcription factor Npas4 (neuronal PAS domain protein 4), which regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity, decreased in the hippocampus and prefrontal cortex of stressed SAMP10 mice, but increased in mice that ingested theanine. Lipocalin 2 (Lcn2), the expression of which increased in response to stress, was significantly high in the hippocampus and prefrontal cortex of stressed SAMP10 mice, but not in mice that ingested theanine. These data suggest that Npas4 and Lcn2 are involved in the brain atrophy and stress vulnerability of SAMP10 mice, which are prevented by the consumption of theanine, causing changes in the expression of these genes.

Background Pulmonary vein (PV) reconnection is the main cause of atrial fibrillation (AF) recurrence. This study aimed to examine the effect of first‐pass PV isolation (PVI) on PV reconnection frequency during the procedure and on AF ablation outcomes. Methods This retrospective study included 446 patients with drug‐refractory AF (370 men, aged 64 ± 10 years) who underwent initial PVI using an open‐irrigated contact force catheter between January 2015 and October 2016. We investigated the effect of first‐pass PVI on PV reconnection during spontaneous PV reconnection and dormant conduction after an adenosine triphosphate challenge. Results First‐pass PVI was achieved in 69% (617/892) of ipsilateral PVs, of which we observed PV reconnection during the procedure in 134 (22%) PVs. This value was significantly lower than that observed in those without first‐pass PVI (50%, 138/275) (P < .0001). We divided the subjects into two groups based on the presence or absence of first‐pass PVI in at least one of two ipsilateral PVs: first‐pass (n = 383, 86%) and non‐first‐pass groups (n = 63, 14%). The 2‐year AF recurrence‐free rate was significantly higher in the first‐pass group than in the other group (75% vs 59%, log‐rank P = .032). In 78 patients with repeat AF ablation, the PV reconnection rate in the second procedure was significantly lower in PVs that had first‐pass isolation in the first procedure (34% vs 73%, P < .0001). Conclusions Absence of first‐pass PVI was associated with a higher frequency of spontaneous PV reconnection and dormant conduction and poor ablation outcomes. First‐pass isolation may be a useful marker for better PVI durability. The 2‐year AF recurrence‐free rate was significantly higher in the first‐pass group than in the other group (75% vs. 59%, log‐rank P = 0.032). Absence of first‐pass PVI was associated with a higher frequency of spontaneous PV reconnection and dormant conduction and poor ablation outcomes. First‐pass isolation may be a useful marker for better PVI durability.