Assessing the ability of the Cancer and Aging Research Group tool to predict chemotherapy toxicity in older Japanese patients: A prospective observational study.

INTRODUCTION: The Cancer and Aging Research Group (CARG) prediction tool was designed in the United States to predict grade ≥ 3 chemotherapy-related adverse events (CRAE) in older patients. However, its usefulness among Japanese people, who have different sensitivities to anticancer drugs and life expectancy, remains unknown. We aimed to prospectively evaluate the utility of the CARG tool for predicting severe CRAE in older Japanese patients with cancer. MATERIAL AND METHODS: Patients with solid tumors aged 65 years and older who commenced anticancer drug regimens from April 2018 to October 2020 were divided into three groups (low, medium, and high-risk) based on their CARG risk scores. Toxicity was prospectively observed by a pharmacist. The primary objective was to evaluate the correlation between the incidence of grade ≥ 3 CRAE and the CARG risk score. The secondary objective was to evaluate hematological and non-hematological toxicities. CRAE incidence was compared among the three groups using a closed testing procedure: (1) Cochran-Armitage test for trend and (2) chi-square test for paired comparison. RESULTS: The patients (N = 165) had a median age of 71 years (range: 65-89 years). CRAE in patients divided into low-, medium-, and high-risk groups, based on CARG risk scores, were 39%, 55%, and 82%, respectively (low vs high; p < 0.001, medium vs high; p < 0.01). The incidence of severe hematologic toxicity was 37%, 35%, and 50% in the low-, medium-, and high-risk groups, respectively; the incidence of severe non-hematologic toxicity was 15%, 36%, and 65%, respectively (low vs medium; p < 0.01, low vs high; p < 0.001, and medium vs high; p < 0.01). DISCUSSION: To our knowledge, this is the first prospective observational study to validate the CARG prediction tool in older Japanese patients with cancer. The CARG risk score may be effective in predicting the development of non-hematologic toxicities. These results should be considered when administering chemotherapy to older Japanese patients with advanced solid tumors.

[Early to Long-term Results of Left Atrial Appendage Closure Using Clip Device in Patients with Atrial Fibrillation].

Oral anticoagulants for atrial fibrillation are the standard approach to prevent stroke in patients with atrial fibrillation. However, oral anticoagulant therapy carries the risk of cerebral infarction recurrence, not to mention hemorrhagic complications, even under appropriate drug therapy. Surgical treatments targeting the left atrial appendage include left atrial appendage closure( LAAO) and left atrial appendage resection (LAAR). Our hospital uses AtriClip (approved and available in Japan since 2018) as a device for LAAO, and we investigated the early and long-term results of LAAO using AtriClip in our hospital. As a result, stable early to long-term results were expected for left atrial appendage closure using AtriClip device, suggesting that it may be an option that can be considered as a method for preventing stroke in patients with atrial fibrillation. But further investigation is required in the future.

Incidence of Acute Thrombosis After Surgical Left Atrial Appendage Occlusion for Atrial Fibrillation.

BACKGROUND: The clinical implications of acute phase thrombosis after surgical left atrial appendage (LAA) closure remain unclear. This study sought to determine the frequency, prognosis, and factors involved in thrombogenesis after surgical LAA occlusion. METHODS: In this study, data from patients who underwent 2 types of standalone surgical LAA closure (either resection or clipping) between July 2014 and March 2020 at a single center were analyzed. RESULTS: A total of 239 consecutive patients with atrial fibrillation underwent minimally invasive standalone surgical LAA occlusion (184 resection cases and 55 clipping cases). On postoperative day 2, electrocardiogram synchronized contrast-enhanced computed tomography (CT) was performed in 223 cases (93.3%), and echocardiography follow-up was performed in 16 cases when CT was contraindicated. Acute postoperative thrombus on the closed stump was detected in 35 cases (14.7%), of which 29 cases (15.8%) belonged to the resection group and 6 cases (10.9%) belonged to the clipping group. No significant difference was detected between the groups, and no significant predictors of acute-phase thrombosis were found. Thromboembolism occurred in 4 patients before postoperative imaging follow-up, and there was no evidence of thrombi in these patients on postoperative day 2 CT. Three months after the first CT, thrombi were no longer detected in 34 of 35 patients (97.1%). CONCLUSIONS: Thrombosis can occur after surgical LAA occlusion. Although the clinical significance is yet unclear, it may be reasonable to continue anticoagulation therapy until a lack of thrombosis is confirmed, unless there are contraindications.

Characterization of CD90/Thy-1 as a crucial molecular signature for myogenic differentiation in human urine-derived cells through single-cell RNA sequencing.

Human urine-derived cells (UDCs) are primary cultured cells originating from the upper urinary tract and are known to be multipotent. We previously developed MYOD1-transduced UDCs (MYOD1-UDCs) as a model recapitulating the pathogenesis of Duchenne muscular dystrophy (DMD) caused by a lack of dystrophin. MYOD1-UDCs also allow evaluation of the efficacy of exon skipping with antisense oligonucleotides. However, despite the introduction of MYOD1, some MYOD1-UDCs failed to form myotubes, possibly because of heterogeneity among UDCs. Here, we carried out single-cell RNA-sequencing analyses and revealed that CD90/Thy-1 was highly expressed in a limited subpopulation of UDCs with high myogenic potency. Furthermore, CD90-positive MYOD1-UDCs, but not CD90-negative cells, could form myotubes expressing high levels of myosin heavy chain and dystrophin. Notably, overexpression of CD90 in CD90-negative MYOD1-UDCs did not enhance myogenic differentiation, whereas CD90 suppression in CD90-positive UDCs led to decreased myotube formation and decreased myosin heavy chain expression. CD90 may thus contribute to the fusion of single-nucleated MYOD1-UDCs into myotubes but is not crucial for promoting the expression of late muscle regulatory factors. Finally, we confirmed that CD90-positive MYOD1-UDCs derived from patients with DMD were a valuable tool for obtaining a highly reproducible and stable evaluation of exon skipping using antisense oligonucleotide.

A comparison between stand-alone left atrial appendage occlusion and resection as a method of preventing cardiogenic thromboembolic stroke.

OBJECTIVE: The present study evaluated the differences between left atrial appendage occlusion (LAAO) and left atrial appendage resection (LAAR) in terms of the safety and efficacy. MATERIALS AND METHODS: From January 2018 to August 2022, 94 patients underwent a stand-alone LAAO, and 90 patients underwent stand-alone LAAR in our institution. All of these patients were included in this study. LAAO was performed via left mini-thoracotomy, and LAAR was performed via a left thoracoscopic approach. The patients' characteristics and perioperative and postoperative data were obtained by retrospectively reviewing their medical records. RESULTS: The mean age of the patients was 72.4 ± 10.2 (LAAO) and 66.2 ± 9.4 (LAAR) years old (P < 0.05). There were no marked differences in the mean duration of atrial fibrillation (AF) or the ratio of AF type between both groups. The average CHA2DS2-Vasc scores were 4.4 ± 1.6 (LAAO) and 2.7 ± 1.8 (LAAR) (P < 0.05), and the average HAS-BLED scores were 2.9 ± 1.0 (LAAO) and 2.2 ± 1.2 (LAAR) (P < 0.05). The mean operation time was 49 ± 20 min (LAAO) and 34 ± 15 min (LAAR) (P < 0.05). No substantial gaps were detected in preoperative echo-graphic findings between the groups. No significant differences were observed in the amount of intraoperative or postoperative bleeding or the rate of intraoperative massive bleeding events between the groups. Successful LAA closure was achieved in all cases in both groups. Approximately 50% of patients underwent concomitant left pulmonary vein isolation (LPVI) during surgery, indicating no significant differences between the groups (P = 0.872). The early mortality rate was 1.04% in the LAAO group and 0% in the LAAR group (P = 0.132). There was no significant difference in the rate of postoperative LAA stump thrombus between the groups (8.5% in the LAAO group and 6.7% in the LAAR group; P = 0.320). The mean follow-up period was 851 ± 500 (6-1618) days in the LAAO group and 1208 ± 357 (49-1694) days in the LAAR group. Postoperative stroke events were detected in 1 patient in each group (P = 0.432). There was no significant difference in the sinus rhythm recovery rate after LPVI between these groups (31.1% in the LAAO group and 28.6% in the LAAR group; P = 0.763). CONCLUSION: There were no significant differences between LAAO and LAAR in terms of the feasibility and the effectiveness as a method for stroke prophylaxis only to selected patients for both procedures, although further studies including the comparison between groups with the same backgrounds to confirm the authentic differences in the clinical results between these procedures.

Spontaneous and multifaceted ATP release from astrocytes at the scale of hundreds of synapses.

Astrocytes participate in information processing by releasing neuroactive substances termed gliotransmitters, including ATP. Individual astrocytes come into contact with thousands of synapses with their ramified structure, but the spatiotemporal dynamics of ATP gliotransmission remains unclear, especially in physiological brain tissue. Using a genetically encoded fluorescent sensor, GRABATP1.0 , we discovered that extracellular ATP increased locally and transiently in absence of stimuli in neuron-glia co-cultures, cortical slices, and the anesthetized mouse brain. Spontaneous ATP release events were tetrodotoxin-insensitive but suppressed by gliotoxin, fluorocitrate, and typically spread over 50-250 µm2 area at concentrations capable of activating purinergic receptors. Besides, most ATP events did not coincide with Ca2+ transients, and intracellular Ca2+ buffering with BAPTA-AM did not affect ATP event frequency. Clustering analysis revealed that these events followed multiple distinct kinetics, and blockade of exocytosis only decreased a minor group of slow events. Overall, astrocytes spontaneously release ATP through multiple mechanisms, mainly in non-vesicular and Ca2+ -independent manners, thus potentially regulating hundreds of synapses all together.

Cholesterol-load evokes robust calcium response in macrophages: An early event toward cholesterol-induced macrophage death.

Macrophages in atherosclerotic lesions accumulate large amounts of unesterified cholesterol. Excess cholesterol load leads to cell death of macrophages, which is associated with the progression of atherosclerotic lesions. Calcium depletion in the endoplasmic reticulum (ER) and subsequent pro-apoptotic aberrant calcium signaling are key events in cholesterol-induced macrophage death. Although these concepts imply cytoplasmic calcium events in cholesterol-loaded macrophages, the mechanisms linking cholesterol accumulation to cytoplasmic calcium response have been poorly investigated. Based on our previous finding that extracellularly applied cholesterol evoked robust calcium oscillations in astrocytes, a type of glial cells in the brain, we hypothesized that cholesterol accumulation in macrophages triggers cytoplasmic calcium elevation. Here, we showed that cholesterol application induces calcium transients in THP-1-derived and peritoneal macrophages. Inhibition of inositol 1,4,5-trisphosphate receptors (IP3Rs) and l-type calcium channels (LTCCs) prevented cholesterol-induced calcium transients and ameliorated cholesterol-induced macrophage death. These results suggest that cholesterol-induced calcium transients through IP3Rs and LTCCs are crucial mechanisms underlying cholesterol-induced cell death of macrophages.

Aortic Remodeling After Stepwise External Wrapping for Type A Acute Aortic Dissection.

BACKGROUND: The optimal repair technique for type A acute aortic dissection is graft replacement; however, the treatment approach in high-risk patients remains controversial or suboptimal. METHODS: We have retrospectively analyzed a cohort of high-risk patients who were admitted to our center for type A acute aortic dissection and who were treated by a new surgical approach using artificial grafts (stepwise external wrapping) between January 2016 and January 2020. The primary endpoints included inhospital mortality and survival during follow-up. Secondary endpoints included the assessment of aortic remodeling after ascending aorta wrapping. RESULTS: Among the 134 patients admitted for type A acute aortic dissection, 43 patients underwent stepwise external wrapping. The mean patient age was 79.1 ± 6.8 years. The new standard European System for Cardiac Operative Risk Evaluation score was 64% ± 12%. There was one hospital death (2.3%). There were two major complications of persistent cerebral disorder (4.6%). Minor complications included temporary neurologic disorder (2.3%) and renal failure (2.3%). The intensive care unit and hospital stays were 2.8 ± 1.0 days and 11.7 ± 2.5 days, respectively. The follow-up survival rate was 95.3% ± 6.2% and 91% ± 10.2% at 1 and 3 years, respectively, after surgery. There was no aortic-related death during follow-up. At 1 year after surgery, complete remodeling of the ascending aorta was obtained in 30 patients (85.7%), and 5 patients (14.3%) showed partial remodeling. CONCLUSIONS: Our stepwise external wrapping technique was associated with excellent outcomes for high-risk patients with type A acute aortic dissection.

Cholesterol-induced robust Ca oscillation in astrocytes required for survival and lipid droplet formation in high-cholesterol condition.

Cholesterol, one of the major cell membrane components, stabilizes membrane fluidity and regulates signal transduction. Beside its canonical roles, cholesterol has been reported to directly activate signaling pathways such as hedgehog (Hh). We recently found that astrocytes, one of the glial cells, respond to Hh pathway stimulation by Ca signaling. These notions led us to test if extracellularly applied cholesterol triggers Ca signaling in astrocytes. Here, we found that cholesterol application induces robust Ca oscillation only in astrocytes with different properties from the Hh-induced Ca response. The Ca oscillation has a long delay which corresponds to the onset of cholesterol accumulation in the plasma membrane. Blockade of the Ca oscillation resulted in enhancement of astrocytic cell death and disturbance of lipid droplet formation, implying a possibility that the cholesterol-induced Ca oscillation plays important roles in astrocytic survival and cholesterol handling under pathological conditions of cholesterol load such as demyelination.

Impact of the Cardioplegia Interval on Myocardial Protection Using the Modified St. Thomas Solution in Minimally Invasive Mitral Valve Surgery: A Double-Center Study.

It has been reported that a single-dose cardioplegia interval is useful, but the safe interval doses are not clear. We aimed to investigate the impact of the cardioplegia interval on myocardial protection using the modified St. Thomas solution. We included consecutive isolated minimally invasive mitral valvuloplasty procedures (n = 229) performed at a hospital and medical center from January 2014 to December 2020. We compared postoperative peak creatine kinase MB and creatine kinase levels and other indicators between the short (Group S, n = 135; maximum myocardial protection interval <60 minutes) and long (Group L, n = 94; maximum myocardial protection interval ≥60 minutes) interval groups. Propensity score matching was used to adjust for confounders between the two groups. After propensity score matching, Groups S and L contained 47 patients each. Groups S and L did not differ significantly in peak creatine kinase MB (45.8 ± 26.3 IU/L and 41.5 ± 27.9 IU/L, respectively; p = .441) and creatine kinase levels (1,133 ± 567 IU/L and 1,100 ± 916 IU/L, respectively; p = .837) after admission to the intensive care unit on the day of surgery based on propensity score matching. In multivariate analysis, a cardioplegia dosing interval ≥60 minutes was not significantly associated with the maximum creatine kinase MB level after admission to the intensive care unit on the day of surgery (p = .354; 95% confidence interval: -1.67 to 4.65). Using the antegrade modified St. Thomas solution, the long interval dose method is useful and safe in minimally invasive mitral valvuloplasty.

Involvement of Cdk5 activating subunit p35 in synaptic plasticity in excitatory and inhibitory neurons.

Cyclin-dependent kinase 5 (Cdk5) /p35 is involved in many developmental processes of the central nervous system. Cdk5/p35 is also implicated in synaptic plasticity, learning and memory. Several lines of conditional Cdk5 knockout mice (KO) have been generated and have shown different outcomes for learning and memory. Here, we present our analysis of p35 conditional KO mice (p35cKO) in hippocampal pyramidal neurons or forebrain GABAergic neurons using electrophysiological and behavioral methods. In the fear conditioning task, CamKII-p35cKO mice showed impaired memory retention. Furthermore, NMDAR-dependent long-term depression (LTD) induction by low-frequency stimuli in hippocampal slices from CamkII-p35cKO mice was impaired compared to that in control mice. In contrast, Dlx-p35cKO mice showed no abnormalities in behavioral tasks and electrophysiological analysis in their hippocampal slices. These results indicated that Cdk5/p35 in excitatory neurons is important for the hippocampal synaptic plasticity and associative memory retention.

Development and internal validation of a clinical prediction model for acute adjacent vertebral fracture after vertebral augmentation : the AVA score.

AIMS: To develop and internally validate a preoperative clinical prediction model for acute adjacent vertebral fracture (AVF) after vertebral augmentation to support preoperative decision-making, named the after vertebral augmentation (AVA) score. METHODS: In this prognostic study, a multicentre, retrospective single-level vertebral augmentation cohort of 377 patients from six Japanese hospitals was used to derive an AVF prediction model. Backward stepwise selection (p < 0.05) was used to select preoperative clinical and imaging predictors for acute AVF after vertebral augmentation for up to one month, from 14 predictors. We assigned a score to each selected variable based on the regression coefficient and developed the AVA scoring system. We evaluated sensitivity and specificity for each cut-off, area under the curve (AUC), and calibration as diagnostic performance. Internal validation was conducted using bootstrapping to correct the optimism. RESULTS: Of the 377 patients used for model derivation, 58 (15%) had an acute AVF postoperatively. The following preoperative measures on multivariable analysis were summarized in the five-point AVA score: intravertebral instability (≥ 5 mm), focal kyphosis (≥ 10°), duration of symptoms (≥ 30 days), intravertebral cleft, and previous history of vertebral fracture. Internal validation showed a mean optimism of 0.019 with a corrected AUC of 0.77. A cut-off of ≤ one point was chosen to classify a low risk of AVF, for which only four of 137 patients (3%) had AVF with 92.5% sensitivity and 45.6% specificity. A cut-off of ≥ four points was chosen to classify a high risk of AVF, for which 22 of 38 (58%) had AVF with 41.5% sensitivity and 94.5% specificity. CONCLUSION: In this study, the AVA score was found to be a simple preoperative method for the identification of patients at low and high risk of postoperative acute AVF. This model could be applied to individual patients and could aid in the decision-making before vertebral augmentation. Cite this article: Bone Joint J 2022;104-B(1):97-102.

Stepwise external wrapping procedure for type A intramural hematoma.

BACKGROUND: The optimal treatment for Stanford type A acute intramural hematoma remains controversial, especially in elderly or high-risk patients. METHODS: We have developed a new surgical approach using artificial grafts (stepwise external wrapping) for high-risk patients. The aim of this study is to report our results using the stepwise external wrapping procedure in the treatment of high-risk patients with type A intramural hematoma. Among the 129 patients admitted for type A intramural hematoma between January 2016 and January 2020, 49 patients underwent stepwise external wrapping. The mean patient age was 78 ± 7 years. The new standard European system for cardiac operative risk evaluation II was 54% ± 23%. The mean overall operation and cardiopulmonary bypass times were 96 ± 13 minutes and 35 ± 10 minutes, respectively. RESULTS: There were no hospital deaths. Two cases of temporary neurologic disorder, 1 case of renal failure, and 2 cases of wound infection occurred during the postoperative period. The intensive care unit and hospital stays were 2 ± 1 days and 10 ± 3 days, respectively. The thickness of intramural hematoma that had been the target of the stepwise external wrapping procedure decreased significantly from 18.0 ± 10.7 mm preoperatively to 5.2 ± 4.4 mm at 3 months after surgery (P < .05). The follow-up survival was 97.7% ± 4.4 % at 1 year after surgery and 89.8% ± 11.4% at 3 years after surgery. There was no aortic-related death during follow-up. CONCLUSIONS: Our stepwise external wrapping is a feasible alternative to conventional graft replacement for high-risk patients with type A intramural hematoma. The early and midterm outcomes of the procedure were satisfactory, but further careful follow-up is needed.

Requirement of CRMP2 Phosphorylation in Neuronal Migration of Developing Mouse Cerebral Cortex and Hippocampus and Redundant Roles of CRMP1 and CRMP4.

The mammalian cerebral cortex is characterized by a 6-layer structure, and proper neuronal migration is critical for its formation. Cyclin-dependent kinase 5 (Cdk5) has been shown to be a critical kinase for neuronal migration. Several Cdk5 substrates have been suggested to be involved in ordered neuronal migration. However, in vivo loss-of-function studies on the function of Cdk5 phosphorylation substrates in neuronal migration in the developing cerebral cortex have not been reported. In this study, we demonstrated that Cdk5-mediated phosphorylation of collapsing mediator protein (CRMP) 2 is critical for neuronal migration in the developing cerebral cortex with redundant functions of CRMP1 and CRMP4. The cerebral cortices of triple-mutant CRMP1 knock-out (KO); CRMP2 knock-in (KI)/KI; and CRMP4 KO mice showed disturbed positioning of layers II-V neurons in the cerebral cortex. Further experiments using bromodeoxyuridine birthdate-labeling and in utero electroporation implicated radial migration defects in cortical neurons. Ectopic neurons were detected around the CA1 region and dentate gyrus in CRMP1 KO; CRMP2 KI/KI; and CRMP4 KO mice. These results suggest the importance of CRMP2 phosphorylation by Cdk5 and redundancy of CRMP1 and CRMP4 in proper neuronal migration in the developing cerebral cortex and hippocampus.

Lateralization of CA1 assemblies in the absence of CA3 input.

In the hippocampal circuit CA3 input plays a critical role in the organization of CA1 population activity, both during learning and sleep. While integrated spatial representations have been observed across the two hemispheres of CA1, these regions lack direct connectivity and thus the circuitry responsible remains largely unexplored. Here we investigate the role of CA3 in organizing bilateral CA1 activity by blocking synaptic transmission at CA3 terminals through the inducible transgenic expression of tetanus toxin. Although the properties of single place cells in CA1 were comparable bilaterally, we find a decrease of ripple synchronization between left and right CA1 after silencing CA3. Further, during both exploration and rest, CA1 neuronal ensemble activity is less coordinated across hemispheres. This included degradation of the replay of previously explored spatial paths in CA1 during rest, consistent with the idea that CA3 bilateral projections integrate activity between left and right hemispheres and orchestrate bilateral hippocampal coding.

Notch Signaling between Cerebellar Granule Cell Progenitors.

Cerebellar granule cells (GCs) are cells which comprise over 50% of the neurons in the entire nervous system. GCs enable the cerebellum to properly regulate motor coordination, learning, and consolidation, in addition to cognition, emotion and language. During GC development, maternal GC progenitors (GCPs) divide to produce not only postmitotic GCs but also sister GCPs. However, the molecular machinery for regulating the proportional production of distinct sister cell types from seemingly uniform GCPs is not yet fully understood. Here we report that Notch signaling creates a distinction between GCPs and leads to their proportional differentiation in mice. Among Notch-related molecules, Notch1, Notch2, Jag1, and Hes1 are prominently expressed in GCPs. In vivo monitoring of Hes1-promoter activities showed the presence of two types of GCPs, Notch-signaling ON and OFF, in the external granule layer (EGL). Single-cell RNA sequencing (scRNA-seq) and in silico analyses indicate that ON-GCPs have more proliferative and immature properties, while OFF-GCPs have opposite characteristics. Overexpression as well as knock-down (KD) experiments using in vivo electroporation showed that NOTCH2 and HES1 are involved cell-autonomously to suppress GCP differentiation by inhibiting NEUROD1 expression. In contrast, JAG1-expressing cells non-autonomously upregulated Notch signaling activities via NOTCH2-HES1 in surrounding GCPs, eventually suppressing their differentiation. These findings suggest that Notch signaling results in the proportional generation of two types of cells, immature and differentiating GCPs, which contributes to the well-organized differentiation of GCs.

An iPSC-based neural model of sialidosis uncovers glycolytic impairment-causing presynaptic dysfunction and deregulation of Ca2+ dynamics.

Sialidosis is a neuropathic lysosomal storage disease caused by a deficiency in the NEU1 gene-encoding lysosomal neuraminidase and characterized by abnormal accumulation of undigested sialyl-oligoconjugates in systemic organs including brain. Although patients exhibit neurological symptoms, the underlying neuropathological mechanism remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from skin fibroblasts with sialidosis and induced the differentiation into neural progenitor cells (NPCs) and neurons. Sialidosis NPCs and neurons mimicked the disease-like phenotypes including reduced neuraminidase activity, accumulation of sialyl-oligoconjugates and lysosomal expansions. Functional analysis also revealed that sialidosis neurons displayed two distinct abnormalities, defective exocytotic glutamate release and augmented α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated Ca2+ influx. These abnormalities were restored by overexpression of the wild-type NEU1 gene, demonstrating causative role of neuraminidase deficiency in functional impairments of disease neurons. Comprehensive proteomics analysis revealed the significant reduction of SNARE proteins and glycolytic enzymes in synaptosomal fraction, with downregulation of ATP production. Bypassing the glycolysis by treatment of pyruvate, which is final metabolite of glycolysis pathway, improved both the synaptsomal ATP production and the exocytotic function. We also found that upregulation of AMPAR and L-type voltage dependent Ca2+ channel (VDCC) subunits in disease neurons, with the restoration of AMPAR-mediated Ca2+ over-load by treatment of antagonists for the AMPAR and L-type VDCC. Our present study provides new insights into both the neuronal pathophysiology and potential therapeutic strategy for sialidosis.

Characteristics of recurrent in-stent restenosis after second- and third-generation drug-eluting stent implantation.

BACKGROUND: In second- and third-generation drug-eluting stent (DES) era, in-stent restenosis (ISR) is not commonly seen. However, a few patients still need repeat revascularizations for recurrent ISR even after second- and third-generation DES implantation. METHODS: From January 2012 to March 2017, 2339 lesions underwent second- and third-generation DES (Nobori, Promus Element, Resolute Integrity, Xience, Ultimaster and Synergy) implantation, of which 95 lesions (4.1%) underwent revascularization for first ISR. All lesions were divided into two groups of recurrent ISR group and non-recurrent ISR group. After successful optical coherence tomography (OCT) guided revascularization for all lesions, we investigated characteristics of recurrent ISR, and 2 years follow-up were completed. RESULTS: The mean age was 70.8 ± 11.7 years, and 73.2% were males. Among 56 DES-ISR lesions which were assessed by OCT, recurrent ISR was seen in 33.9% (N = 19) at 2 years follow-up after revascularization for first ISR. Serum low-density lipoprotein-cholesterol (LDL-C) level was higher in recurrent ISR group compared with non-recurrent ISR group (114.1 ± 53.9 mg/dl vs. 90.9 ± 27.8 mg/dl, P = 0.04) and heterogeneous tissue pattern was more frequently found in recurrent ISR group compared with non-recurrent ISR group (63.2% vs. 27.0%, P = 0.03). Multivariate analysis identified a heterogeneous tissue pattern (odds ratio 3.71; 95% confidence interval 1.09-12.59; P = 0.03) as an independent predictor of recurrent restenosis. CONCLUSION: Recurrent ISR of second- and third-generation DES was associated with heterogeneous tissue pattern of first ISR, and high LDL-C level was associated with recurrence.

Traceable stimulus-dependent rapid molecular changes in dendritic spines in the brain.

Dendritic spines function as microcompartments that can modify the efficiency of their associated synapses. Here, we analyzed stimulus-dependent molecular changes in spines. The F-actin capping protein CapZ accumulates in parts of dendritic spines within regions where long-term potentiation has been induced. We produced a transgenic mouse line, AiCE-Tg, in which CapZ tagged with enhanced green fluorescence protein (EGFP-CapZ) is expressed. Twenty minutes after unilateral visual or somatosensory stimulation in AiCE-Tg mice, relative EGFP-CapZ signal intensification was seen in a subset of dendritic spines selectively in stimulated-side cortices; this right-left difference was abolished by NMDA receptor blockade. Immunolabeling of α-actinin, a PSD-95 binding protein that can recruit AMPA receptors, showed that the α-actinin signals colocalized more frequently in spines with the brightest EGFP-CapZ signals (top 100) than in spines with more typical EGFP-CapZ signal strength (top 1,000). This stimulus-dependent in vivo redistribution of EGFP-CapZ represents a novel molecular event with plasticity-like characteristics, and bright EGFP-CapZ in AiCE-Tg mice make high-CapZ spines traceable in vivo and ex vivo. This mouse line has the potential to be used to reveal sequential molecular events, including synaptic tagging, and to relate multiple types of plasticity in these spines, extending knowledge related to memory mechanisms.

Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia.

Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale). It is likely that each scale affects the others, from the microscale to the mesoscale to the macroscale, and vice versa. Thus, to consider the intricate complexity of schizophrenia across multiple layers, we introduce a multi-scale, hierarchical view of the nature of this disorder, focusing especially on N-methyl-D-aspartate-type glutamate receptors (NMDARs). The reason for placing emphasis on NMDAR is its clinical relevance to schizophrenia, as well as its diverse functions in neurons, including the robust supralinear synaptic integration provided by N-methyl-D-aspartate-type glutamate (NMDA) spikes and the Ca2+ permeability of the NMDAR, which facilitates synaptic plasticity via various calcium-dependent proteins. Here, we review recent evidence implicating NMDARs in the pathophysiology of schizophrenia from the multi-scale perspective. We also discuss recent advances from optical techniques, which provide a powerful tool for uncovering the mechanisms of NMDAR synaptic pathology and their relationships, with subsequent behavioral manifestations.