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Background An insertable cardiac monitor (ICM) and transesophageal echocardiography (TEE) are useful for investigating potential embolic sources in cryptogenic stroke, of which atrial fibrillation (AF) is a critical risk factor for stroke recurrence. The association of left atrial appendage flow velocity (LAA-FV) on TEE with ICM-detected AF is yet to be elucidated. Methods CRYPTON-ICM (CRYPTOgenic stroke evaluation in Nippon using ICM) is a multicenter registry of cryptogenic stroke with ICM implantation, and patients whose LAA-FV was evaluated on TEE were enrolled. The primary outcome was the detection of AF (> 2 min) on ICM. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off of LAA-FV, and factors associated with ICM-detected AF were assessed. Results A total of 307 patients (age 66.6 ± 12.3 years; 199 males) with median follow-up of 440 (interquartile range 169–726) days were enrolled; AF was detected in 101 patients. The lower-tertile LAA-FV group had older age, more history of congestive heart failure, and higher levels of B-type natriuretic peptide (BNP) or N-terminal proBNP (all P  < 0.05). On ROC analysis, LAA-FV < 37.5 cm/s predicted ICM-detected AF with sensitivity of 26.7% and specificity of 92.2%. After adjustment for covariates, the lower tertile of LAA-FV (hazard ratio [HR], 1.753 [1.017–3.021], P  = 0.043) and LAA-FV < 37.5 cm/s (HR 1.987 [1.240–3.184], P  = 0.004) predicted ICM-detected AF. Conclusions LAA-FV < 37.5 cm/s predicts AF. TEE is useful not only to evaluate potential embolic sources, but also for long-term detection of AF on ICM by measuring LAA-FV in cryptogenic stroke. http://www.umin.ac.jp/ctr/ (UMIN000044366).

Cucumber anthracnose is a destructive fungal disease caused by Colletotrichum orbiculare. Common control strategies include chemical fungicides. However, this can lead to the development of pathogenic resistance. Therefore, it is necessary to identify natural compounds or microorganisms to develop new chemicals and the biological control of fungal pathogens. Isolate GT2, a bacterial isolate from soil samples collected in Shimane Prefecture, Japan, significantly inhibited in vitro mycelial growth and conidial germination of C. orbiculare, indicating a fungicidal effect against this pathogen. Furthermore, anthracnose lesion formation was significantly suppressed without phytotoxicity when cucumber leaves were pretreated with a cell culture suspension of the isolate GT2 before inoculation with C. orbiculare. Bioautography of the culture filtrate (CF) of the isolate GT2 using thin-layer chromatography showed that the compound inhibiting C. orbicularegrowth had an Rf value of 0.38. The effective compound in GT2-CF was ethyl acetate insoluble and heat-stable at 121 °C and has a molecular weight larger than 1 000 Da. In conclusion, Paenibacillus polymyxa GT2 demonstrated the potential for developing a new fungicide and biological agent against anthracnose disease caused by C. orbiculare.

Objectives: Insertable cardiac monitors (ICM) allow continuous long-term electrocardiogram monitoring and the detection of paroxysmal atrial fibrillation (PAF) in patients with cryptogenic stroke (CS). Several years have passed since ICM was indicated for CS, and many stroke neurologists will experience cases in which ICM removal is required. As a standard protocol, reincision of the wound at the time of implantation has been proposed by ICM brands. However, it may be difficult due to adhesions of subcutaneous tissue, migration of the device from its original position, and the capsule formed around the device. Our objective is to describe simple alternative techniques for successful ICM removal. Materials and Methods: From December 2016 to September 2021, 37 patients with CS underwent ICM removal at our institution. The device was removed through an incision directly above the proximal end of the device, perpendicular to the wound at the time of ICM implantation. The subcutaneous tissue was removed bluntly using forceps along the edges of the proximal end of the device. When a capsule was attached to the device, we cut the capsule with the blade to release the device. Once the device was visible, the proximal end of the device was grasped with forceps, and the device was pulled from the pocket with gentle traction. All patients undergoing ICM removal received a systematic check for wound dehiscence, wound infection, bleeding, and tissue ischemia at an outpatient examination of 1 week. The 37 patients who underwent removal of ICM were retrospectively reviewed in the medical record and analyzed for procedural success, intraoperative complications, and wound course at one week. Results: All patients achieved procedural success. There were no intraoperative complications, wound dehiscence, bleeding, or skin ischemia at one week postoperatively. The reasons for removal were battery depletion in 65%, early removal before battery life after PAF detection in 32%, and exposure to the body surface in 3%. The devices removed were 62% Reveal LINQ (Medtronic, Minneapolis), 30% Confirm Rx (Abbott, Illinois), and 8% BioMonitor 2 (BIOTRONIK, Berlin), indicating that our method is effective regardless of model. Conclusion: We describe a simple technique for ICM removal for CS that is safe, reliable, and potentially effective in wound healing.

The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by rhosin. We found that rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with rhosin inhibited lung metastasis in vivo. Moreover, rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer.

A revolute pair with a flexible translational constraint on a plane is proposed as simple mechanism for safe robots. The mechanism is composed of two pairing elements, one with a circular and one with a cam profile that are connected by a linear spring. Flexible translational constraint is generated by spring forces and the reaction force between the two pairing elements. Two methods for designing the cam profile are proposed in order to implement the specified non-linear stiffness in the flexible constraint. Design examples with various stiffness characteristics are shown. Some prototypes are fabricated, and it is confirmed that they perform as designed. As an application, a flexible, underactuated link mechanism with the proposed pairs is synthesized, and its flexibility and kinematic performance are investigated.

Endovascular therapy for stroke is generally avoided if the cerebral infarction is large. In a trial conducted in Japan, the percentage of patients who had a good functional outcome at 90 days was higher with endovascular therapy than with medical care, but there were more cerebral hemorrhages with endovascular therapy.

BackgroundThe safety and effectiveness of stent retriever use for patients with acute large vessel occlusion (LVO) due to intracranial atherosclerotic disease (ICAD) is not well established. We investigated the differences in clinical outcomes in patients with and without ICAD.MethodsWe analyzed the Japan Trevo Registry, a nationwide registry which enrolled patients with acute LVO who underwent endovascular therapy (EVT) using the Trevo retriever alone or in combination with an aspiration catheter. We compared the technical and clinical outcomes of EVT between the ICAD and No-ICAD groups. The primary outcome was effective reperfusion and the secondary outcome was modified Rankin scale (mRS) score 0–2 at 90 days. Safety outcomes were worsening of neurologic symptoms within 24 hours, any intracranial hemorrhage within 24 hours, vessel dissection/vessel perforation related to using the Trevo retriever and mortality at 90 days.ResultsA total of 835 patients (45 in the ICAD group and 790 in the No-ICAD group) were analyzed. In the ICAD group, more men (68.9% vs 50.8%, P=0.02) and a lower median National Institutes of Health Stroke Scale score at admission (11 vs 18, P<0.0001) were observed. The primary outcome was significantly more common in the No-ICAD group (92.5%) than in the ICAD group (80.0%) (adjusted odds ratio (aOR) 0.21, 95% CI 0.09 to 0.50). The proportion of patients with mRS score 0–2 at 90 days was significantly lower in the ICAD group (44.4% vs 42.4%, aOR 0.49, 95% CI 0.23 to 1.00, P=0.0496). Other secondary and safety outcomes were not significantly different between the two groups.ConclusionsPatients with LVO with ICAD had a lower rate of effective reperfusion than those with No-ICAD.

BackgroundAlthough randomized clinical trials (RCTs) demonstrated short-term benefits of endovascular therapy (EVT) for acute ischemic stroke (AIS) with a large ischemic region, little is known about the long-term cost-effectiveness or its difference by the extent of the ischemic areas. We aimed to assess the cost-effectiveness of EVT for AIS involving a large ischemic region from the perspective of Japanese health insurance payers, and analyze it using the Alberta Stroke Program Early CT Score (ASPECTS).MethodsThe Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Large Ischemic Core Trial (RESCUE-Japan LIMIT) was a RCT enrolling AIS patients with ASPECTS of 3–5 initially determined by the treating neurologist primarily using MRI. The hypothetical cohort and treatment efficacy were derived from the RESCUE-Japan LIMIT. Costs were calculated using the national health insurance tariff. We stratified the cohort into two subgroups based on ASPECTS of ≤3 and 4–5 as determined by the imaging committee, because heterogeneity was observed in treatment efficacy. EVT was considered cost-effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay of 5 000 000 Japanese yen (JPY)/quality-adjusted life year (QALY).ResultsEVT was cost-effective among the RESCUE-Japan LIMIT population (ICER 4 826 911 JPY/QALY). The ICER among those with ASPECTS of ≤3 and 4–5 was 19 396 253 and 561 582 JPY/QALY, respectively.ConclusionEVT was cost-effective for patients with AIS involving a large ischemic region with ASPECTS of 3–5 initially determined by the treating neurologist in Japan. However, the ICER was over 5 000 000 JPY/QALY among those with an ASPECTS of ≤3 as determined by the imaging committee.

Background The mutations in the presenilin 1 gene ( PSEN1 ) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Method Using the proband’s samples, we performed genetic analysis of the PSEN1 , APP , MAPT , and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1 . Results The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Conclusion Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Background and Objectives DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS. Methods The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed. Results Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity. Conclusions Single doses of DS-1040 0.6–4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy. Clinical trial registration number NCT03198715; JapicCTI-163164.