Real-World Patent Foramen Ovale (PFO) Closure in Japan　- 30-Day Clinical Outcomes From the AmplatzerTM PFO Occluder Japan Post-Marketing Surveillance Study.

BACKGROUND: The AmplatzerTM PFO Occluder was approved for marketing in Japan in May 2019, and the Amplatzer PFO Occluder Japan Post-marketing Surveillance (PFO Japan PMS) study was initiated in December 2019. This analysis presents 30-day clinical outcomes for PFO Japan PMS study patients.Methods and Results: PFO Japan PMS is a prospective single-arm non-randomized multicenter clinical study. Eligible patients were indicated for patent foramen ovale (PFO) closure and underwent an implant attempt with the AmplatzerTM PFO Occluder. Technical success was defined as successful delivery and release of the occluder; procedural success was defined as technical success with no serious adverse events (SAEs) within 1 day of the procedure. The primary safety endpoint includes predefined device- and/or procedure-related SAEs through 30 days after the procedure. From December 2019 to July 2021, 500 patients were enrolled across 53 Japanese sites. The mean (±SD) patient age was 52.7±15.4 years, and 29.8% of patients were aged >60 years. Technical and procedural success rates were both high (99.8% and 98.8%, respectively). Further, there was only one primary safety endpoint event (0.2%): an episode of asymptomatic paroxysmal atrial fibrillation that occurred 26 days after the procedure. CONCLUSIONS: In this real-world Japanese study with almost one-third of patients aged >60 years, PFO closure with the AmplatzerTM PFO Occluder was performed successfully and safely, with a low incidence of procedure-related atrial arrhythmias.

Comparison of transposition and interposition methods in microvascular decompression for hemifacial spasm: an analysis of 109 cases performed by a single surgeon in a single-center retrospective study.

BACKGROUND: Microvascular decompression (MVD), the standard surgical approach for hemifacial spasm (HFS), can be divided into the interposition and transposition methods. Although the risk of HFS recurrence following interposition has been reported, there is limited data comparing long-term outcomes between both methods performed by a single surgeon. This study aimed to investigate the efficacy of MVD techniques on HFS by comparing surgical outcomes performed by a single surgeon in a single-center setting. METHODS: A total of 109 patients who underwent MVD were analyzed and divided into the transposition (86 patients) and interposition (23 patients) groups. Postoperative outcomes at 1 month and 1 year were assessed and compared, including rates of spasm relief, complications, and recurrence. RESULTS: Outcome assessment revealed higher rates of early spasm relief in the interposition group (66.3% vs. 100%, transposition vs. interposition, respectively, p = 0.0004), although spasm relief at 1-year postoperatively was comparable between the two groups (84.9% vs. 95.7%, transposition vs. interposition, respectively, p = 0.2929). No significant differences were observed in complication and recurrence rates. Kaplan-Meier analysis demonstrated no significant differences in the duration of spasm resolution by MVD method (p = 0.4347, log-rank test). CONCLUSION: This study shows that both the transposition (Surgicel® and fibrin glue) and interposition (sponge) methods were excellent surgical techniques. The interposition method may achieve earlier spasm resolution compared to the transposition method.

Predicting Isocitrate Dehydrogenase Status in Non-Contrast-Enhanced Adult-Type Astrocytic Tumors Using Diffusion Tensor Imaging and 11C-Methionine, 11C-Choline, and 18F-Fluorodeoxyglucose PET.

We aimed to differentiate the isocitrate dehydrogenase (IDH) status among non-enhanced astrocytic tumors using preoperative MRI and PET. We analyzed 82 patients with non-contrast-enhanced, diffuse, supratentorial astrocytic tumors (IDH mutant [IDH-mut], 55 patients; IDH-wildtype [IDH-wt], 27 patients) who underwent MRI and PET between May 2012 and December 2022. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) values using diffusion tensor imaging. We evaluated the tumor/normal brain uptake (T/N) ratios using 11C-methionine, 11C-choline, and 18F-fluorodeoxyglucose PET; extracted the parameters with significant differences in distinguishing the IDH status; and verified their diagnostic accuracy. Patients with astrocytomas were significantly younger than those with glioblastomas. The following MRI findings were significant predictors of IDH-wt instead of IDH-mut: thalamus invasion, contralateral cerebral hemisphere invasion, location adjacent to the ventricular walls, higher FA value, and lower MD value. The T/N ratio for all tracers was significantly higher for IDH-wt than for IDH-mut. In a composite diagnosis based on nine parameters, including age, 84.4% of cases with 0-4 points were of IDH-mut; conversely, 100% of cases with 6-9 points were of IDH-wt. Composite diagnosis using all parameters, including MRI and PET findings with significant differences, may help guide treatment decisions for early-stage gliomas.

Posttraumatic epilepsy in chronic disorders of consciousness due to severe traumatic brain injury after traffic accidents.

PURPOSE: To evaluate the clinical state of posttraumatic epilepsy (PTE) in patients with chronic disorders of consciousness (CDC) due to severe traumatic brain injury (STBI) after traffic accidents and clarify the risk factors for seizure occurrence in such patients. METHODS: Two hundred ninety-three patients with CDC due to STBI (mean age at admission [±standard deviation]: 36.4 ± 17.9 years; men: 71.7 %; mean duration of injury to admission: 416 ± 732 days; mean hospitalization time: 899 ± 319 days) were enrolled in this study. We retrospectively investigated the relationship between seizure conditions (type and frequency) and clinical data, including age, sex, pathological types of brain injury, with/without surgical intervention, degree of CDC, and administration of antiseizure medications (ASMs). RESULTS: Overall, 52.9 % (n = 155/293) and 64.2 % of the patients (n = 183/of 285 patients surviving at discharge) were administered ASMs at admission and discharge, respectively. One hundred thirty-two patients (45.1 %) experienced epileptic seizures during hospitalization, and the mean seizure frequency was 4.0 ± 0.4 times per year. In multivariate analysis, significant and independent risk factors of seizure occurrence were revealed to be male sex, high National Agency for Automotive Safety and Victims' Aid score, hypoxic encephalopathy, and history of the neurosurgical operations. CONCLUSION: The high prevalence of PTE in patients with CDC due to STBI, and the significant and independent risk factors for seizure occurrence in the chronic clinical phase were revealed. We expect that this study will aid toward improving clinical assessment and management of epileptic seizures in the population.

Inverse relationship between platelet Akt activity and hippocampal atrophy: A pilot case-control study in patients with diabetes mellitus.

BACKGROUND: Akt plays diverse roles in humans. It is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), which is caused by insulin resistance. Akt also plays a vital role in human platelet activation. Furthermore, the hippocampus is closely associated with memory and learning, and a decrease in hippocampal volume is reportedly associated with an insulin-resistant phenotype in T2DM patients without dementia. AIM: To investigate the relationship between Akt phosphorylation in unstimulated platelets and the hippocampal volume in T2DM patients. METHODS: Platelet-rich plasma (PRP) was prepared from the venous blood of patients with T2DM or age-matched controls. The pellet lysate of the centrifuged PRP was subjected to western blotting to analyse the phosphorylation of Akt, p38 mitogen-activated protein (MAP) kinase and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Phosphorylation levels were quantified by densitometric analysis. Hippocampal volume was analysed using a voxel-based specific regional analysis system for Alzheimer's disease on magnetic resonance imaging, which proposes the Z-score as a parameter that reflects hippocampal volume. RESULTS: The levels of phosphorylated Akt corrected with phosphorylated p38 MAP kinase were inversely correlated with the Z-scores in the T2DM subjects, whereas the levels of phosphorylated Akt corrected with GAPDH were not. However, this relationship was not observed in the control patients. CONCLUSION: These results suggest that an inverse relationship may exist between platelet Akt activation and hippocampal atrophy in T2DM patients. Our findings provide insight into the molecular mechanisms underlying T2DM hippocampal atrophy.

Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes with Alteplase at 0.6 mg/kg in Clinical Practice: THAWS2 Study.

INTRODUCTION: The aim of this study was to determine the safety and efficacy of intravenous (IV) alteplase at 0.6 mg/kg for patients with acute wake-up or unclear-onset strokes in clinical practice. METHODS: This multicenter observational study enrolled acute ischemic stroke patients with last-known-well time >4.5 h who had mismatch between DWI and FLAIR and were treated with IV alteplase. The safety outcomes were symptomatic intracranial hemorrhage (sICH) after thrombolysis, all-cause deaths, and all adverse events. The efficacy outcomes were favorable outcome defined as an mRS score of 0-1 or recovery to the same mRS score as the premorbid score, complete independence defined as an mRS score of 0-1 at 90 days, and change in NIHSS at 24 h from baseline. RESULTS: Sixty-six patients (35 females; mean age, 74 ± 11 years; premorbid complete independence, 54 [82%]; median NIHSS on admission, 11) were enrolled at 15 hospitals. Two patients (3%) had sICH. Median NIHSS changed from 11 (IQR, 6.75-16.25) at baseline to 5 (3-12.25) at 24 h after alteplase initiation (change, -4.8 ± 8.1). At discharge, 31 patients (47%) had favorable outcome and 29 (44%) had complete independence. None died within 90 days. Twenty-three (35%) also underwent mechanical thrombectomy (no sICH, NIHSS change of -8.5 ± 7.3), of whom 11 (48%) were completely independent at discharge. CONCLUSIONS: In real-world clinical practice, IV alteplase for unclear-onset stroke patients with DWI-FLAIR mismatch provided safe and efficacious outcomes comparable to those in previous trials. Additional mechanical thrombectomy was performed safely in them.

Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding.

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

Japanese nationwide questionnaire survey on delayed cerebral infarction due to vasospasm after subarachnoid hemorrhage.

Background and purpose: Various prophylactic drugs for cerebral vasospasm and delayed cerebral infarction (DCI) after subarachnoid hemorrhage (SAH) have been used in Japan. To investigate the treatment trends for cerebral vasospasm and frequency of DCI after SAH throughout Japan in 2021. Methods: In 2021 we conducted an anonymous questionnaire survey on management for preventing cerebral vasospasm after aneurysmal SAH, and the frequency of DCI. The questionnaire was emailed to 955 certified neurosurgeons at 553 hospitals in Japan. Of them, 162 hospitals (29% response rate) responded to the questionnaire. Of these, 158 were included in this study, while four hospitals that responded insufficiently were excluded. The efficacy of treatments for reducing DCI were examined through a logistic regression analysis. Results: Among 3,093 patients treated with aneurysmal SAH, 281 patients (9.1%) were diagnosed with DCI related to cerebral vasospasm. Coil embolization had significantly lower DCI frequency (6.9%), compared to microsurgical clipping (11.8%, odds ratio, 0.90; 95% confidential intervals, 0.84-0.96; P, 0.007). In addition, cilostazol administration was associated with significantly lower DCI frequency (0.48; 0.27-0.82; 0.026). The efficacy of cilostazol in reducing DCI remained unchanged after adjustment for covariates. The most effective combination of multiple prophylactic drugs in reducing DCI related to cerebral vasospasm was cilostazol, fasudil, and statin (0.38; 0.22-0.67; 0.005). Conclusions: This study elucidated the trends in prophylactic drugs to prevent cerebral vasospasm and frequency of DCI after aneurysmal SAH in Japan. Coil embolization and cilostazol administration showed effectiveness in reducing DCI related to cerebral vasospasm in 2021.

Resection of positive tissue on methionine-PET is associated with improved survival in glioblastomas.

BACKGROUND AND PURPOSE: The volume of excised tumor in contrast-enhanced areas evaluated via magnetic resonance imaging is known to have a strong influence on the survival of patients with glioblastoma (GBM). In this study, we investigated the effect of tumor resection on the survival of patients with GBM in the 11 C-methionine (MET) accumulation area using MET-positron emission tomography (MET-PET). METHODS: A total of 26 patients (median age, 69 years; 15 males) who had undergone tumor resection and MET-PET before and after surgery, after being newly diagnosed with GBM, were included in the study. MET-PET before and after tumor resection were compared. The association between the decrease in the maximum standardized uptake value (SUV) of the tumor divided by the normal cortical mean SUV (%; ΔT/N), the MET extent of resection (MET-EOR) from the % reduction in the MET accumulation area (%), and residual MET accumulation area (in cm3 ; MET-residual tumor volume [RTV]), as well as the survival time of patients with GBM, were evaluated via univariate analysis. RESULTS: ΔT/N were positively associated with survival (hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.97-0.99], p = .02). MET-RTV revealed a negative association with survival (HR, 1.02 [95% CI, 1.01-1.04], p = .04). Additionally, MET-EOR showed a strong trend with survival (HR, 0.99 [95% CI, 0.97-1.01], p = .06). CONCLUSIONS: Surgical resection of MET-accumulated areas in GBM significantly prolongs the survival of patients with GBM. However, a prospective large-scale multicenter study is needed to confirm our findings.

Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac.

CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses synergistically activates platelets via not CXCR7 but CXCR4, a specific receptor for CXCL12 on the plasma membrane. Recently, we reported that not Rho/Rho kinase, but Rac is involved in the platelet aggregation induced by this combination. Ristocetin is an activator of the von Willebrand factor that interacts with glycoprotein (GP) Ib/IX/V, which generates thromboxane A2 via phospholipase A2 activation, resulting in the release of the soluble CD40 ligand (sCD40L) from human platelets. In the present study, we investigated the effects of a combination of ristocetin and CXCL12 at low doses on human platelet activation and its underlying mechanisms. Simultaneous stimulation with ristocetin and CXCL12 at subthreshold doses synergistically induce platelet aggregation. A monoclonal antibody against not CXCR7 but CXCR4 suppressed platelet aggregation induced by the combination of ristocetin and CXCL12 at low doses. This combination induces a transient increase in the levels of both GTP-binding Rho and Rac, followed by an increase in phosphorylated cofilin. The ristocetin and CXCL12-induced platelet aggregation as well as the sCD40L release were remarkably enhanced by Y27362, an inhibitor of Rho-kinase, but reduced by NSC23766, an inhibitor of the Rac-guanine nucleotide exchange factor interaction. These results strongly suggest that the combination of ristocetin and CXCL12 at low doses synergistically induces human platelet activation via Rac and that this activation is negatively regulated by the simultaneous activation of Rho/Rho-kinase.

Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion.

Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.

Combining methionine-PET and MRI fluid-attenuated inversion-recovery mismatch to determine glioma molecular subtype.

BACKGROUND AND PURPOSE: 11 C-methionine (MET)-PET is a useful tool in neuro-oncology. The T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign on MRI is a characteristic finding in lower grade gliomas with isocitrate dehydrogenase (IDH) mutations and the absence of the 1p/19q codeletion; however, the T2-FLAIR mismatch sign has low sensitivity in differentiating gliomas and does not aid in identifying glioblastomas with IDH mutations. We therefore investigated the efficacy of the combination of the T2-FLAIR mismatch sign and MET-PET for accurately determining the molecular subtype of gliomas of all grades. METHODS: The present study comprised 208 adult patients diagnosed with supratentorial glioma confirmed by molecular genetics and histopathology. The ratio of the maximum lesion MET accumulation to the mean normal frontal cortex MET accumulation (T/N) was measured. The presence or absence of the T2-FLAIR mismatch sign was determined. The presence or absence of the T2-FLAIR mismatch sign and the MET T/N ratio were compared between glioma subtypes to evaluate individual and combined utility in identifying gliomas with IDH mutations and no 1p/19q codeletion (IDHmut-Noncodel) or gliomas with IDH mutations (IDHmut). RESULTS: The addition of MET-PET to MRI for the presence of the T2-FLAIR mismatch sign improved diagnostic accuracy, with the area under the curve values increasing from .852 to .871 for IDHmut-Noncodel and from .688 to .808 for IDHmut. CONCLUSIONS: The combination of the T2-FLAIR mismatch sign and MET-PET may provide improved diagnostic utility in differentiating gliomas according to molecular subtype, particularly in determining IDH mutation status.

Methionine-PET to differentiate between brain lesions appearing similar on conventional CT/MRI scans.

BACKGROUND AND PURPOSE: 11 C-Methionine (MET)-PET is a useful tool in neuro-oncology. This study aimed to examine whether a combination of diagnostic variables associated with MET uptake could help distinguish between brain lesions that are often difficult to discriminate in conventional CT and MRI. METHODS: MET-PET was assessed in 129 patients with glioblastoma multiforme, primary central nervous lymphoma, metastatic brain tumor, tumefactive multiple sclerosis, or radiation necrosis. The accuracy of the differential diagnosis was analyzed using five diagnostic characteristics in combination: higher maximum standardized uptake value (SUV) of MET in the lesion/the mean normal cortical SUV of MET ratio, overextension beyond gadolinium, peripheral pattern indicating abundant MET accumulation in the peripheral region, central pattern denoting abundant MET accumulation in the central region, and dynamic-up suggesting increased MET accumulation during dynamic study. The analysis was conducted on sets of two of the five brain lesions. RESULTS: Significant differences in the five diagnostic traits were observed among the five brain lesions, and differential diagnosis could be achieved by combining these diagnostic features. The area under the curve between each set of two of the five brain lesions using MET-PET features ranged from .85 to 1.0. CONCLUSIONS: According to the findings, combining the five diagnostic criteria could help with the differential diagnosis of the five brain lesions. MET-PET is an auxiliary diagnostic technique that could help in distinguishing these five brain lesions.

Differentiation of astrocytoma between grades II and III using a combination of methionine positron emission tomography and magnetic resonance spectroscopy.

Objective: This study aimed to establish a method for differentiating between grades II and III astrocytomas using preoperative imaging. Methods: We retrospectively analyzed astrocytic tumors, including 18 grade II astrocytomas (isocitrate dehydrogenase (IDH)-mutant: IDH-wildtype = 8:10) and 56 grade III anaplastic astrocytomas (37:19). We recorded the maximum methionine (MET) uptake ratios (tumor-to-normal: T/N) on positron emission tomography (PET) and three MRS peak ratios: choline (Cho)/creatine (Cr), N-acetyl aspartate (NAA)/Cr, and Cho/NAA, between June 2015 and June 2020. We then evaluated the cut-off values to differentiate between grades II and III. We compared the grading results between contrast enhancement effects on MR and combinational diagnostic methods (CDM) on a scatter chart using the cutoff values of the T/N ratio and MRS parameters. Results: The IDH-mutant group showed significant differences in the Cho/NAA ratio between grades II and III using univariate analysis; however, multiple regression analysis results negated this. The IDH-wildtype group showed no significant differences between the groups. Contrast enhancement effects also showed no significant differences in IDH status. Accordingly, regardless of the IDH status, no statistically independent factors differentiated between grades II and III. However, CDMs showed higher sensitivity and negative predictive value in distinguishing them than MRI contrast examinations for both IDH statuses. We demonstrated a significantly higher diagnostic rate of grade III than of grade II with CDM, which was more striking in the IDH-mutant group than in the wild-type group. Conclusions: CDM could be valuable in differentiating between grade II and III astrocytic tumors.

How I do it: combined bypass for adult moyamoya disease with maximal consideration of cosmetic aspects.

BACKGROUND: Combined bypass, including direct and indirect procedures, has been recognized as the maximal revascularization to prevent further hemorrhagic or ischemic stroke in adult moyamoya disease (MMD). It is also important to consider cosmetic aspects when planning combined bypass for MMD. However, there are few reports that have described the cosmetic considerations in bypass surgery for MMD. METHODS: We demonstrate our surgical techniques aimed at achieving extended revascularization as well as excellent cosmetic outcomes with figures and video. CONCLUSION: Our combined bypass procedures which focus on achieving maximal cosmetic results are effective methods that require no special instruments or techniques.

National trends in the outcomes of subarachnoid haemorrhage and the prognostic influence of stroke centre capability in Japan: retrospective cohort study.

OBJECTIVES: To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan. DESIGN: Retrospective study. SETTING: Six hundred and thirty-one primary care institutions in Japan. PARTICIPANTS: Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database. PRIMARY AND SECONDARY OUTCOME MEASURES: Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3-6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1-25 points). RESULTS: In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality. CONCLUSIONS: The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Non-invasive regional cerebral blood flow quantification in the 123I-IMP autoradiography using artificial neural network.

PURPOSE: Regional cerebral blood flow (rCBF) quantification using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) requires an invasive, one-time-only arterial blood sampling for measuring the 123I-IMP arterial blood radioactivity concentration (Ca10). The purpose of this study was to estimate Ca10 by machine learning (ML) using artificial neural network (ANN) regression analysis and consequently calculating rCBF and cerebral vascular reactivity (CVR) in the dual-table autoradiography (DTARG) method. MATERIALS AND METHODS: This retrospective study included 294 patients who underwent rCBF measurements through the 123I-IMP DTARG. In the ML, the objective variable was defined by the measured Ca10, whereas the explanatory variables included 28 numeric parameters, such as patient characteristic values, total injection 123I-IMP radiation dose, cross-calibration factor, and the distribution of 123I-IMP count in the first scan. ML was performed with training (n = 235) and testing (n = 59) sets. Ca10 was estimated in testing set by our proposing model. Alternatively, the estimated Ca10 was also calculated via the conventional method. Subsequently, rCBF and CVR were calculated using estimated Ca10. Pearson's correlation coefficient (r-value) for the goodness of fit and the Bland-Altman analysis for assessing the potential agreement and bias were performed between the measured and estimated values. RESULTS: The r-value of Ca10 estimated by our proposed model was higher compared with the conventional method (0.81 and 0.66, respectively). In the Bland-Altman analysis, mean differences of 4.7 (95% limits of agreement (LoA): -18-27) and 4.1 (95% LoA: -35-43) were observed using proposed model and the conventional method, respectively. The r-values of rCBF at rest, rCBF after the acetazolamide challenge, and CVR calculated using the Ca10 estimated by our proposed model were 0.83, 0.80 and 0.95, respectively. CONCLUSION: Our proposed ANN-based model could accurately estimate the Ca10, rCBF, and CVR in DTARG. These results would enable non-invasive rCBF quantification in DTARG.

Tramadol regulates the activation of human platelets via Rac but not Rho/Rho-kinase.

Tramadol is a useful analgesic which acts as a serotonin and noradrenaline reuptake inhibitor in addition to µ-opioid receptor agonist. Cytoplasmic serotonin modulates the small GTPase activity through serotonylation, which is closely related to the human platelet activation. We recently reported that the combination of subthreshold collagen and CXCL12 synergistically activates human platelets. We herein investigated the effect and the mechanism of tramadol on the synergistic effect. Tramadol attenuated the synergistically stimulated platelet aggregation (300 µM of tramadol, 64.3% decrease, p<0.05). Not morphine or reboxetine, but duloxetine, fluvoxamine and sertraline attenuated the synergistic effect of the combination on the platelet aggregation (30 µM of fluvoxamine, 67.3% decrease, p<0.05; 30 µM of sertraline, 67.8% decrease, p<0.05). The geranylgeranyltransferase inhibitor GGTI-286 attenuated the aggregation of synergistically stimulated platelet (50 µM of GGTI-286, 80.8% decrease, p<0.05), in which GTP-binding Rac was increased. The Rac1-GEF interaction inhibitor NSC23766 suppressed the platelet activation and the phosphorylation of p38 MAPK and HSP27 induced by the combination of collagen and CXCL12. Tramadol and fluvoxamine almost completely attenuated the levels of GTP-binding Rac and the phosphorylation of both p38 MAPK and HSP27 stimulated by the combination. Suppression of the platelet aggregation after the duloxetine administration was observed in 2 of 5 patients in pain clinic. These results suggest that tramadol negatively regulates the combination of subthreshold collagen and CXCL12-induced platelet activation via Rac upstream of p38 MAPK.

The Height and Mobility of Protruding Plaque After Carotid Artery Stenting Are Associated with Postoperative Ischemic Lesions.

BACKGROUND: Tissue protrusion (TP) is a possible cause of cerebral infarction after carotid artery stenting (CAS). Using optical frequency domain imaging (OFDI) and angioscopy, we investigated the relationship between the morphological features of TP and postoperative new ischemic lesions on magnetic resonance imaging (MRI)-diffusion weighted imaging (DWI) after CAS. METHODS: Fifty patients who underwent CAS and subsequent poststenting intravascular evaluation using both OFDI and angioscopy were included. CAS was performed for proximal protection via the femoral artery approach, and intravascular evaluation with OFDI and angioscopy were performed after stent placement. We compared the background and poststenting intravascular findings between patients with and without postoperative new ischemic lesions on MRI-DWI. RESULTS: TP was observed in 42 patients (84%), and postoperative new ischemic lesions on MRI-DWI were observed in 32 patients (64%). The frequency of TP did not differ between the 2 groups, but the height of TP was higher in the DWI-positive group (0.62 mm vs. 0.29 mm, P = 0.0028), and mobile TP was observed only in the DWI-positive group. The height of TP (P = 0.023) was an independent predictor of new periprocedural ischemic brain lesions after CAS, and its cut-off value for mobility was 0.55 mm on the receiver operating characteristic curve (area under the curve, 0.93). CONCLUSIONS: The height of TP on OFDI and mobile-TP on angioscopy after CAS were associated with postoperative new ischemic lesions on MRI-DWI. The intravascular evaluation using OFDI and angioscopy could be helpful for a detailed evaluation of TP.

Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK.

Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic drugs affecting SGLT2. Recent studies have shown various cancers expressing SGLT2, and SGLT2 inhibitors attenuating tumor proliferation. We evaluated the antitumor activities of canagliflozin, a SGLT2 inhibitor, on glioblastoma (GBM). Three GBM cell lines, U251MG (human), U87MG (human), and GL261 (murine), were used. We assessed the expression of SGLT2 of GBM through immunoblotting, specimen-use, cell viability assays, and glucose uptake assay with canagliflozin. Then, we assessed phosphorylation of AMP-activated protein kinase (AMPK), p70 S6 kinase, and S6 ribosomal protein by immunoblotting. Concentrations of 5, 10, 20, and 40 µM canagliflozin were used in these tests. We also evaluated cell viability and immunoblotting using U251MG with siRNA knockdown of SGLT2. Furthermore, we divided the mice into vehicle group and canagliflozin group. The canagliflozin group was administrated with 100 mg/kg of canagliflozin orally for 10 days starting from the third days post-GBM transplant. The brains were removed and the tumor volume was evaluated using sections. SGLT2 was expressed in GBM cell and GBM allograft mouse. Canagliflozin administration at 40 µM significantly inhibited cell proliferation and glucose uptake into the cell. Additionally, canagliflozin at 40 µM significantly increased the phosphorylation of AMPK and suppressed that of p70 S6 kinase and S6 ribosomal protein. Similar results of cell viability assays and immunoblotting were obtained using siRNA SGLT2. Furthermore, although less effective than in vitro, the canagliflozin group significantly suppressed tumor growth in GBM-transplanted mice. This suggests that canagliflozin can be used as a potential treatment for GBM.