Treatment Outcome of Flow Diverter Device for Medium-Sized Cerebral Aneurysms: A Single-Center Report.

Objective: Flow diverters (FDs), first introduced in Japan in 2015, were initially limited to wide-necked large cerebral aneurysms, which pose a high treatment risk. However, based on the results of the PREMIER study, the indications have expanded since 2020, and the number of treatment cases is increasing in Japan. At our hospital, FD placement with adjunctive coil embolization has been actively performed for medium-sized cerebral aneurysms, as indicated in the PREMIER study; herein, we report the outcomes of this treatment. Methods: Of the 25 patients with 28 aneurysms who underwent FD placement at our institution between April 2022 and June 2023, 15 with 17 wide-necked unruptured cerebral aneurysms with a maximum diameter of <12 mm in the internal carotid artery (ICA) or vertebral artery (VA) were included. Postoperative complications were investigated in each case, and the aneurysm occlusion status was assessed using ultrashort echo time (UTE)-MRA at 3 months postoperatively and angiography at 6 months postoperatively. Fifteen patients who underwent coiling or stent-assisted coiling (SAC) for the same criteria during the same period were compared. Baseline characteristics and treatment results were compared between FD and coiling/SAC cases. Results: Four males and 11 females with a mean age of 61.7 ± 12.8 years were included, and the median follow-up period was 9 months (6-18 months). There were 14 aneurysms of the ICA and 3 of the VA, and the mean maximum aneurysm diameter was 7.9 ± 1.7 mm. All patients were treated using the Pipeline Flex with Shield Technology (Medtronic, Minneapolis, MN, USA), and 14 aneurysms (82.4%) were treated with adjunctive coil embolization. There were no symptomatic strokes in the perioperative period; only one patient receiving corticosteroid therapy for thyroid eye disease had asymptomatic ICA occlusion at 3 months. Fifteen aneurysms (88.2%) were not visible on UTE-MRA at 3 months postoperatively, and angiography at 6 months showed complete occlusion in 16 (94.1%) aneurysms. The coiling/SAC group had a smaller neck size and higher volume embolization ratio than the FD group; however, complete occlusion was higher in the FD group. Conclusion: FD placement with adjunctive coil embolization for medium-sized cerebral aneurysms is expected to result in good occlusion rates in the early postoperative period.

Signal flow in the NMDA receptor-dependent phosphoproteome regulates postsynaptic plasticity for aversive learning.

Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca2+-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.

Risk factors for nausea and vomiting requiring the daily administration of 5-HT3 receptor antagonists in radiotherapy combined with temozolomide for high-grade glioma.

Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT3RA) for the first 3 days. The daily administration of 5-HT3RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT3RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT3RA) and resuming 5-HT3RA group (patients who resumed 5-HT3RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT3RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT3RA group following the resumption of 5-HT3RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT3RA according to the condition of each patient.

Ulceration location is associated with clinical course in carotid stenosis.

OBJECTIVE: Plaque ulceration in carotid artery stenosis is a risk factor for cerebral ischemic events; however, the characteristics that determine plaque vulnerability are not fully understood. We thus assessed the association between plaque ulceration sites and cerebrovascular ischemic attack. METHODS: We retrospectively collected the clinical data of 72 consecutive patients diagnosed with carotid artery stenosis with plaque ulcers. After excluding patients with pseudo-occlusion, a history of previous carotid endarterectomy or carotid artery stenting before the ulcer was first discovered, follow-up data of less than 1 month, or carotid endarterectomy or carotid artery stenting performed within 1 month after the ulcer was first discovered, 60 patients were ultimately included. Patients were divided into proximal and distal groups based on the ulcer location relative to the most stenotic point. The primary endpoints were ipsilateral cerebrovascular ischemic events ("ischemic events"), such as amaurosis fugax, transient ischemic attack, or ischemic stroke due to carotid artery stenosis with plaque ulceration. The association between ulcer location and ischemic events was also assessed. RESULTS: In the patients with plaque ulcer, more patients had proximal than distal plaque ulcers (39 vs 21; P = .028). The median follow-up duration was 3.8 years (interquartile range, 1.5-6.2 years). Nineteen patients (32%) experienced ischemic event. Ischemic events occurred more frequently in the distal than in the proximal group (18% vs 59%; P = .005). Kaplan-Meier curves demonstrated a significantly shorter event-free time in the distal group (log-rank P = .021). In univariate analysis, distal ulcer location was associated with ischemic events (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.13-7.65; P = .03). Multivariate analysis using two different models also showed that distal ulcer location was independently associated with ischemic events (Model 1: OR, 3.85; 95% CI, 1.26-11.78; P = .03; Model 2: OR, 4.31; 95% CI, 1.49-12.49; P = .009). CONCLUSIONS: Patients with carotid artery stenosis and plaque ulcers located distal to the most stenotic point are more likely to experience cerebrovascular ischemic attacks. Therefore, carotid plaques with ulcers located distal to the most stenotic point may be a potential indication for surgical treatment.

Real-World Outcomes of Carotid Artery Stenting in Symptomatic and Asymptomatic Patients With Carotid Artery Stenosis.

BACKGROUND: The effectiveness and safety of carotid artery stenting (CAS) are comparable to those of carotid endarterectomy in both symptomatic and asymptomatic patients with carotid artery stenosis, but real-world outcomes are not well-known. OBJECTIVES: The purpose of this study was to investigate the real-world clinical outcomes of CAS in symptomatic and asymptomatic patients with carotid artery stenosis. METHODS: We conducted a nationwide retrospective registry study of 156 centers between January 2015 and December 2019. We enrolled consecutive patients with CAS managed by certified specialists from the Japanese Society of Neuroendovascular Therapy. Outcomes between symptomatic and asymptomatic patients were compared. The primary outcome was a composite of ischemic stroke and all-cause death at 30 days after CAS. Secondary outcomes were ischemic stroke, all-cause death, intracranial hemorrhage (ICH), and procedural complications. RESULTS: We analyzed 9,792 patients (symptomatic, n = 5,351; asymptomatic, n = 4,441). The mean age was 73.5 years, and men were dominant (86.4%). Embolism protection devices were used in 99% of patients. The primary outcome was not significantly different between the symptomatic and asymptomatic groups (120 [2.2%] vs 65 [1.5%]; adjusted OR: 1.30; 95% CI: 0.92-1.83). The incidences of symptomatic ICH, any ICH, acute in-stent occlusion, and hyperperfusion syndrome were significantly more prevalent in the symptomatic group (47 [0.9%] vs 8 [0.2%], aOR: 4.41 [95% CI: 1.68-11.6]; 73 [1.4%] vs 12 [0.3%], aOR: 3.56 [95% CI: 1.71-7.39]; 45 [0.8%] vs 19 [0.4%], aOR: 2.18 [95% CI: 1.08-4.40]; and 102 [1.9%] vs 36 [0.8%], aOR: 1.78 [95% CI: 1.17-2.71], respectively). Other secondary outcomes were not significantly different between the 2 groups. CONCLUSIONS: The complication rate after specialist-involved CAS at 30 days was low in real-world practice.

One-Stage Combined Open and Endovascular Treatment Using a Hybrid Operating Room is Safe and Effective for Distal Middle Cerebral Artery Aneurysms.

BACKGROUND: Aneurysms located in the distal middle cerebral artery (DMCA) are relatively rare and lack an established treatment strategy. For DMCA aneurysms, we performed a one-stage combined procedure of endovascular parent artery occlusion (PAO) with coils and superficial temporal artery to middle cerebral artery (STA-MCA) bypass in a hybrid operating room (HOR). The aim of this study was to evaluate the safety and efficacy of this procedure. METHODS: Cases of unruptured DMCA aneurysms treated with the one-stage combined PAO and STA-MCA bypass in HOR were retrospectively examined, and patients' and aneurysmal backgrounds, surgical procedures, and treatment outcomes were analyzed. RESULTS: Six patients were included in the study. The average maximum diameter of the aneurysms was 14.4 mm. One aneurysm was located at M2 and five at M3. All aneurysms had a fusiform shape. No cases were associated with infection, trauma, or malignant tumors. In all 6 cases, the combined PAO and STA-MCA bypass was successfully completed. No postoperative hemorrhagic complications occurred. A symptomatic ischemic complication occurred in 1 case whose symptom disappeared in a week. Three months after surgery, complete obliteration of the aneurysm and patency of the bypass was confirmed in all cases. CONCLUSIONS: The one-stage combined PAO and STA-MCA bypass in the HOR is safe and effective for DMCA aneurysms, potentially serving as a treatment option for this complex aneurysm.

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature.

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Risk Factors for Thrombocytopenia Induced by Capecitabine Plus Oxaliplatin Therapy in Patients With Colorectal Cancer.

BACKGROUND/AIM: Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients. PATIENTS AND METHODS: Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores. RESULTS: Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×103/µl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients. CONCLUSION: Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC.

A Review of Current Flow Diverters.

Flow diverter (FD) devices are new-generation stents placed in the parent artery at the aneurysmal neck to obstruct intra-aneurysmal blood flow, thus favoring intra-aneurysmal thrombosis. In Japan, about eight years have passed since health insurance approval was granted for FD devices, and FD placement to treat aneurysms has become widespread. Treatment indications have also been expanded with the introduction of novel devices. At present, three types of FD (Pipeline, FRED, and Surpass Streamline) are available in Japan. This report represents a compilation of available FD technologies and describes the current consensus on this treatment.

Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

Development of a rapid detection method for the macrolide resistance gene in Mycobacterium avium using the amplification refractory mutation system-loop-mediated isothermal amplification method.

Macrolide antibiotics such as clarithromycin (CLR) and azithromycin are the key drugs used in multidrug therapy for Mycobacterium avium complex (MAC) diseases. For these antibacterial drugs, drug susceptibility has been correlated with clinical response in MAC diseases. We have previously demonstrated the correlation between drug susceptibility and mutations in the 23S rRNA gene, which confers resistance to macrolides. Herein, we developed a rapid detection method using the amplification refractory mutation system (ARMS)-loop-mediated isothermal amplification (LAMP) technique to identify mutations in the 23S rRNA gene of M. avium. We examined the applicability of the ARMS-LAMP method to genomic DNA extracted from six genotypes of M. avium clinical isolates. The M. avium isolates were classified into 21 CLR-resistant and 9 CLR-susceptible strains based on the results of drug susceptibility tests; the 23S rRNA genes of these strains were sequenced and analyzed using the ARMS-LAMP method. Sequence analysis revealed that the 9 CLR-sensitive strains were wild-type strains, whereas the 21 CLR-resistant strains comprised 20 mutant-type strains and one wild-type strain. Using ARMS-LAMP, no amplification from genomic DNAs of the 10 wild-type strains was observed using the mutant-type mismatch primer sets (MTPSs); however, amplification from the 20 mutant-type strain DNAs was observed using the MTPSs. The rapid detection method developed by us integrates ARMS-LAMP with a real-time turbidimeter, which can help determine drug resistance in a few hours. In conclusion, ARMS-LAMP might be a new clinically beneficial technology for rapid detection of mutations.IMPORTANCEMultidrug therapy for pulmonary Mycobacterium avium complex disease is centered on the macrolide antibiotics clarithromycin and azithromycin, and resistance to macrolides is an important prognosticator for clinical aggravation. Therefore, it is important to develop a quick and easy method for detecting resistance to macrolides. Drug resistance is known to be correlated with mutations in macrolide resistance genes. We developed a rapid detection method using amplification refractory mutation system (ARMS)-loop-mediated isothermal amplification (LAMP) to identify a mutation in the 23S rRNA gene, which is a macrolide resistance gene. Furthermore, we examined the applicability of this method using M. avium clinical isolates. The rapid method developed by us for detection of the macrolide resistance gene by integrating ARMS-LAMP and a real-time turbidimeter can help in detection of drug resistance within a few hours. Since this method does not require expensive equipment or special techniques and shows high analytical speed, it would be very useful in clinical practice.

Pathological changes in the lenticulostriate artery indicate the mechanisms leading to intracranial hemorrhage in Moyamoya disease: a case report.

This case report details the pathological findings of a vessel wall identified as the bleeding point for intracranial hemorrhage associated with Moyamoya disease. A 29-year-old woman experienced intracranial hemorrhage unrelated to hyperperfusion following superficial temporal artery-middle cerebral artery bypass surgery. A pseudoaneurysm on the lenticulostriate artery (LSA) was identified as the causative vessel and subsequently excised. Examination of the excised pseudoaneurysm revealed a fragment of the LSA, with a disrupted internal elastic lamina and media degeneration. These pathological findings in a perforating artery, akin to the circle of Willis, provide insights into the underlying mechanisms of hemorrhage in Moyamoya disease.

Plaque Ulcerations are Associated with Recurrence in Symptomatic Low-Grade Carotid Stenosis.

OBJECTIVE: Surgical indications for low-grade carotid stenosis have not yet been established. This study aimed to clarify the characteristics of low-grade carotid stenosis refractory to medical treatment. METHODS: We retrospectively analyzed 48 patients with symptomatic low-grade carotid stenosis (<50%). Recurrence was defined as an ipsilateral ischemic event in the symptomatic lesions during the follow-up period. Patient demographics and imaging findings were compared between the recurrence and nonrecurrence groups to investigate risk factors associated with medical treatment. RESULTS: The mean age was 74.1 (58-90 years), and the mean follow-up period was 35.4 months (2.0-97 months). Recurrence occurred in 15 of the symptomatic patients. Ulceration was significantly associated with recurrence under medical treatment (P = 0.001). The median time to recurrence was 26.1 months in patients with ulcers and 54.3 months in those without ulcers (P = 0.04). Pathological study with recurrence showed plaque rupture with multilayered lesions, indicating lesions refractory to medical treatment. CONCLUSIONS: In cases of low-grade carotid stenosis, lesions with ulcerations are likely refractory to medical therapy. Consideration of the indications for surgical treatment may be warranted for lesions with ulceration, even if the degree of stenosis is low.

Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Irreversible postoperative cognitive impairment after unruptured intracranial aneurysm treatment in the elderly.

PURPOSE: Postoperative cognitive dysfunction and recovery remain unclear in older patients undergoing interventional therapies for unruptured intracranial aneurysms (UIAs). This study aimed to compare changes in postoperative cognitive function between younger and older patients and to detect factors associated with non-recovery from postoperative cognitive dysfunction. METHODS: This study reviewed 59 consecutive patients with UIAs who underwent interventional therapies, including microsurgical clipping or endovascular treatment, from 2021 to 2022. All patients were divided into the older (aged ≥ 70 years) and younger (aged < 70 years) groups. Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) were performed within 2 months before interventions, at 1 week postoperatively (POW1), and 3-6 months postoperatively (POM3-6). RESULTS: MMSE and FAB scores decreased more frequently in the older group than in the younger group at POW1 (older vs. younger: MMSE: 48% vs. 21%, p < 0.05; FAB: 56% vs. 18%, p < 0.01). In the older group, the FAB Z-score decreased in POW1 and recovered by POM3-6 (p < 0.01), while the MMSE Z-score continued to decrease (p = 0.04). Age and the preoperative MSME Z-score were significantly associated with non-recovery from decreased MMSE score at POM3-6 (recovery vs. non-recovery, age: 62 years old vs. 72 years old, p = 0.03, preoperative MMSE Z-score: 0.16 vs. - 0.90, p < 0.01). CONCLUSIONS: This retrospective study found that older patients were more likely to have a postoperative cognitive decline after UIA treatment and implicated that global cognitive function tended to decline more than executive function in the long term. In addition, this study demonstrated that lower preoperative cognitive function was associated with inadequate postoperative cognitive recovery. The findings potentially contribute to the establishment of indications for treating UIAs in older patients.

Difficulties in Carotid Artery Stenting Due to Calcified Nodules: A Case Report.

The feasibility of carotid artery stenting (CAS) for carotid stenosis with severely calcified plaque remains controversial. Understanding the features associated with CAS difficulty in lesions with severe calcification is crucial. Calcified nodules, one of the morphological patterns of calcified plaques, have not been assessed for their association with the feasibility of CAS, even though they are associated with failure of percutaneous coronary intervention (PCI) in coronary arteries. We present a rare case of carotid stenosis with calcified nodules in whom CAS was unsuccessful and who was subsequently successfully treated by carotid endarterectomy (CEA). A 79-year-old man presented with a transient ischemic attack caused by severe stenosis of the right internal carotid artery and opted for CAS. During the procedure, multiple attempts at balloon angioplasty using a 3.5-mm balloon were made, but effective dilation could not be achieved, resulting in recoil. Subsequently, the patient underwent carotid endarterectomy (CEA), and the excised specimen revealed a calcified nodule, a large nodular calcified plaque protruding into the lumen. The patient was discharged with a modified Rankin Scale score of 0 at 19 days after the CEA. The protrusion of this large calcified nodule into the lumen was deemed responsible for the inadequate stent dilation. Although rarely reported in carotid stenosis, calcified nodules might represent a challenging plaque type for CAS treatment.

Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target.

Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in Arhgap10 S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways.

Impact of tailored multimodal treatment for unruptured brain arteriovenous malformation: comparison with a randomized trial of unruptured brain arteriovenous malformations.

PURPOSE: The first randomized controlled study on unruptured brain arteriovenous malformations (bAVM), the ARUBA trial, demonstrate the superiority of medical management; however, it failed to completely rule out the efficacy of therapeutic interventions due to several limitations. This study aimed to examine the outcomes of multimodal interventional treatment for bAVM in terms of safety and efficacy. METHODS: We reviewed 226 consecutive patients with unruptured bAVM admitted to our institute between 2002 and 2022. Treatment methods were divided into medical management and therapeutic intervention, including microsurgery, stereotactic surgery, and endovascular intervention. First, the choice of therapeutic modalities was assessed in the pre-ARUBA (before February 2014) and post-ARUBA (after March 2014) eras. Second, the incidence of symptomatic stroke or death and functional prognosis with a modified Rankin scale (mRS) score of ≥2 at 5 years was compared between the medical management and therapeutic intervention. RESULTS: In the pre- and post-ARUBA groups, 73% and 84% of patients underwent therapeutic interventions, respectively (p = 0.053). The rate of symptomatic stroke or death was lower in patients who underwent interventional therapies than in those who underwent medical management (9.7% vs. 22%, p = 0.022); however, the opposite was observed in the ARUBA trial (31% vs. 10%). The annual incidence of stroke or death was also lower in the interventional therapy group (4.3%/y vs. 1.8%/year, hazard ratio = 0.45, 95% confidence interval: 0.18-1.08, p = 0.032). The rate of mRS score of ≥2 after a 5-year follow-up was 18% and 6% in the medical treatment and intervention groups (p = 0.14). CONCLUSIONS: The therapeutic intervention rate did not decrease, even after the publication of the ARUBA trial. The rate of stroke or death was lower in the intervention group, indicating that a tailored choice of multimodality is safe and effective for managing unruptured bAVM.

Emotional behaviors as well as the hippocampal reelin expression in C57BL/6N male mice chronically treated with corticosterone.

Depression is a common psychiatric disorder affecting around 300 million people worldwide. Serum cortisol and glucocorticoid levels in humans are reportedly higher in patients with depression compared to controls. Furthermore, rodents repeatedly treated with exogenous corticosterone (CORT), a glucocorticoid in rodents, exhibit deficits in emotional behaviors. To confirm the availability of mice with chronic CORT treatment as an animal model of depression, we investigated the effect of chronic CORT treatment on depression-like behavioral and neuropathological phenotypes in C57BL/6N male mice. Behavioral studies showed depression- and anxiety-like behaviors in mice treated with CORT compared with control mice in the forced-swim and elevated-plus maze tests. Additionally, treated mice represented anhedonia and social behavior impairments in the sucrose preference and social interaction tests, respectively. Brains of depression patients have altered expression of reelin, an extracellular matrix protein involved in neuronal development and function. Likewise, in the present study, mice with chronic CORT treatment also exhibited reelin downregulation in cells of the hippocampus. Hence, we investigated therapeutic effects of reelin supplementation on CORT-induced behavioral abnormalities in mice. Microinjections of recombinant reelin protein into the hippocampus did not rescue behavioral deficits in mice with chronic CORT treatment. These results suggest that C57BL/6N male mice chronically treated with CORT are a suitable animal depression model, in which depressive behaviors may occur independently of the alternation of hippocampal Reelin expression.