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A 59-year-old man was admitted to our hospital with hyponatremia. An endocrine examination indicated panhypopituitarism, and magnetic resonance imaging revealed a mass-like lesion in the pituitary gland. Sinus endoscopy revealed a fungal mass in the sphenoid sinus, and the patient was diagnosed with hypopituitarism due to aspergillosis of the central nervous system (CNS). The patient's hyponatremia resolved with hydrocortisone replacement. Although the right internal carotid artery was eventually occluded, antifungal medications were administered for the aspergillosis, and the patient's general condition improved. The patient's CNS lesions have remained under control since discharge. This is the first case to suggest that ACTH secretion may be relatively preserved in Aspergillus-induced hypopituitarism.

Campylobacter gracilis inhabits the gingival sulcus and has been reported to cause various periodontal diseases; it has rarely been reported to cause bacteremia. We describe a case of a two-year-old boy who presented with a consciousness disorder and was transferred to our hospital for treatment of a brain abscess. Magnetic resonance imaging (MRI) showed a 6-cm brain abscess in the right frontal lobe. Urgent drainage and antibiotic administration resulted in a favorable clinical course, and the patient was discharged on the 34th day of hospitalization. Streptococcus anginosus and C. gracilis were identified in the pus. Brain abscesses caused by C. gracilis have rarely been reported, which makes this a valuable case., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This work was supported by the Kochi Organization for Medical Reformation and Renewal (to YA). . Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Arakawa et al.)

NLR family proteins act as intracellular receptors. Gene duplication amplifies the number of NLR genes, and subsequent mutations occasionally provide modifications to the second gene that benefits immunity. However, evolutionary processes after gene duplication and functional relationships between duplicated NLRs remain largely unclear. Here, we report that the rice NLR protein Pit1 is associated with its paralogue Pit2. The two are required for the resistance to rice blast fungus but have different functions: Pit1 induces cell death, while Pit2 competitively suppresses Pit1-mediated cell death. During evolution, the suppression of Pit1 by Pit2 was probably generated through positive selection on two fate-determining residues in the NB-ARC domain of Pit2, which account for functional differences between Pit1 and Pit2. Consequently, Pit2 lost its plasma membrane localization but acquired a new function to interfere with Pit1 in the cytosol. These findings illuminate the evolutionary trajectory of tandemly duplicated NLR genes after gene duplication., (© 2024. The Author(s).)

Background: Acute embolic occlusion of the common carotid artery (CCA) alone is rare. However, once it occurs, recanalization is challenging due to the large volume of the clot, larger diameter of the CCA, and risk of procedure-related distal embolism into the intracranial arteries., Observations: The authors report two cases of acute embolic occlusion of CCA alone, caused by a cardiac embolus trapped at the proximal end of a preexisting atherosclerotic plaque at the cervical carotid bifurcation. In both cases, the CCA was successfully recanalized using retrograde thrombectomy in a hybrid operating room. In case 1, a 78-year-old male with acute right CCA occlusion underwent retrograde thrombectomy, where the cervical carotid bifurcation was exposed and incised, and the entire embolus was retrieved with forceps. Despite successful revascularization, massive bleeding from the CCA just after the retrieval remained a concern. In case 2, a 79-year-old female with acute right CCA occlusion underwent retrograde thrombectomy in the same manner. Because manual retrieval failed, a Fogarty balloon catheter inserted from the arteriotomy successfully retrieved the entire thrombus with minimal blood loss., Lessons: Retrograde thrombectomy through the arteriotomy of the cervical carotid bifurcation safely and effectively recanalizes acute embolic occlusion of the CCA alone.

Background: Although non-stroke vertebral artery dissection (VAD) is diagnosed using MRI, detecting the subtle intravascular structure remains challenging. This study aimed to evaluate the validity of quantitative intravascular scanning based on novel zoomed high-resolution black blood (Z-HB) MRI for distinguishing VAD from other vessel pathologies., Methods: Twenty-one patients with non-stroke VAD and 18 with symptomatic atherosclerotic plaques in their vertebral artery underwent Z-HB MRI and subsequent profile curve processing. Axial Z-HB imaging was obtained from dissected and normal segments in patients with VAD and atherosclerotic plaque in patients with ischemia. We investigated the qualitative categorization of the scanning patterns of the intravascular signals. We also evaluated the quantitative ability of each profile curve to discriminate multiple vessel pathologies by analyzing the receiver operating characteristics curves., Results: Profile curve processing of 140 Z-HB images categorized the intravascular signal patterns into luminal, asymmetrical, and omega types. The asymmetrical type included both dissecting and atherosclerotic vessels, and the omega type included dissecting and normal vessels. In the asymmetrical type, quantitative evaluation successfully distinguished intramural hematomas of VAD from atherosclerotic plaque with an area under the curve of 0.80. The intimal flap of the VAD was distinguished from the blood flow artifact of the normal vessel with an area under the curve of 0.93 in the omega type., Conclusions: A combination of novel Z-HB MRI and profile curve processing provided an ultra-high-resolution analysis of the intravascular structure of non-stroke VAD and successfully distinguished VAD from normal vessels or atherosclerotic plaques., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To examine whether the Areal Deprivation Index (ADI), an indicator of the socioeconomic status of the community the patient resides in, is associated with delayed arrival at the hospital and poor outcomes in patients with acute ischaemic stroke from a prefecture-wide stroke database in Japan., Design: Retrospective study., Setting: Twenty-nine acute stroke hospitals in Kochi prefecture, Japan., Participants: Nine thousand and six hundred fifty-one patients with acute ischaemic stroke who were urgently hospitalised, identified using the Kochi Acute Stroke Survey of Onset registry. Capital and non-capital areas were analysed separately., Primary and Secondary Outcome Measures: Prehospital delay defined as hospital arrival ≥4-hour after stroke onset, poor hospital outcomes (in-hospital mortality and discharge to a nursing facility) and the opportunities of intravenous recombinant tissue plasminogen activator (rt-PA) and endovascular reperfusion therapy., Results: In the overall cohort, prehospital delay was observed in 6373 (66%) patients. Among individuals residing in non-capital areas, those living in municipalities with higher ADI (more deprived) carried a significantly higher risk of prehospital delay (per one-point increase, OR (95% CI) 1.45 (1.26 to 1.66)) by multivariable logistic regression analysis. In-hospital mortality (1.45 (1.02 to 2.06)), discharge to a nursing facility (1.31 (1.03 to 1.66)), and delayed candidate arrival ≥2-hour of intravenous rt-PA (2.04 (1.30 to 3.26)) and endovascular reperfusion therapy (2.27 (1.06 to 5.00)), were more likely to be observed in the deprived areas with higher ADI. In the capital areas, postal-code-ADI was not associated with prehospital delay (0.97 (0.66 to 1.41))., Conclusions: Living in socioeconomically disadvantaged municipalities was associated with prehospital delays of acute ischaemic stroke in non-capital areas in Kochi prefecture, Japan. Poorer outcomes of those patients may be caused by delayed treatment of intravenous rt-PA and endovascular reperfusion therapy. Further studies are necessary to determine social risk factors in the capital areas., Trial Registration Number: This article is linked to a clinical trial to UMIN000050189, No.: R000057166 and relates to its Result stage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Apathy is frequently observed in idiopathic normal pressure hydrocephalus (iNPH) and worsens cognitive impairment and gait disturbance. In this study, we evaluated the regions associated with apathy in iNPH using statistical imaging analysis on the whole brain, both in terms of cerebral blood flow and gray matter volume. Twenty-seven patients with iNPH were assigned to two groups based on their scores on the neuropsychiatric inventory items related to apathy; 18 patients were assigned to the group with apathy (iNPH + APA) and 9 to the group without apathy (iNPH - APA). The magnetic resonance images and cerebral blood flow single-photon emission computed tomography data of the two groups were compared using statistical parametric mapping 12. The regional gray matter volume of the right precuneus was significantly larger in the iNPH + APA group than in the iNPH - APA group, but the regional cerebral blood flow in any region of the brain was not significantly different between the two groups. These results suggested that the larger gray matter volume, which is thought to reflect gray matter compression, in the precuneus might be involved in apathy in iNPH., (© 2022. The Author(s).)

The "Izumo Study" revealed the incidence rate of subarachnoid hemorrhage (SAH) in Izumo City, Shimane Prefecture, Japan, from 1980 to 1998. However, no study has been published regarding the incidence of SAH in Shimane Prefecture after 1998. Most studies reporting the incidence of SAH in Japan have been conducted before 2000, although a few have been reported after 2000. This study aimed to assess the estimated age-adjusted incidence rate (AAIR) of SAH in Shimane Prefecture after 1998, following the Izumo Study. A retrospective study was conducted to identify the estimated AAIR of SAH in Shimane Prefecture, using the age-adjusted SAH mortality rate for this population from 1999 to 2017 and assuming that the case-fatality rate of SAH decreased by 0.7% annually from 45% in 1999 to 32.4% in 2017. We used linear regression analysis for trend to the estimated AAIR of SAH. Sensitivity analyses were also conducted by various case-fatality rates of SAH using assuming case-fatality rate based on previous reports. The estimated AAIR of SAH in Shimane Prefecture declined from 33.6 (95% confidence interval [CI]: 29.7-37.9) per 100,000 person-years in 1999, by 26.5%, to 24.7 (95% CI: 21.4-28.5) in 2017 (p < 0.01, r = 0.58). Declining trend of incidence rate of SAH in Shimane Prefecture from 1999 to 2017 was confirmed in this study.

Background: Surgical clipping of anterior communicating artery (ACoA) aneurysms remains challenging due to their complex anatomy. Anatomical risk factors for ACoA aneurysm surgery require further elucidation. The aim of this study is to investigate whether proximity of the midline perforating artery, subcallosal artery (SubCA), and associated anomaly of the ACoA complex affect functional outcomes of ACoA aneurysm surgery., Methods: A total of 92 patients with both unruptured and ruptured ACoA aneurysms, who underwent surgical clipping, were retrospectively analyzed from a multicenter, observational cohort database. Association of ACoA anatomy with SubCA origin at the aneurysmal neck under microsurgical observation was analyzed in the interhemispheric approach subgroup (n = 56). Then, we evaluated whether anatomical factors associated with SubCA neck origin affected surgical outcomes in the entire cohort (both interhemispheric and pterional approaches, n = 92)., Results: In the interhemispheric approach cohort, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was stratified to have the highest probability of the SubCA neck origin by a decision tree analysis. Then, among the entire cohort using either interhemispheric or pterional approach, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was significantly associated with poor functional outcomes by multivariable logistic regression analysis (OR 6.76; 95% CI 1.19-38.5; p = 0.03) as compared with A1 symmetry group in the acute subarachnoid hemorrhage settings., Conclusion: Combination of A1 asymmetry and larger aneurysmal size was significantly associated with SubCA aneurysmal neck origin and poor functional outcomes in ACoA aneurysm surgery. Interhemispheric approach may be proposed to provide a wider and unobstructed view of SubCA for ACoA aneurysms with this high-risk anatomical variant., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Delirium in patients with acute decompensated heart failure (ADHF) is associated with poor clinical outcomes. Although some medications have been reported as risk factors for delirium, their impact on patients with ADHF is still unclear. This study aimed to determine the association of specific medication use with delirium and their additive predictive value in models based on conventional risk factors., Methods and Results: In this single-center, retrospective study, 650 patients treated for ADHF were included. Fifty-nine patients (9.1%) had delirium. In multivariate analysis, anxiolytic benzodiazepines [odds ratio (OR): 6.4, 95% confidence interval (CI): 2.8-15], mechanical ventilation or noninvasive positive pressure ventilation (OR: 6.0, 95% CI: 2.9-12), depression (OR: 3.2, 95% CI: 1.5-6.5), intensive care or high care unit admission (OR: 2.9, 95% CI: 1.5-5.6), male sex (OR: 2.0, 95% CI: 1-3.7), and age (OR: 1.1, 95% CI: 1-1.1) were independently associated with severe delirium. The predictive model that included anxiolytic benzodiazepines had a significantly better discriminatory ability for the incidence of severe delirium than the conventional model., Conclusions: The use of anxiolytic benzodiazepines was independently correlated with severe delirium, and their use in models based on conventional risk factors had an additive value for predicting delirium in patients with ADHF., Competing Interests: The authors have declared that no competing interests exist.

Background: 5-Aminolevulinic acid (5-ALA) is useful as a photodynamic agent, but its use commonly leads to hypotension. Although avoiding a mean arterial pressure (MAP) < 60 mmHg is important, the incidence of MAP < 60 mmHg when using 5-ALA is unclear. Therefore, we conducted a retrospective study to assess the incidence of post-induction hypotension and identified risk factors of this phenomenon., Methods: One-hundred and seventy-two consecutive patients who underwent transurethral resection of the bladder tumor or craniotomy with the use of 5-ALA were enrolled. The primary outcome was the incidence of post-induction hypotension, defined as MAP < 60 mmHg during the first 1 h after anesthesia induction. We divided participants into the normal blood pressure group (group N) and the hypotension group (group L)., Results: The incidence of post-induction hypotension was 70% (group L = 121, group N = 51). Multivariate analysis revealed that female sex was an independent factor of post-induction hypotension (odds ratio [OR] 3.95; 95% confidence interval [CI] 1.21-12.97; p = 0.02). Systolic blood pressure < 100 mmHg before anesthesia induction and general anesthesia were also identified as significant independent factors (OR 13.30; 95% CI 1.17-151.0; p = 0.04 and OR 25.84; 95% CI 9.80-68.49; p < 0.001, respectively)., Conclusions: The incidence of post-induction hypotension was 70% in patients using 5-ALA. Female sex, systolic blood pressure < 100 mmHg before anesthesia induction, and general anesthesia might be independent factors of post-induction hypotension when using 5-ALA.

We report the use of small interfering RNAs (siRNAs) against ARHGEF4 , CCDC88A , LAMTOR2 , mTOR , NUP85 , and WASF2 and folic acid (FA)-modified polyethylene glycol (PEG)-chitosan oligosaccharide lactate (COL) nanoparticles for targeting, imaging, delivery, gene silencing, and inhibition of invasiveness and metastasis in an orthotopic xenograft model. In vitro assays revealed that these siRNA-FA-PEG-COL nanoparticles were specifically inserted into pancreatic cancer cells compared to immortalized normal pancreatic epithelial cells and knocked down expression of the corresponding targets in pancreatic cancer cells. Cell motility and invasion were significantly inhibited by adding target siRNA-FA-PEG-COL nanoparticles into the culture medium. In vivo mouse experiments confirmed that when intravenously delivered, these siRNA-FA-PEG-COL nanoparticles became incorporated into human pancreatic cancer cells in mouse pancreatic tumors. Little accumulation was seen in the normal pancreas and vital organs. All target siRNA-FA-PEG-COL nanoparticles significantly inhibited retroperitoneal invasion. The siRNA-FA-PEG-COL nanoparticles against LAMTOR2 , mTOR , and NUP85 , which strongly inhibited retroperitoneal invasion and significantly inhibited peritoneal dissemination compared to the other nanoparticles, improved prognosis of the mice. Our results imply that siRNA-FA-PEG-COL nanoparticles against these six targets could have great potential as biodegradable drug carriers. In particular, siRNA nanoparticles against LAMTOR2 , mTOR , and NUP85 may hold significant clinical promise., Competing Interests: CONFLICTS OF INTEREST The authors have declared that no competing interests exist.

Background: We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality., Methods: We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks., Results: Our trial met neither the primary (overall survival [OS]) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio [HR]: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (<70 y old, ≤70 kg, or PS0-2) was significantly longer than that for the corresponding placebo patients (HR: 0.49, 0.44, and 0.51), respectively. Preexisting immunity against both all 12 warehouse peptides besides SART2-93 and the other cytotoxic T lymphocyte epitope peptides was significantly depressed in the patients with SART2-93 selection (n = 21) compared with that of the patients without SART2-93 selection (n = 67). Biomarkers correlative for favorable OS of the PPV patients were a lower percentage of CD11b+CD14+HLA-DRlow immunosuppressive monocytes and a higher percentage of CD4+CD45RA- activated T cells, the intermediate levels of chemokine C-C ligand 2 (CCL2), vascular endothelial growth factor, interleukin (IL)-6, IL-17, or haptoglobin, respectively., Conclusion: This phase III trial met neither the primary nor secondary endpoints., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: We have demonstrated that i.c.v.-administered (±)-epibatidine, a nicotinic ACh receptor (nAChR) agonist, induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla with dihydro-β-erythroidin (an α4β2 nAChR antagonist)-sensitive brain mechanisms. Here, we examined central mechanisms for the (±)-epibatidine-induced responses, focusing on brain NOS and NO-mediated mechanisms, soluble GC (sGC) and protein S-nitrosylation (a posttranslational modification of protein cysteine thiol groups), in urethane-anaesthetized (1.0 g·kg -1 , i.p.) male Wistar rats., Experimental Approach: (±)-Epibatidine was i.c.v. treated after i.c.v. pretreatment with each inhibitor described below. Then, plasma catecholamines were measured electrochemically after HPLC. Immunoreactivity of S-nitrosylated cysteine (SNO-Cys) in α4 nAChR subunit (α4)-positive spinally projecting neurones in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of adrenomedullary outflow) after i.c.v. (±)-epibatidine administration was also investigated., Key Results: (±)-Epibatidine-induced elevation of plasma catecholamines was significantly attenuated by L-NAME (non-selective NOS inhibitor), carboxy-PTIO (NO scavenger), BYK191023 [selective inducible NOS (iNOS) inhibitor] and dithiothreitol (thiol-reducing reagent), but not by 3-bromo-7-nitroindazole (selective neuronal NOS inhibitor) or ODQ (sGC inhibitor). (±)-Epibatidine increased the number of spinally projecting PVN neurones with α4- and SNO-Cys-immunoreactivities, and this increment was reduced by BYK191023., Conclusions and Implications: Stimulation of brain nAChRs can induce elevation of plasma catecholamines through brain iNOS-derived NO-mediated protein S-nitrosylation in rats. Therefore, brain nAChRs (at least α4β2 subtype) and NO might be useful targets for alleviation of catecholamines overflow induced by smoking., (© 2018 The British Pharmacological Society.)

Extracellular zinc, which is released from hippocampal neurons in response to brain ischaemia, triggers morphological changes in microglia. Under ischaemic conditions, microglia exhibit two opposite activation states (M1 and M2 activation), which may be further regulated by the microenvironment. We examined the role of extracellular zinc on M1 activation of microglia. Pre-treatment of microglia with 30-60 μM ZnCl 2 resulted in dose-dependent increases in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNFα) secretion when M1 activation was induced by lipopolysaccharide administration. In contrast, the cell-permeable zinc chelator TPEN, the radical scavenger Trolox, and the P2X7 receptor antagonist A438079 suppressed the effects of zinc pre-treatment on microglia. Furthermore, endogenous zinc release was induced by cerebral ischaemia-reperfusion, resulting in increased expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, without hippocampal neuronal cell loss, in addition to impairments in object recognition memory. However, these effects were suppressed by the zinc chelator CaEDTA. These findings suggest that extracellular zinc may prime microglia to enhance production of pro-inflammatory cytokines via P2X7 receptor activation followed by reactive oxygen species generation in response to stimuli that trigger M1 activation, and that these inflammatory processes may result in deficits in object recognition memory.

The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m 2 /day) (Day 1-5) plus various doses of ACNU (30, 35, 40, 45 mg/m 2 /day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70-100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m 2 ) plus ACNU (40 mg/m 2 ). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12-35%) and 8% (95% CI, 4-15%). Median PFS was 13 months (95% CI, 9.2-17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67-89%) and 49% (95% CI, 33-57%). Median OS was 11.8 months (95% CI, 8.2-14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS., Competing Interests: The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices in the article. All authors who are members of The Japan Neurosurgical Society (JNS) have registered online Self-reported COI Disclosure Statement Forms through the website for JNS members. This manuscript has no COI that should be disclosed.

A 64-year-old man was referred to our hospital for treatment of a cerebral aneurysm that was incidentally found. The aneurysm was 7 mm in size and located on the left anterior communicating artery. Using a balloon assisted technique, we performed coil embolization. During the second coil insertion, the first coil was dislodged into the anterior communicating artery. We attempted coil retrieval using a snare, which was unsuccessful. We applied a direct aspiration first pass technique (ADAPT) and advanced a Penumbra 4MAX immediately proximal to the dislodged coil; the dislodged coil was then successfully retrieved. ADAPT is a simple procedure for retrieval of a detached coil, and it can be used as an alternative to the snare technique., (2015 BMJ Publishing Group Ltd.)

Background: The association between human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM) is becoming a new concept. However, information on the geographic variability of HCMV prevalence in GBM remains scarce. Moreover, the potential roles of various viruses, such as polyomaviruses and oncogenic viruses, in gliomagenesis remain unclear. Our aim was to investigate the prevalence of HCMV in GBM among Japanese patients. Furthermore, this was the first study that evaluated infection with four new human polyomaviruses in GBMs. This study also provided the first data on the detection of human papillomavirus (HPV) in GBM in the Eastern world., Methods: We measured the number of various viral genomes in GBM samples from 39 Japanese patients using real-time quantitative PCR. The tested viruses included HCMV, Merkel cell polyomavirus, human polyomavirus (HPyV) 6, HPyV7, HPyV9, Epstein-Barr virus, human herpesvirus 8, and HPV. Our quantitative PCR analysis led to the detection of eight copies of the HCMV DNA mixed with DNA extracted from 10(4) HCMV-negative cells. The presence of HCMV and HPV genomes was also assessed by nested PCR. Immunohistochemical study was also carried out to detect HPV-derived protein in GBM tissues., Results: The viral DNAs were not detectable, with the exception of HPV, which was present in eight out of 39 (21%) GBMs. All HPV-positive cases harbored high-risk-type HPV (HPV16 and HPV18). Moreover, the HPV major capsid protein was detected in GBM tumor cells., Conclusions: In contrast with previous reports from Caucasian patients, we did not obtain direct evidence in support of the association between HCMV and GBM. However, high-risk-type HPV infection may play a potential etiological role in gliomagenesis in a subset of patients. These findings should prompt further worldwide epidemiological studies aimed at defining the pathogenicity of virus-associated GBM.

Cancer stem cells (CSCs) are the sole population possessing high self-renewal activity in tumors, with their existence affecting tumor recurrence. However, the invasive activity of CSCs has yet to be fully understood. In this article, we established a tumor sphere culture of RSV-M mouse glioma cells (RSV-M-TS) and evaluated their migration and invasion activities. Histological analysis of a tumor formed by cranial injection of the RSV-M-TS cells showed highly invasive properties and similarities with human malignant glioma tissues. When the migration activity of both RSV-M and RSV-M-TS cells were compared by intracranial injection, rapid migration of RSV-M-TS cells was observed. To confirm the invasive capabilities of RSV-M-TS cells, a three-dimensional collagen invasion assay was performed in vitro using RSV-M, RSV-M-TS, and RSV-M-TS cells cultured with medium containing serum. RSV-M and RSV-M-TS cultured with medium containing serum for 8 days indicated low migration activity, while moderate invasion activity was observed in RSV-M-TS cells. This activity was further enhanced by incubation with medium containing serum overnight. To identify the genes involved in this invasion activity, we performed quantitative polymerase chain reaction (PCR) array analysis of RSV-M and RSV-M-TS cells. Of 84 cancer metastasis-related genes, up-regulation was observed in 24 genes, while 4 genes appeared to be down-regulated in RSV-M-TS cells. These results suggest that the enhanced invasive activity of glioma sphere cells correlates with a number of tumor metastasis-related genes and plays a role in the dissemination and invasion of glioma cells.

Angiotensin II (AngII) plays important roles in the regulation of cardiovascular function. Both peripheral and central actions of AngII are involved in this regulation, but mechanisms of the latter actions as a neurotransmitter/neuromodulator within the brain are still unclear. Here we show that (1) intracerebroventricularly (i.c.v.) administered AngII in urethane-anesthetized male rats elevates plasma adrenaline derived from the adrenal medulla but not noradrenaline with valsartan- (AT1 receptor blocker) sensitive brain mechanisms, (2) peripheral AT1 receptors are not involved in the AngII-induced elevation of plasma adrenaline, although AngII induces both noradrenaline and adrenaline secretion from bovine adrenal medulla cells, and (3) i.c.v. administered AngII elevates blood pressure but not heart rate with the valsartan-sensitive mechanisms. From these results, i.c.v. administered AngII acts on brain AT1 receptors, thereby inducing the secretion of adrenaline and pressor responses. We propose that the central angiotensinergic system can activate central adrenomedullary outflow and modulate blood pressure.

Brain concussions are a serious public concern and are associated with neuropsychiatric disorders, such as depression. Patients with concussion who suffer from depression often experience distress. Nevertheless, few pre-clinical studies have examined concussion-induced depression, and there is little information regarding its pharmacological management. Edaravone, a free radical scavenger, can exert neuroprotective effects in several animal models of neurological disorders. However, the effectiveness of edaravone in animal models of concussion-induced depression remains unclear. In this study, we examined whether edaravone could prevent concussion-induced depression. Mice were subjected to a weight-drop injury and intravenously administered edaravone (3.0 mg/kg) or vehicle immediately after impact. Serial magnetic resonance imaging showed no abnormalities of the cerebrum on diffusion T1- and T2-weighted images. We found that edaravone suppressed concussion-induced depressive-like behavior in the forced swim test, which was accompanied by inhibition of increased hippocampal and cortical oxidative stress (OS) and suppression of 5-lipoxygenase (5-LOX) translocation to the nuclear envelope in hippocampal astrocytes. Hippocampal OS in concussed mice was also prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, and administration of BWB70C, a 5-LOX inhibitor, immediately and 24 h after injury prevented depressive-like behaviors in concussed mice. Further, antidepressant effects of edaravone were observed in mice receiving 1.0 or 3.0 mg/kg of edaravone immediately after impact, but not at a lower dose of 0.1 mg/kg. This antidepressant effect persisted up to 1 h after impact, whereas edaravone treatment at 3 h after impact had no effect on concussion-induced depressive-like behavior. These results suggest that edaravone protects against concussion-induced depression, and this protection is mediated by suppression of OS and 5-LOX translocation.

Knowledge of anatomy visualized endoscopically is necessary to perform endoscopic surgical procedures safely. The cavernous sinuses are complicated structures with major blood vessels and nerves seated deeply in the center of the skull base. Anatomical orientation during surgery is essential for deep and narrow skull base surgery. While performing surgery involving the cavernous sinuses, understanding of the structures identifiable via a transsphenoidal view can allow comprehension of the relationship between a lesion and the surrounding structures, thus preventing intraoperative complications. The objective of this study was to dissect the neurovascular structures in the cavernous sinus deeply inside the oculomotor trigone through a transsphenoidal view, and to determine the relationships among anatomical landmarks in the path of surgery. Ten fresh silicone-injected cadaveric heads were evaluated. Four millimeter-diameter rigid endoscopes with 0° and 30° rod-lenses were utilized to perform an endonasal transsphenoidal approach. The detailed position and course of the major components in each cavernous sinus were assessed under panoramic view. We also validated the utility of this approach by successfully excising a huge pituitary adenoma.

Acute phase rehabilitation is an important treatment for improving the functional outcome of patients after stroke. The present cohort study analyzed the feasibility and safety of acute phase rehabilitation using the hybrid assistive limb robot suit in 22 patients, 7 males and 15 females (mean age 66.6 ± 17.7 years). Neurological deterioration, mortality, or other accidents were recorded as adverse events. Baseline characteristics of each patient were recorded at the first hybrid assistive limb rehabilitation. Hybrid assistive limb rehabilitation was conducted for 12.1 ± 7.0 days with the patients in stable condition. Acute phase hybrid assistive limb rehabilitation was performed a total of 84 times with no adverse events recorded except for orthostatic hypotension. Good functional outcomes were obtained in 14 patients. Orthostatic hypotension was observed during the first hybrid assistive limb rehabilitation in four patients, and was significantly associated with intracerebral hemorrhage (p = 0.007) and lower Brunnstrom stage (p = 0.033). Acute phase rehabilitation using the hybrid assistive limb suit is feasible and safe. Patients with intracerebral hemorrhage and lower Brunnstrom stage should be carefully monitored for orthostatic hypotension.

Myosin light chain (MLC) phosphorylation plays important roles in various cellular functions such as cellular morphogenesis, motility, and smooth muscle contraction. MLC phosphorylation is determined by the balance between activities of Rho-associated kinase (Rho-kinase) and myosin phosphatase. An impaired balance between Rho-kinase and myosin phosphatase activities induces the abnormal sustained phosphorylation of MLC, which contributes to the pathogenesis of certain vascular diseases, such as vasospasm and hypertension. However, the dynamic principle of the system underlying the regulation of MLC phosphorylation remains to be clarified. Here, to elucidate this dynamic principle whereby Rho-kinase regulates MLC phosphorylation, we developed a mathematical model based on the behavior of thrombin-dependent MLC phosphorylation, which is regulated by the Rho-kinase signaling network. Through analyzing our mathematical model, we predict that MLC phosphorylation and myosin phosphatase activity exhibit bistability, and that a novel signaling pathway leading to the auto-activation of myosin phosphatase is required for the regulatory system of MLC phosphorylation. In addition, on the basis of experimental data, we propose that the auto-activation pathway of myosin phosphatase occurs in vivo. These results indicate that bistability of myosin phosphatase activity is responsible for the bistability of MLC phosphorylation, and the sustained phosphorylation of MLC is attributed to this feature of bistability.

Aim: The aim of this study was to clarify the relationship between platelet-derived microparticles (PDMPs) and the Framingham 10-yr coronary heart disease (CHD) risk score., Methods: A cross-sectional study of healthy volunteers free of medication, and cardiovascular or cerebrovascular disease was conducted. The subjects were 190 Japanese men (median age 41). An ELISA kit and monoclonal antibodies against CD42b and CD42a (glycoprotein Ib and IX) were used., Results: PDMPs are correlated with platelet count, high sensitivity C-reactive protein (hsCRP), and diastolic blood pressure by multivariate analysis (R(2)=0.316, p <0.001). Quartile range of PDMPs is significantly associated with the 10-yr CHD risk score after adjusting for age, platelet count, hsCRP, and hypertension (p=0.033) and for age, platelet count, hsCRP, and presence of metabolic syndrome (MS) (p=0.020). In individuals with a predicted 10-yr risk for CHD >or=8% (corresponding with the highest quartile), compared to those with a predicted 10-yr risk <8%, the odds ratio (OR), adjusted for age, platelet count, hsCRP, and hypertension, was 3.3 (1.2-8.9) and adjusted for age, platelet count, hsCRP, and MS, was 4.5 (1.6-11.8). The age-, platelet count-, hsCRP- and hypertension-adjusted OR for a 10-yr CHD risk score >or=8% was 0.8 (0.5-1.3) for hsCRP and 3.9 (1.6-9.4) for hypertension. The age-, platelet count-, hsCRP- and MS -adjusted OR for a 10-yr CHD risk score >or=8% was 0.7 (0.4-1.2) for hsCRP and 7.9 (2.6-24.5) for MS., Conclusion: Elevated PDMPs are associated with the 10-yr CHD risk score in healthy men.

The preventive effect of aggressive blood pressure lowering on hematoma enlargement was investigated in patients with ultra-acute spontaneous intracerebral hemorrhage (ICH). Retrospective review of 248 patients (145 males, 103 females) with spontaneous ICH treated in our hospital between 2005 and 2008 identified patients with ultra-acute ICH who were directly taken to our institute by ambulance within 3 hours after onset. Patients who could not be assessed twice by computed tomography (CT) within 24 hours after arrival were excluded. Systolic blood pressure (SBP) was aggressively controlled in all patients using intravenous nicardipine to below 140 mmHg as soon as possible after diagnosis of ICH with CT. Hematoma enlargement was defined as increase in volume of more than 33% or more than 12.5 ml in the first 24 hours. Hematoma enlargement was observed in 11 of the 73 patients (15.0%). The time course of SBP change was not significantly different in patients with and without hematoma enlargement. The incidence of hematoma enlargement in patients with ultra-acute ICH in this study was 15.0%, which was lower than that in other series in which blood pressure was not reduced aggressively. This finding suggests that aggressive SBP lowering to below 140 mmHg has a preventive effect on hematoma enlargement in patients with ultra-acute ICH.

A 67-year-old woman presented with symptomatic infarction in the territory of the anterior inferior cerebellar artery manifesting as vertigo, vomiting, and right facial weakness. Basiparallel anatomic scanning (BPAS) magnetic resonance (MR) imaging combined with MR angiography demonstrated the occluded anterior inferior cerebellar artery. Common anatomic variations and limited detection of the smaller branches on MR angiography sometimes hinder evaluation of the occluded artery. BPAS-MR imaging may have a supplementary role to MR angiography in the diagnosis of cerebellar artery occlusions.

The validity of regular use of antiplatelet agents was retrospectively assessed in 106 patients with intracerebral hemorrhage (ICH) (supratentorial hemorrhage 92, lobar 22 and deep 70; and infratentorial hemorrhage 14) who underwent T(2)*-weighted gradient-echo magnetic resonance (MR) imaging between January 2005 and December 2006 in Kishiwada City Hospital. The prevalence of cerebral microbleeds was 54.7% (58/106), and the presence was significantly associated with higher age (odds ratio 3.09, p = 0.007), presence of white matter hyperintensity on T(2)-weighted MR imaging (odds ratio 2.36, p = 0.032), and previous ICH and/or cerebral infarction (odds ratio 4.77, p = 0.020). Previous ICH and/or cerebral infarction was independently associated with the presence of cerebral microbleeds after adjustment for age, white matter hyperintensity, and hypertension (odds ratio 4.07, p = 0.043). Regular use of antiplatelet agents was not associated with the presence of cerebral microbleeds, whether the patients had cerebrovascular diseases or not. Our findings suggest that antiplatelet medication can be justified for patients with cerebral microbleeds.

Aim: The aim of this study was to evaluate the significance of endothelial cell-derived microparticles (EDMP), angiopoietin-2 (Ang-2) and adiponectin in hyperlipidemic patients with and without type 2 diabetes mellitus, and to compare the two for the effects of eicosapentaenoic acid (EPA) on these markers., Methods: One hundred and twenty-six hyperlipidemic patients with and without type 2 diabetes mellitus received EPA 1,800 mg daily, and 50 of the patients were non-diabetic., Results: EDMP and Ang-2 levels prior to treatment were higher in diabetic patients than in non-diabetic patients, whereas adiponectin levels were lower in diabetics. When diabetic patients were classified into two groups on the basis of Ang-2 levels, the levels of all markers remained unchanged in those without a high Ang-2 level after EPA treatment. In contrast, all markers except for adiponectin were decreased significantly in diabetic patients with high Ang-2 levels after 6 months of EPA treatment. These diabetic patients with high Ang-2 levels displayed a more significant increase in adiponectin levels after EPA treatment than those who did not., Conclusion: These results suggest that EPA possesses an adiponectin-dependent anti-atherosclerotic effect and may be beneficial for the prevention of vascular complications in diabetic patients with high Ang-2 levels.

A 45-year-old man presented with bilateral acute subdural hematomas (ASDHs) without subarachnoid hemorrhage (SAH). He was found comatose in a parked car. Computed tomography showed left frontal intracerebral hemorrhage (ICH) and bilateral ASDHs but no signs of SAH. Magnetic resonance angiography demonstrated an internal carotid artery dorsal wall aneurysm. Emergent surgical intervention was performed. However, he died of cerebral herniation 6 days later. We inferred that massive intracranial bleeding might have ruptured through the cortex and lacerated the arachnoid membrane. Aneurysm rupture generally results in unilateral SDH, whereas trauma is the usual cause of bilateral ASDHs with ICH. Our case suggests that ruptured aneurysm should be considered in patients with non-traumatic bilateral ASDHs without SAH.

DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1-/- mice. MBD1-/- mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1-/- neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1-/- mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.