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We report a rare case of a basilar artery occlusion (BAO) caused by thrombosis as an initial magnification of acute myelogenous leukemia (AML) and performed mechanical thrombectomy (MT) to treat it. A 67-year-old female presented left hemiparalysis of her arm and right-sided blindness. Magnetic resonance imaging (MRI) and magnetic resonance angiography revealed acute infarction in the left occipital and anterior lobes of the cerebellum and incomplete BAO. Her blood test showed hyperleukocytosis with precursor cells and high levels of C-reactive protein, and we diagnosed AML and disseminated intravascular coagulation (DIC). We decided to treat conservatively with rapid rehydration and heparin, but three hours after admission, she suddenly lost consciousness. We performed acute MT with a direct aspiration first-pass technique (ADAPT). A white elastic embolus was aspirated, and DSA showed successful recanalization of the basilar artery. The next day, MRI revealed acute infarction in the midbrain and bilateral thalamus. The patient remained unconscious after MT and so chemotherapy to treat the acute leukemia could not be performed. The patient died of the primary disease 14 days after BAO. Thrombosis in association with AML is very rare disease and could occur in arterial vessels because of hypercoagulation, and this tendency may not respond to anticoagulation therapy. Although ADAPT might be performed safety without complications even in cases of DIC, indications for treatment with MT should be carefully considered in patients in whom hemorrhage is a possibility.

Highlights • COVID-19 epidemic challenged medical systems’ capacity to provide adequate care. • Kobe City stroke facilities operated optimally due to among-facility cooperation. • Stroke incidence decreased but treatment rates increased during the outbreak. • No case of symptomatic stroke in patients with confirmed COVID-19 was recorded., Background The novel coronavirus disease 2019 (COVID-19) outbreak raised concerns over healthcare systems’ ability to provide suitable care to stroke patients. In the present study, we examined the provision of stroke care in Kobe City during the COVID-19 epidemic, where some major stroke centers ceased to provide emergency care. Methods This was a cross-sectional study. The Kobe Stroke Network surveyed the number of stroke patients admitted to all primary stroke centers (PSCs) in the city between March 1 and May 23, 2020, and between March 3 and May 25, 2019. In addition, online meetings between all PSC directors were held regularly to share information. The survey items included emergency response system characteristics, number of patients with stroke hospitalized within 7 days of onset, administered treatment types (IV rt-PA, mechanical thrombectomy, surgery, and endovascular therapy), and stroke patients with confirmed COVID-19. Results During the period of interest in 2020, the number of stroke patients hospitalized across 13 PSCs was 813, which was 15.5% lower than that during the same period of 2019 (p=0.285). The number of patients admitted with cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage decreased by 15.4% (p=0.245), 16.1% (p=0.659), and 14.0% (p=0.715), respectively. However, the rates of mechanical thrombectomy and surgery for intracerebral hemorrhage were slightly increased by 12.1% (p=0.754) and 5.0% (p=0.538), respectively. PSCs that ceased to provide emergency care reported a decrease in the number of stroke cases of 65.7% compared with the same period in 2019, while other PSCs reported an increase of 0.8%. No case of a patient with stroke and confirmed COVID-19 was reported during the study period. Conclusion Kobe City was able to maintain operation of its stroke care systems thanks to close cooperation among all city PSCs and a temporal decrease in the total number of stroke cases.

Background Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. Methods Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. Results Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. Conclusion Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed.

Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NFκB via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1. GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination. Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway. Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells.

Arterial spin labeling (ASL) involves perfusion imaging using the inverted magnetization of arterial water. If the arterial arrival times are longer than the post-labeling delay, labeled spins are visible on ASL images as bright, high intra-arterial signals (IASs); such signals were found within occluded vessels of patients with acute ischemic stroke. The identification of the occluded segment in the internal carotid artery (ICA) is crucial for endovascular treatment. We tested our hypothesis that high IASs on ASL images can predict the occluded segment.Our study included 13 patients with acute ICA occlusion who had undergone angiographic and ASL studies within 48 h of onset. We retrospectively identified the high IAS on ASL images and angiograms and recorded the occluded segment and the number of high IAS-positive slices on ASL images. The ICA segments were classified as cervical (C1), petrous (C2), cavernous (C3), and supraclinoid (C4).Of seven patients with intracranial ICA occlusion, five demonstrated high IASs at C1-C2, suggesting that high IASs could identify stagnant flow proximal to the occluded segment. Among six patients with extracranial ICA occlusion, five presented with high IASs at C3-C4, suggesting that signals could identify the collateral flow via the ophthalmic artery. None had high IASs at C1-C2. The mean number of high IAS-positive slices was significantly higher in patients with intra- than extracranial ICA occlusion.High IASs on ASL images can identify slow stagnant and collateral flow through the ophthalmic artery in patients with acute ICA occlusion and help to predict the occlusion site.

Approximately half of surgically-treated patients with low-grade-glioma (LGG) suffer recurrence or metastasis. Currently there is no effective drug treatment. While the selective COX-2 inhibitor celecoxib showed anti-neoplastic activity against several malignant tumors, its effects against LGG remain to be elucidated. Ours is the first report that the expression level of COX-2 in brain tissue samples from patients with LGG and in LGG cell lines is higher than in the non-neoplastic region and in normal brain cells. We found that celecoxib attenuated LGG cell proliferation in a dose-dependent manner. It inhibited the generation of prostaglandin E2 and induced apoptosis and cell-cycle arrest. We also show that celecoxib hampered the activation of the Akt/survivin- and the Akt/ID3 pathway in LGGs. These findings suggest that celecoxib may have a promising therapeutic potential and that the early treatment of LGG patients with the drug may be beneficial. Electronic supplementary material The online version of this article (doi:10.1007/s11060-017-2380-5) contains supplementary material, which is available to authorized users.

As the safety and effectiveness of urgent carotid artery stenting (CAS) for neurologically progressing patients remain controversial, we retrospectively analyzed the outcome of urgent CAS based on the patients’ pathophysiological condition and neuroimaging findings. We divided 71 patients who underwent CAS within 14 days of stroke onset into two groups. Group 1 (n = 35) was comprised of patients with progressing neurologic signs and a reversible ischemic penumbra on magnetic resonance images (MRI). They were treated by urgent CAS. Group 2 (n = 36) was neurologically stable and underwent prophylactic CAS. In all patients we recorded the National Institutes of Health Stroke Scale (NIHSS) score and the modified Rankin scale (mRS). Urgent CAS resulted in significant improvement in the NIHSS score, when compared before and after CAS in group 1 (5.3 ± 4.3, P < 0.01). The rate of good outcomes (mRS 0–2 at 3 months post-CAS) was 48.6% in group 1, and 75% in group 2. The cumulative incidence of ipsilateral stroke between 31 days and 1 year was 5.9% in group 1, and 0% in group 2. The procedural complication rate was similar in both groups (group 1: 5.7%, n = 2; group 2: 5.6%, n = 2). No patient suffered a symptomatic intracerebral hemorrhage. When the pathophysiological status and neuroimaging findings are used to determine patient eligibility for urgent CAS, this treatment improve neurologic outcome and can be performed as safely as prophylactic CAS in our cohort of patients with acute ischemic stroke.

Estrogen deficiency worsens ischemic stroke outcomes. In ovariectomized (OVX(+)) rats fed a high-salt diet (HSD), an increase in the body Na(+)/water ratio, which characterizes water-free Na(+) accumulation, was associated with detrimental vascular effects independent of the blood pressure (BP). We hypothesized that an increase in brain water-free Na(+) accumulation is associated with ischemic brain damage in OVX(+)/HSD rats. To test our hypothesis we divided female Wistar rats into 4 groups, OVX(+) and OVX(-) rats fed HSD or a normal diet (ND), and subjected them to transient cerebral ischemia. The brain Na(+)/water ratio was increased even in OVX(+)/ND rats and augmented in OVX(+)/HSD rats. The increase in the brain Na(+)/water ratio was positively correlated with expansion of the cortical infarct volume without affecting the BP. Interestingly, OVX(+) was associated with the decreased expression of ATP1α3, a subtype of the Na(+) efflux pump. HSD increased the expression of brain Na(+) influx-related molecules and the mineralocorticoid receptor (MR). The pretreatment of OVX(+)/HSD rats with the MR antagonist eplerenone reduced brain water-free Na(+) accumulation, up-regulated ATP1α3, down-regulated MR, and reduced the cortical infarct volume. Our findings show that the increase in the brain Na(+)/water ratio elicited by estrogen deficiency or HSD is associated with ischemic brain damage BP-independently, suggesting the importance of regulating the accumulation of brain water-free Na(+). The up-regulation of ATP1α3 and the down-regulation of MR may provide a promising therapeutic strategy to attenuate ischemic brain damage in postmenopausal women.

We report a rare case of aberrant internal carotid artery in the middle ear. The patient was a 30-year-old man with pulsatile tinnitus. MRA and 3D-CTA revealed an aberrant course of the internal carotid artery in the middle ear. 3D-CTA proved useful for radiographic diagnosis, leading to the observation of an aberrant internal carotid artery passing the foramen. We discuss the diagnosis and management of such patients.

Background: The susceptibility vessel sign on gradient echo-type-T2*-weighted imaging is a well-known marker of arterial occlusion. Stagnant flow in front of the middle cerebral artery (MCA) occlusion sites may contribute to the intra-arterial, high-intensity signal on arterial spin labeling magnetic resonance imaging (MRI), making it another potential marker of MCA occlusion. We compared the intra-arterial, high-intensity signal and susceptibility vessel sign in patients with symptomatic MCA occlusion and patients without major vessel occlusion. Methods: We identified transient ischemic attack or ischemic stroke patients with (1) 3-T MRI performed within 24 h after clinical onset including arterial spin labeling, T2*-weighted imaging, and magnetic resonance angiography (MRA) and (2) either having MCA occlusion (n = 34 patients) or without major vessel occlusion (n = 24 patients). The intra-arterial, high-intensity signal was defined as an enlarged circular or linear bright hyperintensity within the artery. The susceptibility vessel sign was defined as an enlarged spot of hypointensity within the MCA, in which the diameter of the hypointense signal within the vessel exceeded the contralateral vessel diameter. The presence or absence of the intra-arterial, high-intensity signal and susceptibility vessel sign were assessed, along with their inter-rater agreement and consistency with the presence of MCA occlusion on MRA. Results: The intra-arterial, high-intensity signal was detectable in 30 patients (52%), and susceptibility vessel sign was observed in 17 patients (29%). The sensitivity of the intra-arterial high-intensity signal was significantly higher than that of the susceptibility vessel sign (88% vs. 50%; p < 0.05). The accuracy of the intra-arterial high-intensity signal was also higher than that of the susceptibility vessel sign (93% vs. 71%; p < 0.05). The intra-arterial high-intensity signal was situated in the proximal regions of the susceptibility vessel sign on T2*WI within the MCA. Neither the intra-arterial high-intensity signal nor the susceptibility vessel sign was observed in patients without major vessel occlusion. Inter-rater agreement was good for intra-arterial high-intensity signal detection (κ = 0.73) and moderate for susceptibility vessel sign detection (κ = 0.47). The presence or absence of the intra-arterial high-intensity signal was highly consistent with that of MCA occlusion on MRA (κ = 0.74). Conclusions: The intra-arterial high-intensity signal on arterial spin labeling appears to be useful to identify the presence of acute MCA occlusion and may be associated with stagnant flow in front of occlusion sites. The intra-arterial high-intensity signal may also be used to identify the occlusion site.

This study investigated the frequency of poor outcome at discharge of acute subdural hematoma (SDH) patients with and without microbleeds. We retrospectively examined the records of 37 patients with acute SDH who were surgically treated with hematoma removal and received magnetic resonance (MR) imaging within 2 weeks of head injury onset. MR images were used to determine the presence or absence of microbleeds and contusional hemorrhage (CH). Patient outcome was categorized as good (moderate disability or good recovery) or poor (severely disability, vegetative state, or dead) according to the Glasgow Outcome Scale at discharge. Microbleeds were found in 23 patients (62%) and CH was found in 26 patients (70%). Fifteen patients (41%) had both microbleeds and CH. Poor outcome at discharge was more common in SDH patients with both microbleeds and CH than in SDH patients with neither microbleeds nor CH (14/15, 93% vs. 14/22, 64%; p = 0.04). Poor outcome at discharge was more common in SDH patients under 60 years of age with microbleeds (6/8, 75%) than patients under 60 years of age without microbleeds (0/4, 0%; p = 0.03). The location of the microbleed was not related to the outcome at discharge. These results suggest that the presence of microbleeds and CH on MR images may indicate poor prognosis in patients with acute SDH.

Background: There are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in ovariectomized rats. This pilot study was designed to evaluate whether it can be used to prevent the growth and rupture of cerebral aneurysms in humans with hypertension. Methods: Between August 2011 and May 2014, 82 patients with 89 aneurysms were enrolled in an open-label uncontrolled clinical trial. Of these, 81 patients (88 unruptured aneurysms) were followed for a mean of 21.2 months (153.7 aneurysm-years). All patients had a history of hypertension and were treated with eplerenone (20 - 100 mg per day). The primary endpoints were rupture and enlargement of the intracranial aneurysms. Results: The mean aneurysmal size was 4.6 ± 2.6 mm. During follow-up period that included 153.7 aneurysm-years, 3 aneurysms enlarged and one large thrombosed aneurysm rupture. The annual rupture was 0.65% overall and 13.16% for aneurysms larger than 10 mm. No aneurysms smaller than 9 mm ruptured. The annual rate for reaching the primary endpoint was 2.60% overall. It was 1.37% for aneurysms smaller than 9 mm and thus seems to be lower than in other studies. Eplerenone had no protective effects in aneurysms larger than 10 mm. In the course of our study, 12 patients (14.8%) permanently discontinued taking the eplerenone. Conclusions: Our observations suggest that it is clinically feasible to prevent growth and rupture of cerebral aneurysms smaller than 9 mm by treatment with eplerenone. Protocols for large clinical trial are needed to assess the possible long-term clinical benefits the drug may confer on patients with unruptured cerebral aneurysms.

A 64-year-old woman presenting with subarachnoid hemorrhage (World Federation of Neurosurgeons grade IV) from the rupture of a right large internal carotid-posterior communicating artery aneurysm suffered neuronal damage associated with post-ischemic hyperperfusion after neck clipping of the aneurysm under suction decompression. She did not completely recover consciousness after the operation. Diffusion-weighted imaging (DWI) performed on the first postoperative day showed subtle cortical hyperintensity in the parietal lobe. Arterial spin-labeling (ASL) and 123 I-iodoamphetamine ( 123 I-IMP) single photon emission computed tomography (SPECT) demonstrated hyperperfusion in the right temporo-parietal lobes. Delayed 123 I-iomazenil ( 123 I-IMZ) SPECT images showed a reduced IMZ uptake in the right temporo-parietal lobe corresponding to the hyperperfusion area on ASL images. DWI repeated on postoperative day 3 revealed progression of a hyperintensity lesion in the right parietal lobe. Blood pressure control and the use of a free radical scavenger relieved her symptoms. One month later, the area of reduced IMZ uptake was further expanded. Our findings suggest that post-ischemic hyperperfusion after suction decompression may result in neuronal damage demonstrated on 123 I-IMZ SPECT images.

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.

STEM-16. SONODYNAMIC 5-ALA PLUS ULTRASOUND THERAPY AUGMENTS ANTI-TUMOR EFFECTS IN THE ONCOGENE KNOCK-IN GLIOMA STEM CELLS Kenji Shono, Teruyoshi Kageji, Yoshihumi Mizobuchi, Toshitaka Fujihara, Keiko Kitazato, Kohei Nakajima, Hideo Mure, Kazuyuki Kuwayama, and Shinji Nagahiro; Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima UniversityGraduateSchool, Tokushima City,Tokusima Prefecture, Japan INTRODUCTION: To overcome the chemoand radiation resistance of glioblastoma multiforme (GBM), new therapeutic strategies are needed. Sonodynamic therapy (SDT) is efficacious in several types of tumor and cancer. However, there are few studies in oncogene knock-in glioma stem cells (GSCs), which are thought to be implicated in the therapeutic resistance of GBM. We tested our hypothesis that SDT is effective in GSCs and GBM cells. METHODS: Using GSCs and U251 MG cells we assessed the efficacy of SDT in vitro. We also studied the anti-tumor effects of SDT in GSC-bearing mice. We compared the efficacy of SDT delivered in a single ultrasound session (1 MHz, 2W/cm) with the results obtained with 5-ALA delivered at 1 mM/well. RESULTS: While no significant effects were observed when cells were exposed to 5-ALA, ultrasound-treated cells lost viability immediately after exposure. SDT enhanced the effects of ultrasonography. Our findings suggest that SDT may be effective in GBM cells and GSCs. CONCLUSION: Ours is the first study to show the efficacy of SDT in GSCs. The mechanisms mediated by SDT and by photodynamic therapy may be different. Studies are underway to confirm the beneficial effects of SDT in GSC-bearing mice and to elucidate the mechanisms underlying its efficacy. Neuro-Oncology 17:v208–v213, 2015. doi:10.1093/neuonc/nov234.16 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Introduction: T2*-weighted imaging (T2*WI) can detect acute endovascular clots by the susceptibility vessel sign (SVS). Stagnant flow in front of middle cerebral artery (MCA) occlusion sites may contribute to intra-arterial high-intensity signal on arterial spin labeling (ASL) magnetic resonance imaging (MRI), making it another potential marker of MCA occlusion. We compared intra-arterial high-intensity signal and SVS in patients with symptomatic and asymptomatic MCA occlusion and patients without major vessel occlusion. Methods: We identified transient ischemic attack or ischemic stroke patients by (a) 3-T MRI, diffusion-weighted imaging, ASL, T2*WI, and magnetic resonance angiography (MRA) performed within 24 h after stroke onset and (b) the presence of MCA occlusion (n=34 patients) or the absence of major vessel occlusion (n=24 patients). We included asymptomatic patients with MCA occlusion (n=6). The presence or absence of intra-arterial high-intensity signal and SVS was recorded as was its coincidence with the presence of MCA occlusion on MRA. Results: In patients with acute ischemic stroke the sensitivity of intra-arterial high-intensity signal was significantly higher than of the SVS (88% vs 50%; p Conclusions: The intra-arterial high-intensity signal on ASL could identify stagnant flow in front of occlusion sites due to acute arterial occlusion.

Introduction: To prevent subarachnoid hemorrhage (SAH), its pathogenesis must be understood. SAH and cerebral aneurysms are located at vascular walls exposed to hemodynamic stress and turbulence. In our experimental aneurysm model, rats were subjected to oophorectomy, right common carotid artery ligation (CCA), and bilateral posterior renal ligation; they received a high-salt diet. Although we noted a high incidence of aneurysms at the anterior cerebral artery-olfactory artery (ACA-OA) bifurcation, no SAH occurred at this site. As hemodynamic changes are thought to stimulate the vascular wall locally, we hypothesized that additive hemodynamic changes lead to the development and rupture of cerebral aneurysms. Methods: We divided 42 rats into 3 groups, group A (n=26) underwent ligation of the right CCA, in group B (n=10) we ligated the right pterygopalatine artery, the right external carotid artery, and the left CCA, and in group C (n=6) we additionally ligated the bilateral vertebral arteries. Results: In the 12 weeks after aneurysm induction, 5 group A (19%)-, 3 group B (30%)-, and 3 group C (50%) rats suffered aneurysmal rupture. As in humans, the ruptured aneurysms were primarily located at the anterior communicating artery, the posterior communicating artery, and the internal carotid-posterior communicating artery. There were no ruptured aneurysms at the ACA-OA bifurcation. Conclusion: Our findings suggest that hemodynamic changes are at least partly associated with the vulnerability of the vascular wall at the circle of Willis. Studies are underway to identify the mechanisms underlying the pathologic vascular changes.

High mobility group box 1 (HMGB1) elevation after cerebral ischemia activates inflammatory pathways via receptors such as the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) and leads to brain damage. Eicosapentaenoic acid (EPA), a peroxisome proliferator–activated receptor gamma (PPARγ) agonist, attenuates postischemic inflammation and brain damage in male animals. However, postischemic HMGB1 signaling and the effects of EPA on ovariectomized (OVX + ) rats remain unclear. We hypothesized that EPA attenuates brain damage in OVX + rats via the inhibition of HMGB1 signaling in a PPARγ-dependent manner. Seven-week-old female Sprague-Dawley rats were divided into 3 groups; nonovariectomized (OVX − ) rats and EPA-treated and EPA-untreated OVX + rats before cerebral ischemia induction. Another set of EPA-treated OVX + rats was injected with the PPARγ inhibitor GW9662. OVX + decreased the messenger RNA level of PPARγ and increased that of HMGB1, RAGE, TLR9, and tumor necrosis factor alpha (TNFα) in parallel with ischemic brain damage. EPA restored the PPARγ expression, downregulated the HMGB1 signal–related molecules, and attenuated the ischemic brain damage. Neither OVX + nor EPA affected the expression of TLR2 or TLR4. Interestingly, GW9662 partially abrogated the EPA-induced neuroprotection and the downregulation of RAGE and TLR9. In contrast, GW9662 did not affect HMGB1 or TNFα. These results suggest that EPA exerts PPARγ-dependent and PPARγ-independent effects on postischemic HMGB1/TLR9 pathway. The cortical infarct volume exacerbated by OVX + is associated with the upregulation of the HMGB1/TLR9 pathway. Suppression of this pathway may help to limit ischemic brain damage in postmenopausal women.

Object. The increased incidence of cerebral aneurysms in postmenopausal women appears to be related to low levels of circulating estrogen. Using a rat model of aneurysm induction, the authors found that oophorectomy increased the incidence of experimental cerebral aneurysms (Part I in this issue). In the current study they examined the effects of hormone replacement therapy (HRT) on the formation of cerebral aneurysms in rats. Methods. Forty-five female Sprague—Dawley rats were divided into three equal groups. The animals in Groups A and B were subjected to a cerebral aneurysm induction procedure (renal hypertension and right common carotid artery ligation) followed 1 month later by bilateral oophorectomy. After an additional week the rats in Group A received 17β estradiol continuous-release pellets. The rats in Group C served as controls. Three months after the aneurysm induction procedure, all the rats were killed and vascular corrosion casts of their cerebral arteries were prepared and checked for aneurysmal changes. Using a scanning electron microscope, the authors recorded aneurysmal changes as endothelial changes alone (Stage I), endothelial changes with intimal pad elevation (Stage II), and saccular aneurysm formation (Stage III). Aneurysmal changes (Stages I, II, and III) occurred in one third of rats that had undergone oophorectomy and were receiving HRT (Group A), compared with 87% of the rats that had undergone oophorectomy but did not receive HRT (Group B). Although most of the aneurysmal changes identified in Group A rats were limited to Stage I or II, most changes in Group B animals were identified as saccular dilation (Stage III). Conclusions. The findings demonstrated the significant protective role of estrogen against the formation and progression of cerebral aneurysms. It appears to be related to the beneficial effects of estrogen on the function and growth of endothelial cells, which play a major role in preserving the integrity of the vascular wall.

Hereditary hemorrhagic telangiectasia (HHT) is easily overlooked in patients with central nervous system (CNS) lesions. Our clinical experience of three patients with CNS lesions associated with HHT stresses the importance of considering HHT. A 23-year-old male presented with consciousness disturbance and right hemiparesis. Emergency cerebral digital subtraction angiography revealed occlusion of the left middle cerebral artery and the left anterior cerebral artery. Pulmonary arteriography showed three pulmonary arteriovenous malformations (AVMs). A 62-year-old male presented with consciousness disturbance and sensory aphasia. Magnetic resonance imaging revealed a ring-enhanced lesion in the left temporal lobe which was removed by left frontotemporal craniotomy. The diagnosis was brain abscess. Chest computed tomography (CT) revealed two pulmonary AVMs. A 32-year-old female presented with progressive mild weakness in her left hand. Initial CT showed subcortical hemorrhage in the right frontal lobe. Cerebral angiography revealed no vascular malformations, but chest CT disclosed five pulmonary AVMs. All three patients had a family history of HHT. The possibility of HHT is important to consider in patients with cerebrovascular disease (CVD) or brain abscess to prevent complications, not only in the patients but also their blood relatives. Therefore, the medical and family history of patients with CVD or brain abscess should be investigated and HHT should be considered during the physical examination.

This report describes a mixed germ cell tumor that underwent dramatic size changes. A 12-year-old boy presented to our hospital with a headache that had persisted for two months. Initial magnetic resonance imaging (MRI) revealed a pineal tumor and hydrocephalus. The patient required external ventricular drainage and underwent two endoscopic biopsies. His evaluation involved a total of nine computed tomography (CT) scans prior to the second biopsy;the tumor size had decreased before the second endoscopic biopsy. The tumor consisted of both a germinoma and a teratoma component. The patient was treated with three courses of carboplatin-etoposide (CBDCA-VP) chemotherapy and whole-ventricle radiotherapy (32.1 Gy). However, during the adjuvant therapy, the tumor size increased, necessitating total tumor resection. We speculate that the tumor's initial size reduction was caused by leakage of the cyst component and exposure to the brain CT irradiation. The tumor's subsequent increase in size was due to the recollection of the cystic components and intracranial growing teratoma syndrome (iGTS). Therefore, frequent brain CTs and angiography should be avoided before definitive pathological diagnosis is achieved. Further, the tumor size should be considered, with surgical resection being performed at the optimal time.

The effect of the third member of the Dickkopf family (DKK3) in the Wnt pathway in glioblastoma remains unclear. We first demonstrated the non-specific interaction of Wnt3a and Wnt5a with the receptors LRP6 and ROR2 and the up-regulation of the Wnt pathway in glioblastoma cells. We used an adenovirus vector and found that an increase in DKK3 protein attenuated the expression of Wnt3a, Wnt5a and LRP6, but not of ROR2, and their interaction, thereby affecting both canonical- and non-canonical Wnt downstream cascades. This produced anti-tumor effects in GBM xenograft models. The suppression of Wnt pathways upstream by DKK3 may have promise for the treatment of glioblastoma.

Interferon-beta (IFN-β) is reported to augment anti-tumor effects by temozolomide in glioblastoma via down-regulation of MGMT. Promyelocytic leukemia (PML), a gene induced by IFN-β, is a tumor suppressor. Here, we report for the first time that in combination therapy, an IFN-β-induced increase in endogenous PML contributes to anti-tumor effects in p53 wild- and mutant glioma cells in a xenograft mice model. The increased PML promoted the accumulation of p73, a structural and functional homolog of p53, to fuse the coactivator Yes-associated-protein in the PML nuclear bodies. The adjuvant therapy targeted at PML may be a promising therapeutic strategy for glioblastoma.

Promyelocytic leukemia (PML) protein plays an essential role in the induction of apoptosis; its expression is reduced in various cancers. As the functional roles of PML in glioblastoma multiforme (GBM) have not been clarified, we assessed the expression of PML protein in GBM tissues and explored the mechanisms of PML-regulated cell death in GBM cells. We examined the PML mRNA level and the expression of PML protein in surgical GBM specimens. PML-regulated apoptotic mechanisms in GBM cells transfected with plasmids expressing the PML gene were examined. The protein expression of PML was significantly lower in GBM than in non-neoplastic tissues; approximately 10% of GBM tissues were PML-null. The PML mRNA levels were similar in both tissue types. The overexpression of PML activated caspase-8 and induced apoptosis in GBM cells. In these cells, PML decreased the expression of transactivated forms of NFkappaB/p65, and c-FLIP gene expression was suppressed. Therefore, PML-induced apoptosis resulted from the suppression of the transcriptional activity of NFkappaB/p65. PML overexpression decreased phosphorylated IkappaBalpha and nuclear NFkappaB/p65 and increased the expression of the suppressor of cytokine signaling (SOCS-1). A proteasome inhibitor blocked the reduction of activated p65 by PML. The reduction of PML is associated with the pathogenesis of GBM. PML induces caspase-8-dependent apoptosis via the repression of NFkappaB activation by which PML facilitates the proteasomal degradation of activated p65 and the sequestration of p65 with IkappaBalpha in the cytoplasm. This novel mechanism of PML-regulated apoptosis may represent a therapeutic target for GBM.

BACKGROUND AND PURPOSE: Some patients with glioblastoma multiforme (GBM) do not respond to temozolomide (TMZ), a target for the multidrug resistance transporter MDR1/ABCB1. The genotype of the MDR1 exon12 C1236T single nucleotide polymorphism is reported as a predictive factor of the efficacy of TMZ in GBM. The expression of MDR1 is inhibited via JNK activation. Elsewhere we reported that the overexpression of DKK3 exerted anti-tumor effects in association with JNK activation. However, the regulation of MDR1 by DKK3 remains to be elucidated. We tested our hypothesis that the DKK3-induced activation of JNK down-regulates MDR1, thereby attenuating the chemoresistance of GBM to TMZ. METHODS: We compared the results of treating GBM cells, i.e. U87MG- and primary TGB105 cells with TMZ alone and with TMZ plus Ad-DKK3. RESULTS: The viability of U87MG- and TGB105 cells was not significantly affected by TMZ or Ad-DKK3 alone. However, in combination, they augmented cell death. In a GBM xenograft mice model, treatment with TMZ or Ad-DKK3 exerted anti-tumor effects that were enhanced by their combined administration without affecting the animals' body weight. The increased expression of MDR1 in GBM cells was reduced by Ad-DKK3. The decrease in MDR1 expression elicited by Ad-DKK3 was inversely correlated with the expression of p-JNK, c-JUN, and p-c-JUN but not of JNK, which was eliminated by the JNK inhibitor SP600125. Our findings suggest that the Ad-DKK3-induced activation of JNK downregulates MDR1, thereby attenuating the chemoresistance of GBM cells to TMZ and enhancing its anti-tumor effects. CONCLUSION: Ad-DKK3 may not only exert anti-tumor effects but also serve as an adjuvant therapy for GBM. Chemotherapy targeting JNK may be a promising treatment option.

A 45-year-old man developed severe cough with cervical pain. The patient was unable to hold an upright position. The origin of the right posterior inferior cerebellar artery was not enhanced by angiography. MRI showed a high signal intensity string-like structure of the right vertebral artery. In young patients, Wallenberg's syndrome related to mild head trauma has been reported. However, none of the previous studies related to vertebral arterial dissection was induced by severe cough. When cervical pain is present in young patients with severe cough, MRI should be performed to evaluate the possibility of vertebral arterial dissection.

We report a case of a dermoid cyst in the parasellar area associated with porencephaly. A 22-year-old man presented with headache and visual disturbance. Non-enhanced brain CT showed a high density mass in the parasellar area and a low density area in the left temporal lobe. On gadolinium-enhanced T1-weighted images, a partial rim enhancement was present in the parasellar region. A presumptive diagnosis of Rathke cleft cyst, craniopharyngioma, non-function pituitary adenoma, or germ cell tumor was considered. A left frontotemporal craniotomy was performed and the tumor was removed almost totally. The tumor was well-capsulated and contained whitish, milky debris. The histologic diagnosis was dermoid cyst. The temporal lobe lesion was porencephaly. The postoperative course was uneventful. Their most typical aspect is the presence of a low-density mass on CT, allowing an easy radiologic diagnosis of dermoid cyst containing lipids. Enhancement following contrast administration is uncommon. The hyperdensity may be related to the high protein content of the lesion. The hyperdense aspect of the lesion on CT, and the presence of rim enhancement made the radiologic diagnosis of a dermoid cyst difficult in this case. A case of dermoid cyst associated with porencephaly has not yet been reported in the literature.

Hereditary hemorrhagic telangiectasia (HHT) is easily overlooked in patients with central nervous system (CNS) lesions. Our clinical experience of three patients with CNS lesions associated with HHT stresses the importance of considering HHT. A 23-year-old male presented with consciousness disturbance and right hemiparesis. Emergency cerebral digital subtraction angiography revealed occlusion of the left middle cerebral artery and the left anterior cerebral artery. Pulmonary arteriography showed three pulmonary arteriovenous malformations (AVMs). A 62-year-old male presented with consciousness disturbance and sensory aphasia. Magnetic resonance imaging revealed a ring-enhanced lesion in the left temporal lobe which was removed by left frontotemporal craniotomy. The diagnosis was brain abscess. Chest computed tomography (CT) revealed two pulmonary AVMs. A 32-year-old female presented with progressive mild weakness in her left hand. Initial CT showed subcortical hemorrhage in the right frontal lobe. Cerebral angiography revealed no vascular malformations, but chest CT disclosed five pulmonary AVMs. All three patients had a family history of HHT. The possibility of HHT is important to consider in patients with cerebrovascular disease (CVD) or brain abscess to prevent complications, not only in the patients but also their blood relatives. Therefore, the medical and family history of patients with CVD or brain abscess should be investigated and HHT should be considered during the physical examination.

BackgroundManaging hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan.MethodsWe recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/β-2-glycoprotein I (β2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-α (TNFα) and recorded their BP before and after olmesartan treatment.ResultsAfter switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/β2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNFα reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (