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Cervical carotid artery aneurysms are rare and sometimes induce not only hemorrhage but also ischemic stroke. Various surgical treatments are reported to prevent hemorrhage and stroke. We report the result of endovascular therapies for 4 patients who had large or giant cervical carotid artery aneurysms. Endovascular therapies were performed for 4 patients and 5 aneurysms, from January 2003 to October 2007. One patient had external carotid artery aneurysm and the other 3 patients had common or internal carotid artery aneurysms. One patient had 2 cervical carotid artery aneurysms. Case 1 had an external carotid artery aneurysm and underwent parent artery occlusion (PAO); the aneurysm was occluded without any event. Case 2 had an internal carotid artery (ICA) aneurysm and also underwent PAO, but the internal carotid artery showed recanalization 2 days later on magnetic resonance image. Therefore, we added endovascular coil embolization and occluded the aneurysm completely. Case 3 had 1 aneurysm and Case 4 had 2 aneurysms on the common carotid artery (CCA) to ICA. Bare metal stents were deployed, followed by endovascular embolization for 2 aneurysms. One aneurysm in Case 4 on which only stenting was performed completely occluded 1 year after procedure. On 2 aneurysms combined stenting and coil embolization were performed. One was completely occluded, and the other had a tiny flow into the aneurysm, only confirmd by cervical ultrasound examination. No procedural complication or neurological symptoms and signs were recognized during these endovascular procedure. Endovascular therapy was effective and safe for the cervical carotid artery areurysms. However, the aneurysm sometimes became recanalized, and it is important to treat the recurrent aneurysm.

A 56-year-old woman with adult idiopathic thrombocytopenic purpura (ITP) diagnosed 17 years previously presented with a fusiform aneurysm manifesting as chronic headache. She had suffered no major hemorrhagic complications, although her platelet counts were between 3.0 × 109/l and 50.0 × 109/l. Magnetic resonance angiography identified a fusiform aneurysm of the right vertebral artery. Endovascular trapping after high-dose gammaglobulin with steroid therapy was performed. The patient received antiplatelet therapy to prevent thromboembolic events. The parent artery and aneurysm were completely occluded with no hemorrhagic complications. Endovascular treatment is considered safe in patients with ITP, although careful periprocedural management of platelet count is required.

Development of a safe method to increase brain-derived neurotrophic factor (BDNF) in the brain is expected to have utility in enhancing learning and memory, in protecting the brain, and in suppressing appetite. We investigated the effects of whole-body exposure to high voltage electric potential (HELP), which generates an electric field and current density in the body, on BDNF levels in the brain, spatial learning, or resistance to cerebral infarction development after focal ischemia. Adult mice (C57BL/6J) were exposed to 3.5 kV, or 5.8 kV for 5 h a day, making indirect contact with the ground via room air, over 1, 3, 6 or 12 consecutive weeks. After treatment, BDNF levels, performances in the Morris water maze task (MWM), or development of infarct lesion after focal ischemia was analyzed. Treatment with 3.5 kV for 1, 3, 6 or 12 weeks, or with 5.8 kV for 1, 3 or 12 weeks increased BDNF levels in the cortex (P

In many cases, the prognosis for acute cervical carotid artery occlusion is poor. However, a standard treatment for the acute stage is not yet established. We report here the results of eight consecutive patients (mean age 71.5 years old) in which revascularization mainly by suction thrombectomy was performed under proximal protection during the acute phase. The occlusion sites were the intracranial internal carotid artery in five patients, tandem lesions of the internal carotid origin and intracranial vessel in two patients, and the common carotid artery in one patient. In addition, the subjects who received the treatment had an extent of infarction in MRI/DWI that was 1/3 or less of the internal carotid artery territory. The mean time from the onset to treatment commencement was 7.25 hours (2–28 hours). For the endovascular treatment, a guiding catheter with a balloon was used for proximal protection of the carotid artery. Revascularization was performed mainly by suction thrombectomy, and if a stenosed lesion was observed, PTA/stenting was added. Local fibrinolysis was not performed in combination with the above procedure. The treatment results were complete recanalization in three patients and partial recanalization in three patients. However, recanalization was not achieved in two patients. No hyperfusion syndrome or hemorrhagic infarction was observed postoperatively. All four patients in whom thrombi were successfully aspirated had occlusions proximal to the ophthalmic artery branch. In three of these four patients, complete recanalization was achieved. The revascularization procedure using suction thrombectomy under proximal protection was considered effective against the acute cervical carotid occlusions, in particular, those proximal to the ophthalmic artery branch.

●Abstract● We report a case of repeatedly occurring subclavian artery occlusive disease presenting as arm claudication, treated with the DCA debulking system. A 63-year-old female was diagnosed with right distal subclavian artery stenosis with arm claudication. In-stent restenosis occurred 4 months after first treatment by PTA and stenting. Recurrent stenosis occurred 7 months after second treatment with PTA using a cutting balloon. Finally, a Directional Coronary Atherectomy (DCA) debulking system was used at the third treatment. DCA debulking treatment resulted in optimal dilatation, and allowed sampling of a histological specimen. Histological diagnosis was a non-specific inflammatory change without any atheromatous findings. DCA debulking treatment is useful for repeatedly occurring occlusive disease and histological diagnosis.

Object. The aim of this study was to propose criteria to determine whether complete resection of cavernous malformations in the brainstem had been achieved. Methods. The authors retrospectively analyzed data in 10 patients harboring a single cavernous malformation who had presented with hemorrhagic symptoms and had been followed up for longer than 2 years postsurgery. The study population consisted of five male and five female patients ranging in age from 13 to 57 years (mean 36.8 years). When preoperative magnetic resonance (MR) images demonstrated the lesion as a homogeneous hyperintense mass, the surgery was defined as complete or incomplete based on intraoperative findings. When preoperative MR images revealed other findings, complete resection was determined according to whether postoperative MR imaging results demonstrated lesions distinct from the peripheral hemosiderin rim. Among the 13 operations in this series, nine resulted in complete resection and were associated with no postoperative clinical relapse of hemorrhage, whereas four operations resulted in incomplete resection and were correlated with postoperative recurrent hemorrhage. The seven patients in whom the outcome of the initial operation was complete demonstrated good neurological recovery in the long-term follow-up period, whereas the three patients in whom the outcome of the initial surgery was judged to be incomplete showed inadequate neurological recovery due to recurrent hemorrhage. Conclusions. The criteria proposed in this study to evaluate surgical treatment may be a reliable means of predicting the recurrence of hemorrhage postoperatively.

We retrospectively analyzed the results of our 16 years of experience in the treatment of unruptured upper basilar artery aneurysms by surgery or coil embolization. This analysis involved 32 basilar tip aneurysms and 18 basilar superior cerebellar artery bifurcation aneurysms in 19 men and 31 women who ranged in age from 26 to 75 years (mean 57.0 years). Thirty-three aneurysms (66%) were small, 13 (26%) were large, and 4 (8%) were giant. Surgery were performed by 4 selected neurosurgeons and coil embolization was performed by 2 selected endovascular interventionalists. Treatment consisted of aneurysm neck clipping in 24, aneurysm coating in 5, and coil embolization in 21 patients. Surgery was mainly performed by the transsylvian approach. Immediate anatomic outcomes demonstrated complete or near-complete occlusion in 16 aneurysms (76.2%). Five aneurysms (23.8%) could not be embolized because of anatomic difficulties. In small aneurysms, 24 of the 26 (91.3%) patients treated with surgery remained neurologically intact or unchanged from their initial clinical status. Procedure-related morbidity and mortality were 7.7% and 0%, respectively. In small aneurysms, 8 of the 9 (88.9%) patients treated with coil embolization remained neurologically intact or unchanged from their initial clinical status. Procedure-related morbidity and mortality were 11.1% and 0%, respectively. In large aneurysms, the postoperative courses were uneventful in all 3 (100%) patients treated with surgery. There was no procedure-related morbidity or mortality. Eight of the 10 (80%) patients with large aneurysms treated with surgery remained neurologically intact or unchanged from their initial clinical status. Procedure-related morbidity and mortality were 10% and 10%, respectively. There were 3 poor results (75%) in patients with giant aneurysms, including 1 death caused by premature rupture. One severe disability patient treated with coil embolization died of rebleeding. Four of the 21 patients treated with coil embolization required additional coils because of coil compaction. Operative results of surgically accessible small aneurysms were satisfactory when patients were treated by selected surgeons. Therapeutic results of coil embolization for small and medium-sized aneurysms were also satisfactory. Aneurysmal neck clipping is superior to coil embolization in therapeutic radicality. Poor results cannot justify the therapeutic indication in every case with asymptomatic unruptured giant BA aneurysms.

Carotid artery stenting (CAS) has been developed in recent years as an alternative to carotid endarterectomy (CEA). We report our clinical experience of CAS and evaluate the feasibility and efficacy of this treatment. Since 1997 Feb, 237 patients (199 male, aged 50-85, mean 67.5), 235 carotid artery stenosis (109 symptomatic, 126 asymptomatic), 5 aortitis, 1 FMD, and 6 dissecting were treated with 259 endovascular stenting procedures. Our method in now is as follows;under local anesthesia, transfemoral approach, using guiding catheter, pre-dilation with low profile 3mm PTA balloon with. 014" long wire, and self-expandable stent deployment. Since 1998 Dec, we have used our originally made distal balloon protective system in post PTA. Procedural success was 99.2%, and complications occurred in 2 (0.77%) major and 6 (2.3%) minor stroke without mortality. Restenosis occurred in 12/155 (7.7%) of F/U angiography, 6-50 months after treatment. No complication occurred in re-treatment. Our results indicate that carotid stenting may well offer a similar safety profile and efficacy to those of carotid endarterectomy. The future status of carotid artery stenting will be determined with randomized trials and improvement in devices, technique and safety.

Cryptococcosis is a fungal infection, which mainly invades the lungs and central nervous system. In Japan, most cases of cryptococcosis are caused by Cryptococcus neoformans(C. neoformans). Until now, only three cases which the infectious agent was Cryptococcus neoformans var. gattii(C. gattii)have been reported. As compared with cryptococcosis caused by C. neoformans, which is often observed in immunocompromised hosts, cryptococcosis caused by C. gattii occurs predominantly in immunocompetent hosts and is resistant to antifungal drugs. Here, we report a case of refractory cerebral cryptococcoma that was successfully treated by surgical resection of the lesions. A 33-year-old man with no medical history complained of headache, hearing disturbance, and irritability. Pulmonary CT showed a nodular lesion in the left lung. Cerebrospinal fluid examination with Indian ink indicated cryptococcal meningitis, and PCR confirmed infection with C. gattii. C. gattii is usually seen in the tropics and subtropics. Since this patient imported trees and soils from abroad to feed stag beetles, parasite or fungal infection was, as such, suspected. Although he received 2 years of intravenous and intraventricular antifungal treatment, brain cryptococcomas were formed and gradually increased. Because of the refractory clinical course, the patient underwent surgical resection of the cerebral lesions. With continuation of antifungal drugs for 6 months after the surgeries, Cryptococcus could not be cultured from cerebrospinal fluid, and no lesions were seen on MR images. If cerebral cryptococcosis responds poorly to antifungal agents, surgical treatment of the cerebral lesion should be considered.

Brain subjected to acute ischemic attack caused by an arterial blockage needs immediate arterial recanalization. However, restoration of cerebral blood flow can cause tissue injury, which is termed reperfusion injury. It is important to inhibit reperfusion injury to achieve greater brain protection. Because oxidative stress has been shown to activate mitogen-activated protein kinases (MAPKs), and because oxidative stress contributes to reperfusion injury, MAPK may be a potential target to inhibit reperfusion injury after brain ischemia. Here, we demonstrate that reperfusion after forebrain ischemia dramatically increases phosphorylation level of extracellular signal-regulated kinase 2 (ERK2) in the gerbil hippocampus. In addition, i.v. administration of U0126 (100–200 mg/kg), a specific inhibitor of MEK (MAPK/ERK kinase), protects the hippocampus against forebrain ischemia. Moreover, treatment with U0126 at 3 h after ischemia significantly reduces infarct volume after transient (3 h) focal cerebral ischemia in mice. This protection is accompanied by reduced phosphorylation level of ERK2, substrates for MEK, in the damaged brain areas. Furthermore, U0126 protects mouse primary cultured cortical neurons against oxygen deprivation for 9 h as well as nitric oxide toxicity. These results provide further evidence for the role of MEK/ERK activation in brain injury resulting from ischemia/reperfusion, and indicate that MEK inhibition may increase the resistance of tissue to ischemic injury.

Background and Purpose— The seleno-organic compound ebselen has both antioxidant and anti-inflammatory properties. Although ebselen has been shown to protect the brain against stroke, it is unclear how ebselen provides neuroprotection. In the present study the authors examined whether ebselen inhibits neuronal apoptosis resulting from transient focal cerebral ischemia in mice. The cytochrome c release and DNA fragmentation, both of which are biochemical markers of apoptosis, were compared between vehicle- and ebselen-treated mice. Methods— Cerebral ischemia was induced by transient middle cerebral artery occlusion for 30 minutes in ICR mice under halothane anesthesia. Ebselen (10 mg/kg) was given orally twice, 30 minutes before ischemia and 12 hours after reperfusion. By Western blot analysis, we examined release of mitochondrial cytochrome c . To evaluate brain damage, the brain sections were treated for terminal deoxynucleotidyl transferase–mediated DNA nick-end labeling (TUNEL) and Nissl staining. Prolonged neuroprotective efficacy of ebselen was determined by counting neuronal nuclei (NeuN) immunopositive cells at 21 days after ischemia. Results— Cytochrome c release was detected in the ischemic hemisphere at 3 to 24 hours after ischemia. Ebselen treatment diminished the cytochrome c release at 12 and 24 hours. In addition, ebselen decreased both DNA fragmentation determined by TUNEL and brain damage volume at 3 days after ischemia. Furthermore, ebselen increased the number of NeuN immunopositive cells at 21 days after ischemia. Conclusions— These results indicate that ebselen attenuates ischemic neuronal apoptosis by inhibiting cytochrome c release. Ebselen may be a potential compound in stroke therapy.

Many asymptomatic non-ruptured intracranial aneurysms are detected by non-invasive radiological examinations. On the other hand, the question has arisen whether surgical treatment of them is justifiable or not because their natural history is not clear. Therefore, we should discuss with patients the possible risk of surgical treatment when they decide to undergo surgery. We retrospectively investigated treatment results and surgical complications involving asymptomatic non-ruptured intracranial aneurysms. From Jan. 1998 to Dec. 1999, we treated 151 patients (56 male, 95 female) aged 22-77 (mean 58.4), with 201 non-ruptured asymptomatic intracranial saccular aneurysms, excluding multiple aneurysms combined with subarachnoidal hemorrhage, within 6 months of onset. Our policy was that surgical treatment was indicated if the aneurismal size was over 3-4 mm, the patient’s age was under 70, and their general condition was satisfactory. Neck clipping was the first choice of the surgical treatment. Direct surgery was difficult for such aneurysms as internal carotid artery aneurysm arising near the dural ring, those involving posterior circulation and those of a large-size. Such aneurysms were treated with intravascular embolization if possible. We evaluated the surgical risk by the number of the operations (169 cases). Permanent morbidity resulted in 7 cases of the 112 direct surgery (6.3%) and 3 cases of the 56 cases of intravascular embolization (5.6%). No deaths resulted. The causes for the morbidity were brain damage or cranial nerve injury at the approach, a perforating artery injury or occlusion of the parent artery at the clipping in the direct surgery, and distal embolism and perforating artery occlusion in the intravascular embolization. The risk factor of the patients with postoperative neurological deficits was the aneurismal size (>10 mm, p The prognosis of severe subarachnoidal hemorrhage caused by the rupture of the aneurysm is poor, and surgical therapy for non-ruptured aneurysm over 10 mm in size is difficult. We have, therefore, decided not to change our treatment policy. However, even for transient or minor complications, surgical risk is accompanied with the treatment of cerebral aneurysm. We should seek to reduce such surgical complications by analyzing their causes.

We retrospectively analyzed clinical courses and outcomes of cerebral arteriovenous malformations in 214 patients (3-79 years old) admitted to our institute between January 1987 and March 2000 in order to determine their natural history and therapeutic outcomes. The cerebral arteriovenous malformations were located in the cerebral hemisphere in 142, basal ganglia-thalamus in 19, cerebellum in 24, corpus callosum in 13, brainstem in 6, and others in 10 (Spetzler & Martin Grade I, 17; II, 44; III, 81; IV, 57; V, 13; and VI, 2). The initial presentation was hemorrhage in 121, seizure in 40, ischemia in 21, headache in 18, and asymptomatic in 14. The annual re-bleeding risk was 11.9% in 121 cases with hemorrhagic onset, and the annual bleeding risk was 3.2% in 93 cases with non-hemorrhagic onset. Bleeding risks between initial treatment and complete obliteration of the lesion were 9.7% and 11.4% in hemorrhagic and non-hemorrhagic groups. In 129 cases who suffered from hemorrhage, total extirpation was achieved in 97 and complete obliteration was obtained in 109 in combination with transarterial embolization and/or radiosurgery. In 85 cases without hemorrhage, complete obliteration was obtained in 55 cases. Surgical morbidity and mortality were 5.8% and 0.6%. Clinical outcome was excellent/good in 141 (92%) out of 154 cases who received surgical treatments, in 18 (86%) out of 21 cases who received radiosurgery, and in 23 (59%) out of 39 cases who received partial transarterial embolization or observation. Cerebral arteriovenous malformations should be treated considering their relatively high re-bleeding risks in hemorrhagic cases and treatment-related bleeding risks.

Background and Purpose —The efficacy of hypothermic intervention for permanent focal ischemia has yet to be clarified. This study investigated the effect of a prolonged moderate or mild hypothermia on permanent focal ischemia in rats. Methods —Two permanent focal ischemia models in male Sprague-Dawley rats were used. Moderate (30°C, in experiment 1) or mild (33°C, in experiment 2) hypothermia was achieved at the time of the induction of focal ischemia and was maintained for 2 hours under general anesthesia. Thereafter, the hypothermic condition was maintained by means of a cold room for a total of 24 hours. The infarct volume and neurological function were analyzed for a maximum of 21 days and compared with that of the normothermia group. Regional cerebral blood flow was monitored for 6 hours in the ischemic core and penumbra region. Results —In experiment 1, the total infarct volume in the normothermic group was 368±59 mm 3 ; in contrast, it was significantly smaller in the hypothermia group: 169±33 mm 3 at 48 hours (mean±SEM, P 3 in the normothermia group and 88±15 mm 3 in the hypothermia group at 21 days ( P 50% of baseline. Conclusions —Prolonged mild hypothermia suppressed the development of cerebral infarct and neurological deficit chronically after the induction of permanent focal ischemia.

This study retrospectively analysed treatment modalities and outcomes in 63 cases of high grade cerebral arteriovenous malformations (Spetzler-Martin's classification grade IV 51, V 12) who were admitted to this institute between January 1986 and April 1998. Twenty-seven of 37 cases with haemorrhagic onset received surgical resection with or without pre-operative embolisation. Total extirpation was achieved in 23 cases, and small residual nidus was treated by postoperative radiosurgery in two of four subtotally resected cases. Another 6 of 37 haemorrhagic cases received radiosurgery with or without preradiosurgical embolisation. Four cases with haemorrhagic onset received partial embolisation. Finally, 29 of 37 haemorrhagic cases obtained complete disappearance of nidus. On the other hand, 4 of 26 non-haemorrhagic cases received surgical total resection, 5 radiosurgery, 9 partial embolisation and 8 observation without treatment. Microsurgical morbidity was 9% and mortality was 0%. Post-treatment haemorrhage was seen in 11 cases (1 after subtotal resection, 4 after radiosurgery, 6 after partial embolisation) and was fatal in 3 cases. Surgical resection can be achieved with acceptable morbidity, and complete obliteration of nidus should be accomplished in any treatment modality to avoid post-treatment haemorrhage.

A prolonged period (48 h) of cortical spreading depression (CSD) induced resistance against severe focal cerebral ischemia (infarct tolerance), however, the mechanism behind this is unknown. The infarct tolerance was a transient phenomenon; the resistance increased linearly for the initial 12 days, peaking from 12 to 15 days after a preconditioning of CSD, and was decreased thereafter. This study examined the time course of brain-derived neurotrophic factor (BDNF), heat shock protein (hsp)27 and 70, and glial fibrillary acidic protein (GFAP) expressions after CSD in the brain. Immunohistochemical expression of BDNF, hsp27, hsp70, or GFAP following a prolonged period of CSD induced by KCl-infusion, or following NaCl-infusion was analyzed by regional densitometry for 24 days in the rat neocortex. In addition, BDNF protein was measured quantitatively by two-site ELISA assay in the neocortex (n=6 at each time point). The GFAP expression was elevated in astrocytes (compared to the normal level of immunodensity) during the period peaking on day 3–6 following the CSD. The hsp27 immunoreactivity was also elevated in astrocytes from day 1 to 12 peaking on day 1 and 6, but there was no expression of hsp70 during the period following CSD. The immunoreactivity for BDNF was elevated in neurons from day 0 to 18 peaking on day 1 and 6. The protein levels of BDNF in the neocortex were significantly elevated from day 0 to 12 peaking on days 0 and 6 (compared to the normal level) (P

Neuronal expression of brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of infarct tolerance (resistance to stroke) (H. Yanamoto et al., Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei, submitted to Brain Res.), a process that takes more than 7 days following a preconditioning of repetitive cortical spreading depression (CSD). To investigate whether an elevated level of BDNF protein in the brain solely protects neurons against temporary focal ischemia, recombinant (r)BDNF was infused into the rat neocortex. Recombinant BDNF (or vehicle: saline) was administered into the left neocortex via an implanted osmotic minipump for 2.5, 7, 10 or 14 days pre-ischemia, during ischemia and for 2 days post-ischemia (8 microgram in total) in male Sprague-Dawley rats (n=6 each). Temporary focal ischemia was induced in the left middle cerebral artery (MCA) territory by three-vessel occlusion of bilateral common carotid arteries (CCAs) and MCA for 2 h, and the cerebral infarct volume was analyzed 2 days after ischemia using TTC staining. Regional cerebral blood flow (rCBF) of the left neocortex was monitored after 14 days of intracerebral administration of BDNF or vehicle (n=10 each). The distribution of BDNF following different periods of rBDNF or vehicle-infusion was analyzed using immunohistochemical techniques (n=5 each). In the groups treated with 8 microgram of rhBDNF for 7, 10, or 14 days pre-ischemia, there were significant reductions of neocortical infarct volume compared to in the control or vehicle-treated groups (p0.05). In the rCBF study, there was no significant change after the infusion of 8 microgram rhBDNF for 14 days. In the histological study, a wide distribution of BDNF-like immunoreactivity in the neuronal nuclei in the ipsilateral neocortex was demonstrated after the infusion of 8 microgram rhBDNF for 14 days. The BDNF-like immunoreactivity in the neuronal nuclei was enhanced at the time that the resistance to stroke was achieved by direct intra-cerebral infusion of exogenous rBDNF. Elucidating the function of the BDNF-like protein located in the neuronal nuclei should reveal a new strategy for neuroprotection against ischemic brain attack in humans.

The purpose of current study was to determine the step at which dietary selenium (Se) regulates the transcriptional expression of the gene for Se-glutathione peroxidase (Se-GPx) in rat brain and transplanted glioma tissue. Wistar rats were fed a Se-free diet or the same diet supplemented with 0.5, 2.0, and 4.0 mg Se/kg as sodium selenite for at least 3 wk. Then, the rats were transplanted with C6 rat glioma cells into the right frontal lobe parenchyma. All rats were observed for 30 d, then tumor and contralateral brain tissue were excised and divided into three portions for purification of selenium content, for the assay of Se concentration, Se-GPx activity, and for Se-GPx mRNA. Se concentration and Se-GPx activity are increased with Se supplementation both in tumor tissue and contralateral brain tissue, and Se concentration in tumor is higher than that in contralateral brain tissue at each dietary Se content. Se-GPx mRNA of brain and tumor were probed with fragments from a rat Se-GPx cDNA in Northern blot analysis. There was significant differences of Se-GPx mRNA transcription in brain tumor tissue among each dietary group of the Se content, and the steady-state level of Se-GPx mRNA was markedly reduced by Se deficiency. These results suggest that dietary Se exerts its augmenting effect on Se-GPx gene transcription.

Objective The pathogenesis of moyamoya disease is unknown. The purpose of this study was to detect proteins associated with the pathogenesis of moyamoya disease. Clinical presentation Cerebrospinal fluid (CSF) samples from three patients with moyamoya disease and four control patients who had cervical lesions but no intracranial lesion were studied. Intervention CSF proteins separated by two-dimensional polyacrylamide gel electrophoresis were analyzed with the SWISS-2DPAGE and SWISS-PROT databases. In the CSF samples from all three patients with moyamoya disease, a polypeptide spot (Mr = 12,000, pI = 5.35) was observed. This spot was not evident in samples from the four control patients and has not been reported in the SWISS-2DPAGE and SWISS-PROT databases. Conclusion A CSF protein, which is possibly novel and associated with moyamoya disease, has been detected. The analysis of CSF by two-dimensional polyacrylamide gel electrophoresis may reveal a clue by which the molecular mechanism of moyamoya disease may be elucidated.

Targeting viral vectors to appropriate cell types so that normal cells are not adversely affected is an important goal for gene therapy. Previously, we described a novel approach to viral gene therapy using a conditional, replication-competent herpes simplex virus (HSV), where replication and associated cytotoxicity are limited to a specific cell-type by the regulated expression of an essential immediate–early viral gene product. In this report we analyze the hepatoma-specific replication, cytotoxicity and anti-tumor effect of recombinant HSV G92A, regulated by the albumin enhancer/promoter. G92A efficiently replicated in vitro in two human hepatoma cell lines expressing albumin, but not in four human non-hepatoma, albumin-non- expressing tumor cell lines, while all cell lines were equally susceptible to a tissue nonspecific HSV recombinant, hrR3. In vivo, G92A replicated well in subcutaneous xenografts of human hepatoma cells (Hep3B) in athymic mice, but not in non-hepatoma subcutaneous tumors (PC3 and HeLa), whereas, hrR3 replicated well in both tumor types. Intratumoral inoculation of G92A inhibited the growth of established subcutaneous hepatoma tumors in nude mice, but not prostate tumors. Replication-competent viral vectors controlled by cell-specific transcriptional regulatory sequences provide a new therapeutic strategy for tumor therapy.

Background and Purpose —In vivo and vitro studies revealed the activation of thrombin and the complement system in vascular lesion formation during the process of atherosclerosis, along with pathological proliferation of smooth muscle cells. We examined the effect of the synthetic serine protease inhibitor FUT-175 (developed as a potent inhibitor of thrombin and the complement system) on vascular lesions using balloon dilatation–induced neointimal formation in the carotid artery of rats. Methods —Sprague-Dawley (SD) rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. Three groups of these rats (n=8, each) were treated with daily intraperitoneal injections of 1 of the following doses of FUT-175: 0.5, 1.0, or 2.0 mg/d in 1 mL of saline for 7 consecutive days. The control group (n=8) was similarly treated with 1 mL of saline for 7 days. The injections were started immediately after balloon injury. Two weeks after the injury, the left carotid arteries were perfusion-fixed, and the areas of the neointimal and medial layer were analyzed under a microscope. Results —A morphometric analysis revealed that there were significant differences in the intima-media ratio between the 4 groups treated with vehicle (saline) or a low, medium, or high dose of FUT-175 (1.45±0.11, 1.08±0.06, 0.71±0.04, or 0.32±0.04, respectively). This suppression was achieved in a dose-dependent manner by the administration of FUT-175 after balloon injury. In the histological study, it was demonstrated that FUT-175 suppresses the production of platelet-derived growth factor (PDGF)-BB in the neointima and the medial smooth muscle cell layer. Conclusions —After balloon injury activated proteases that were inhibited by FUT-175 were demonstrated to have an essential role in the development of the pathological thickening of the arterial wall.

The association between intracranial aneurysms and arteriovenous malformations (AVMs) is well documented. Recent advances in the understanding of the haemodynamics of this association encourage an aggressive approach to these aneurysms. However, the pathophysiology of these aneurysms is not fully understood and a strategy for their management has not been established. We describe seven patients, with eight aneurysms, on the feeding arteries of AVMs. The aneurysms could be divided into those located 1. proximally on the superficial feeding artery (type I; 4 aneurysms); 2. distally on the superficial feeding artery (type II; 3 aneurysms); and 3. on the deep feeding artery (type III; 1 aneurysm). All aneurysms were treated by the endovascular procedure prior to, or simultaneously with, treatment of the AVM, using detachable coils or liquid embolic material. All aneurysms were obliterated successfully, with no adverse events. Each patient further received treatment of the AVM. None of the patients suffered intracranial haemorrhage after treatment for the aneurysms. Based on our experiences, we discuss the indications for this approach for each type of aneurysm. We believe endovascular treatment could be an important alternative for treatment of aneurysms associated with AVMs, thus reducing the risk of haemorrhage.

Basic fibroblast growth factor (FGF-2) and high affinity FGF receptor (FGFR) have been detected in the nucleus as well as the cytoplasm of many human gliomas, and are known to stimulate cellular proliferation and angiogenesis in the tumors. To investigate the effects of inactivation of FGFR on the growth of malignant gliomas, we constructed a replication-deficient recombinant adenovirus vector encoding a truncated form of chicken FGFR1 (AxCA Δ FR). AxCA Δ FR-infected cells were confirmed to express truncated FGFR protein by immunoblotting and FGF-2-dependent clonogenicity of NIH3T3 cells was suppressed by infection with this virus vector. Then human malignant glioma cell lines U-251MG and T98G, both of which have been reported to express FGF-2 and FGFR, were infected with AxCA Δ FR. These infected cells showed nuclear as well as cytoplasmic expression of a truncated FGFR protein. Proliferation rate and the ability to form colonies in soft agar of the cells infected with this virus vector were significantly suppressed compared with those of uninfected and lacZ-expressing adenovirus-infected cells. Moreover, intratumoral injection of AxCA Δ FR significantly suppressed the subcutaneous tumor growth of the glioma cells in nude mice. We concluded that inactivation of the cytoplasmic and nuclear FGFR using this truncated FGFR-expressing adenovirus vector can inhibit the growth of malignant gliomas both in vitro and in vivo.

We demonstrate a new three-vessel occlusion model of temporary focal ischemia in Sprague–Dawley rats ( n =13). Under a surgical microscope, bilateral carotid arteries and the left middle cerebral artery (MCA) were occluded for 2 h using a snare for the neck and a micro-clip for the MCA. The reduction of regional cerebral blood flow (rCBF) monitored by laser Doppler flowmetry was 28% on average compared to the preischemic control value (100%) during ischemia. At that level of CBF reduction, there was no thrombus formation in the proximal MCA trunk, and a full recovery of rCBF was confirmed in the ischemic core within 5 min of reflow. Two days later, the cerebral infarct was limited to the neocortex, and the size and variability of the infarct are considered feasible for the assessment of any therapeutic challenge against the ischemic damage due to temporary focal ischemia in this model. Themes: Disorders of the nervous system Topics: Ischemia

Nitric oxide from neuronal cells plays detrimental roles in glutamate neurotoxicity and in focal brain ischemia. Nitric oxide directly damages DNA, and breaks in the DNA strands activate poly(ADP-ribose) polymerase (PARP), which brings poly(ADP-ribosyl)ation of the nuclear proteins. The excessive activation of PARP is thought to cause depletion of ATP and the energy failure resulting in cell death. To clarify the involvement of poly(ADP-ribosyl)ation in ischemic insult, we examined poly(ADP ribosyl)ation by immunohistochemical methods and the protective effect of 3-aminobenzamide, which is a PARP inhibitor, on focal brain ischemia using an intraluminal permanent middle cerebral artery occlusion model in rats. Poly(ADP ribosyl)ation was widely and markedly detected 2 hours after the ischemic insult in the cerebral cortex and striatum in which infarction developed 24 hours later. The enhanced immunoreactivity of poly(ADP-ribose) gradually decreased, and 16 hours later, no immunoreactivity was detected. Intraventricular administration of 3-aminobenzamide (1 to 30 mg/kg) 30 minutes before the ischemic insult decreased infarction volume in a dose-dependent manner along with the immunohistochemical reduction of poly(ADP-ribosyl)ation. Pretreatment with 7-nitroindazole (25 mg/kg, intraperitoneally), a selective neuronal nitric oxide synthetase inhibitor, partially reduced poly(ADP-ribosyl)ation. These data suggest the involvement of poly(ADP-ribosyl)ation in the development of cerebral infarction.

Cerebral atherosclerotic changes develop most commonly on the lateral side of the bifurcation, one of the sites where the wall shear stress is lowest in the cerebral arteries. Endothelial cells exposed to the lower shear stress appear to be more vulnerable to stimuli such as free radicals. We hypothesized that the difference in endothelial vulnerability on cerebral arteries may be involved in the local preference of atherogenesis. To clarify this hypothesis, the present study was carried out by using a laser-dye technique that causes cell damage by heat and free radicals. A helium-neon laser in the presence of circulating Evans blue was used to illuminate three sites of the rat middle cerebral artery; the straight portion, the apex of the bifurcation, and the lateral side of the bifurcation. The magnitude of endothelial damage was morphologically estimated with the electron microscope. After the laser irradiation, the straight portion and the lateral side of the bifurcation developed severe endothelial damage. However, the apex of the bifurcation developed no appreciable damage, showing significantly milder changes compared with other sites. The results suggest that endothelial cells are more vulnerable to stimuli by free radicals at the straight portion and the lateral side of the bifurcation than at the apex. We conclude that the imbalance between the strength of stress stimuli, such as free radicals, and the vulnerability of endothelium is likely to be one of the key requirements for the development of cerebral atherosclerotic changes.

Synthetic dural substitutes composed of bioabsorbable polymers were used in 20 patients during neurosurgical operation. Clinical manifestations such as operative wound features, white blood cell counts, C-reactive protein, and computed tomography were evaluated after neurosurgical operations. Transient subcutaneous collection of cerebrospinal fluid was observed in three patients. No other significant complication was observed. This preliminary report indicates the effectveness of the bioabsorbable artifical dura mater without risking virally transmitted infection when compared with a cadaveric dura mater graft.

Neuronal death following cerebral vascular occlusion may be caused in part by the action of glutamate acting through the NMDA receptor. Here we demonstrate that gene disruption of the NR2C subunit of the NMDA receptor attenuates focal cerebral ischemic injury after permanent MCA occlusion, and that a low level of NR2C is expressed and active in the cerebral cortex. NR2C-deficient mice do not show impairment of motor coordination or motor learning. Therefore the development of drugs selectively inhibiting NR2C may prove beneficial in the treatment of stroke and traumatic brain injuries.

Objective The effect of ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action, on the outcome of subarachnoid hemorrhage was evaluated in a multicenter placebo-controlled double-blind clinical trial. Methods Patients who suffered aneurysmal subarachnoid hemorrhages of Hunt and Kosnik Grades II through IV at admission and were able to start drug treatment within 96 hours of the ictus were enrolled. Early surgery was performed whenever possible. Oral administration of ebselen granules suspended in water (150 mg, twice a day) or placebo was started immediately after admission and continued for 2 weeks. The major end points were the Glasgow Outcome Scale at 2 weeks, 1 month, and 3 months after the start of treatment. The incidence of delayed ischemic neurological deficits clinically diagnosed as resulting from vasospasm and the incidence and extent of low-density areas on postoperative computed tomographic scans were also studied as secondary outcome measures. Results Intent-to-treat analysis of the 286 patients enrolled in the trial (145 patients administered ebselen and 141 administered placebo) revealed that the incidence of clinically diagnosed delayed ischemic neurological deficits was unaltered. There were 52 (receiving ebselen) and 58 (receiving placebo) patients with delayed deficits; however, a significantly better outcome was observed after ebselen treatment than after placebo (P = 0.005, chi2 test). There was a corresponding decrease in the incidence and extent of low-density areas (P = 0.032, Wilcoxon rank sum test). Conclusion Ebselen reduced brain damage in patients with delayed neurological deficits after subarachnoid hemorrhage and may be a promising neuroprotective agent.

A rat model of ischemic tolerance is useful for studying the intrinsic cellular mechanism of resistance to cerebral ischemia. Many types of preconditioning in the brain have been reported to induce ischemic tolerance; however, evaluation of their neuroprotective effect is primarily limited to differences in counts of surviving cells. A lesser but still large number of neurons die in the neocortex after global ischemia following ischemic tolerance. This study addressed the issue of whether any type of preconditioning could elicit a tolerance that limited the size of cerebral infarct against temporary focal ischemia. Cortical spreading depression was induced for a prolonged period and, after various intervals, the stress of temporary focal ischemia was evaluated in rats. Ten groups of male rats (n=8 each) were studied. In the first group, temporary focal ischemia was induced by occlusion of three vessels (bilateral carotid arteries and left middle cerebral artery, MCA) for 2 h (control). In the second to seventh groups, cortical spreading depression was generated by continuously infusing 4 M potassium chloride (KCl)(1.0 microliter l/h for 2 days) into the left neocortex via an osmotic pump. On days 6, 9, 12, 15, 21 and 24 (day 0=day of pump removal), temporary focal ischemia was induced in one of these groups. In the other three groups, saline was infused instead of KCl, and on day 6, 12 or 21, temporary focal ischemia was induced. All rats were sacrificed 2 days after the ischemia and the infarct volume was analyzed using TTC staining of brain slices. In a separate group of animals, regional cerebral blood flow (rCBF) at the periinfarct area (penumbra) was monitored before and during the ischemia with a laser-Doppler flowmetry (LDF) system on day 12 following saline (n=5) or KCl infusion (n=5) for 48 h. To obtain the absolute rCBF value before ischemia following saline (n=5) or KCl infusion (n=5), hydrogen clearance was examined in the same cortex under the same anesthesia. The cerebral infarct volume was gradually reduced as the interval between the induction of the spreading depression and the induction of temporary focal ischemia was extended. There was a significant reduction in infarct size between the control and the groups in which ischemia was induced on day 12 or 15. There was no significant difference in the preischemic or intraischemic rCBF between the saline and KCl-infused groups. The preconditioning method was demonstrated to limit the size of cerebral infarct after temporary focal cerebral ischemia; tolerance for cerebral infarct developed after an extended interval following a long period of spreading depression.

We report excellent initial results of stenting for stenosis of major cerebral arteries experienced between April 1997 and June 1998. Patients ranged in age from 61 to 78 year old (mean 65 year old). The location of the lesion included cervical carotid artery: 10, orifice of vertebral artery: 3, subclavian artery: 3. All lesion were high grade more than 60%. Ten were symptomatic (TIA 5, minor stroke 1, VBI 2. others 2), and six were asymptomatic. Stents utilized were Palmaz stents, the balloon expandable type originally developed for peripheral arteries. Stents were placed at the lesion after predilatation in some patients and primarily in other patients. Almost complete dilatation was obtained in every patient without any permanent adverse event. Bradycardia and mild hypotension due to vaso-vagal reflex was observed in two patients with carotid stenosis until next day after treatment. TIA was experienced in two patients with carotid stenosis. No further ischemic events were observed during the short-term follow-up period. Usefulness of stenting for major cerebral artery stenosis was indicated by our initial results. Stenting will play an important role in the treatment of cerebrovascular disease in the near future, though the development of better stents for the cerebral arteries and long-term follow-up are mandatory.

Background and Purpose —Using an animal model, we examined the role of apoptosis in the disappearance of medial smooth muscle cells (SMCs) during the development and growth of cerebral aneurysms. Methods —Various degrees of cerebral aneurysms were induced in the right anterior cerebral artery–olfactory artery bifurcations in 65 Sprague-Dawley rats with ligation of the left common carotid artery and renal hypertension. We performed in situ end labeling of fragmented DNA with the lesions in 45 rats and electron microscopic study in the other 20 rats. Results —With in situ end labeling of fragmented DNA, 4±3 apoptotic medial SMCs were detected in 35 of the 45 bifurcations. Apoptotic SMCs appeared in the medial layer in the “preaneurysm” group, the site speculated to show an aneurysmal change in the near future (6±3), and in the media in the “early aneurysm” group, which showed characteristics such as a small depression (5±3). In the “progressive aneurysm” group, they appeared more frequently at the aneurysmal neck (3±2) than the dome (1±1). By electron microscopic study, shrunken medial SMCs exhibiting morphological apoptotic changes such as chromatin condensation and fragmentation of the cytoplasm and nucleus were observed in the preaneurysm and early aneurysm groups and at the neck portion in the progressive aneurysm group. In the aneurysmal dome, SMCs showed late characteristics of apoptosis such as more advanced nuclear and cytoplasmic condensation and formation of apoptotic bodies. Conclusions —The present findings indicate that there is an association between apoptosis of medial SMCs and the formation of saccular cerebral aneurysms.

We previously showed a role for a nonselective cation channel (NSCC) in the ETA-dependent action of endothelin-1 in mouse fibroblast and rabbit aortic smooth-muscle cell. To clarify the physiological significance of NSCCs in endothelin-1 (ET-1)-induced vasocontraction, we examined the effects of NSCC blockers such as mefenamic acid and SKF 96365 on the contractions of deendothelialized rabbit aortic rings induced by a low (10[-10] M) or high (10[-8] M) concentration of ET-1. Mefenamic acid (or =10[-3] M) had little effect on the contraction induced by 45 x 10(-3) M K+ or 1 x 10(-6) M Bay K-8644 in combination with 15 x 10(-3) M K+, indicating that it does not affect voltage-operated calcium channels (VOCs) and contractile mechanisms. The contraction by a low concentration of ET-1 was abolished after removal of extracellular Ca2+, but it was reduced only to 50% by a maximally effective concentration (10[-5] M) of nifedipine, an inhibitor of L-type VOCs (L-VOC). Mefenamic acid and SKF 96365 inhibited the ET-1-induced contraction with 50% inhibitory concentration (IC50) values of 10(-4) M and 2 x 10(-5) M, respectively, and abolished it at 10(-3) M and 10(-4) M. By contrast, nifedipine, mefenamic acid, or SKF 96365 had little effect on the contraction by a high concentration of ET-1. The contraction induced by a low or high concentration of ET-1 was abolished by an ETA antagonist, BQ-123, but not by an ETB antagonist, BQ-788. These results demonstrate that the contraction induced by ET-1 is totally mediated exclusively by ETA, but that Ca2+ entry through NSCCs in addition to L-VOCs plays an important role in contractions induced by low concentrations of ET-1, whereas it plays only a minor role in contractions induced by high concentrations of ET-1.

It has been reported that the acoustic thalamus of the rat sends projection fibers to both the temporal cortical areas and the lateral amygdaloid nucleus to mediate conditioned emotional responses to an acoustic stimulus. In the present study, fluorescent retrograde double labeling with Fast Blue and Diamidino Yellow has been used in the rat to examine whether single neurons in the posterior thalamic region send axon collaterals to both the temporal cortical areas and lateral amygdaloid nucleus. One of the tracers was injected into the lateral amygdaloid nucleus and the other into the temporal cortical areas close to the rhinal sulcus. Neurons double-labeled with both tracers were found mainly in the posterior intralaminar nucleus and suprageniculate nucleus, and to a lesser extent in the subparafascicular nucleus and medial division of the medial geniculate nucleus. No double-labeled neurons were seen in either the dorsal or ventral division of the medial geniculate nucleus. When one of the tracers was injected into the lateral amygdaloid nucleus and the other into either the dorsal portion of the temporal cortex, the dorsal portion of the entorhinal cortex, or the posterior agranular insular cortex, no double-labeled neurons were found in the posterior thalamic region. The present results indicate that a substantial number of single neurons in the acoustic thalamus project to both the limbic cortical areas and lateral amygdaloid nucleus by way of axon collaterals. These neurons may be implicated in affective and autonomic components of responses to multi-sensory stimuli, including acoustic ones.