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We have examined the immunoregulatory effect of local and continuous secretion of interleukin 7 (IL-7) from murine glioma cells (203-glioma) engineered by murine IL-7 gene transfection. Secretion of IL-7 from glioma cells did not result in morphology or growth rate changes but did reduce tumorigenicity in vivo in proportion to the amount of IL-7 produced. This reduction in tumorigenicity could be reversed in a dose-dependent fashion by injection of anti-IL-7 neutralizing monoclonal antibody at the tumor site. Mice immunized with IL-7-producing glioma cells showed a specific immune response to 203-glioma but not to two other syngeneic cell lines (B-16, a melanoma, and YM-12, a fibrosarcoma). IL-7-producing glioma cells were not rejected in mice depleted of CD8+ cells but were rejected in mice depleted of CD4+ or NK1.1+ cells. These results suggest that CD8+ T cells may play an important role in tumor rejection.

✓ With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38% (from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54% (from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.

Using a brief transient ischemic model, we examined changes in regional tissue calcium content and energy metabolism in the hippocampus. In the CA1 region, tissue calcium ions began to increase 24 h after reperfusion, accompanied by changes in tissue pH and ATP. In the CA3 region, energy metabolism remained unchanged for 72 h after reperfusion, and the calcium pool was first noted 24 h after reperfusion, while tissue calcium ions began to increase 48 h after reperfusion. These results suggest that the neurons in the CA3 region seem to survive because of the well-preserved metabolic function to cope with excessive calcium ions.

The effect of the synthetic multiserine protease inhibitor FUT-175 on cerebral vasospasm after subarachnoid hemorrhage (SAH) was investigated in rabbits. The SAH in rabbits was simulated by a single injection of autologous arterial blood into the cisterna magna, and, for 7 days, the caliber of each basilar artery was examined several times via angiogram. In 10 SAH rabbits, the peak of the arterial narrowing was observed on Day 2. In this model, the effect of intravenous administrations of FUT-175 was examined. Twenty-seven SAH rabbits were randomly divided into three groups, and 3 doses of 1, 2, or 3 mg of FUT-175 were administered intravenously. Angiographic arterial narrowing on Day 2 in nontreated SAH rabbits (Control) was 35% compared with 21, 5, and 14% in rabbits treated with a total of 3 (Group A; n = 9), 6 (Group B; n = 13), and 9 mg (Group C; n = 5) of FUT-175, respectively. There were statistically significant differences in the arterial calibers between Group A and the Control on Days 1 and 2, between Group B and the Control from days 1 to 4, and between Group C and the Control from days 1 to 4. In three other rabbits, after vasospasm reached its maximum on Day 2, no vasodilatory effect was observed when a total of 6 mg of FUT-175 was administered intravenously. The results indicate that the inhibition of the plasma serine protease cascades at an early stage of SAH prevents the development of cerebral vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate regional changes in calcium ion concentrations, we developed a new histochemical method using aequorin, a calcium ion-sensitive photoprotein. In this method, reagent film containing aequorin was made and an unfixed slice of frozen brain 16 μm thick was placed on it. Tissue calcium ions permeated the reagent layer and the bioluminescence of aequorin-calcium ions was recorded photographically with high spatial resolution. There was a close linear relationship ( r = 0.903) between the optical density of the bioluminescent images and the logarithmic values of the tissue calcium ion concentration. Using this method, we could visualize the regional tissue calcium ion distribution in pathological states in rat brains.

Tyrosine-specific phosphorylated proteins found exclusively on the cell surface of human astrocytomas were previously identified with murine monoclonal antibodies, designated as GA-17, GB-4 and GC-3. The purpose of this study was to further characterize the antigens and investigate the relationship between them and c-kit protooncogene product. We demonstrated that the antigens had protein kinase activity. Moreover, GA-17 reacted with c-kit protein expressed on the membrane of A172 human glioblastoma cells.

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 x 10(9)/l and 50.0 x 10(9)/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.

Two tightly linked recombination activating genes, RAG-1 and RAG-2, are involved in VDJ recombination of the immune system. Although these genes were originally thought to be expressed exclusively in precursor B and T cells, RAG-1 transcripts were recently found in the murine central nervous system (CNS) [Chun et al., Cell 6, 189, (1991)]. We found that the RAG-2 gene was expressed in CNS tumor cell lines, melanoma (B-16) and skin fibroblast (A9). RAG-1 expression was not found in any non-lymphoid cell lines examined including CNS tumor cell lines. Another VDJ recombination-related gene RBP-Jk was expressed in all tumor cell lines examined. It remains to be seen whether expression of RAG-1 and RAG-2 in CNS is abortive or functionally important.

We report here that a neutralizing mouse monoclonal antibody against basic FGF inhibited both anchorage-dependent and anchorage-independent growth of U-87MG and T98G human glioblastoma cells and HeLa cells, all of which express both the basic FGF and the FGF remptor genes. In addition, the subcutaneous administration of this antibody significantly suppressed the tumor development or these tumor cells in nude mice. Therefore, basic FGF plays an important role in neoplastic growth of these cells. The neutralization or basic FGF will be effective in controlling the growth of tumors, such as glioblastoma and other cancer cells which bear basic FGF and FGF receptors.

✓ Prominent features of moyamoya disease are fibrocellular thickening of the intima and enhanced angiogenesis. The pathogenesis of moyamoya disease is, however, unknown. Basic fibroblast growth factor (FGF) is an angiogenic factor as well as a potent mitogen for a number of cell types including vascular endothelial and smooth-muscle cells. In order to test the possibility that basic FGF takes part in the pathogenesis of moyamoya disease, the authors tested for the presence of this factor using a mouse monoclonal antibody against human recombinant basic FGF. The surgical specimens studied included two sections of the superficial temporal artery (STA) and four samples of dura mater from four patients with moyamoya disease. Surgical specimens were obtained from three patients with other diseases as control tissue. Sections of the STA obtained from the patients with moyamoya disease showed strong basic FGF immunoreactivity in endothelial and smooth-muscle cells, while control sections had only faint and scattered immunoreactivity. All sections of the dura mater obtained from the patients with moyamoya disease also revealed more intense immunohistochemical staining of basic FGF in meningeal and vascular cells than did control sections. These observations indicate that the amount of basic FGF is increased in the tissues of patients with moyamoya disease; thus, basic FGF may play an important role in the pathogenesis of moyamoya disease.

✓ Cerebral arterial bifurcations in rats were treated to induce cerebral aneurysms experimentally, and flow patterns of latex particles introduced under a constant flow rate were analyzed with a 16-mm cine-camera and videocassette recorder. Cerebral aneurysms were produced by ligating one common carotid artery, inducing experimental hypertension, and feeding the animals β-aminopropionitrile. After perfusion and fixation, samples of cerebral arterial bifurcations with shallow invaginations and with small aneurysms were obtained and used for analysis. Bifurcations in rats without experimental treatment were used as control specimens. Flow studies in the control bifurcations showed that the apical intimal pad, not the apex itself, acted as the flow divider. Small particles tended to accumulate at the region just distal to the apical intimal pad, where the initial aneurysmal changes are known to occur. This indicates stagnation of flow at that site. In the bifurcations with shallow invaginations and small aneurysms, a marked pressure gradient was present at the proximal end of the aneurysm orifice. A tendency for stagnation of small particles near the aneurysm wall was also observed. The wall shear stress was highest at the distal end of the aneurysmal orifice, which may be responsible for the development of these lesions.

破裂脳動脈瘤患者690名について, アンケートによる最高約8年間の長期追跡調査を行なった.アンケートの回収率は約80%であり, 追跡時の日常生活, 通院状況に加え, 生命曲線をKaplan-Meier法により求めた.追跡調査可能であった, 544名のうち, 死亡退院は150例に認められ, 退院時ADLは1から6までそれぞれ, 172,105, 59, 26, 13, 17例であった.44例が追跡期間中に死亡しており, 多くは心, 肺合併症であった.生存率については, 年齢と退院時ADLに完全に依存し, 65歳以下でADL1-4については追跡期間中極端な低下は認められなかった。しかしながら, 65歳以上でのADLが3, 4, 5, 6のものと, 年齢を問わず退院時ADLが5, 6の者の生存率は悲観的であり, その約半数が2年以内に死亡していた.生存率向上の為, 退院時ADLを改善させる努力が望まれる.

A hydraulic vascular model with glass and silicone tubes of the intracranial portion of the vertebro-basilar artery was used to determine the critical stenosis causing vertebrobasilar insufficiency, and the minimum diameter of the posterior communicating arteries (PComAs) necessary to tolerate therapeutic vertebrobasilar occlusion for unclippable aneurysms. The critical stenosis of one vertebral artery (VA) or basilar artery (BA) differed greatly depending upon the anatomical variations of the PComA and the posterior cerebral artery (PCA): 1.14 mm diameter when the artery supplies 80 ml/ min to the cerebellum and brainstem only, 1.33 mm when 140 ml/min to these structures and one PCA, and 1.56 mm when 200 ml/min to these structures and both PCAs. The minimum PComA diameter to tolerate therapeutic occlusion depended largely upon the occlusion site: one PComA with 1.54 mm diameter for bilateral VA occlusion and 1.25 mm for BA occlusion distal to the branching of the superior cerebellar arteries. The total volume of collateral flow through both PComAs can be estimated by summing the squares of the diameters. These values cannot be applied rigidly to clinical cases, but are useful standards to evaluate the stenotic lesion or tolerance to occlusion.

The growth autonomy of human tumor cells is considered due to the endogenous production of growth factors. Transcriptional expression of candidates for autocrine stimulatory factors such as basic fibroblast growth factor (FGF), acidic FGF, and transforming growth factor type beta were determined in human brain tumors. Basic FGF was expressed abundantly in 17 of 18 gliomas, 20 of 22 meninglomas, and 0 of 5 metastatic brain tumors. The level of mRNA expression of acidic FGF in gliomas was significant. In contrast, transforming growth factor type beta 1 was expressed in all the samples investigated. The mRNA for basic FGF and its peptide were localized in tumor cells in vivo by in situ hybridization and immunohistochemistry, showing that basic FGF is actually produced in tumor cells. Our results suggest that tumor-derived basic FGF is involved in the progression of gliomas and meningiomas in vivo, whereas acidic FGF is expressed in a tumor origin-specific manner, suggesting that acidic FGF works in tandem with basic FGF in glioma tumorigenesis.

✓ Pathological and experimental studies have shown that cerebral aneurysms develop in part as a result of injury to the blood vessel wall. One of the peculiar aspects of aneurysm development is a defective proliferative or healing response to such injury. To examine this phenomenon, blood coagulation Factor XIII, which is known to enhance the healing process of wounds in general, was given to rats to induce experimental cerebral aneurysms. The rats were subjected to ligation of one common carotid artery and induction of hypertension, and were fed beta-aminoproprionitrile. Two weeks thereafter, Factor XIII was injected intravenously daily for 5 days (10 U/100 gm body weight/day). Twelve days after the start of Factor XIII injections, the rats were sacrificed and examined under light and electron microscopy. In seven of 12 bifurcations which developed small aneurysms, prominent intimal thickening was observed in the aneurysm lumen. In the most advanced cases, the aneurysm lumen was completely filled with proliferated smooth-muscle cells and collagen. In five of nine bifurcations that showed no aneurysm development, apparent intimal thickening was found at the site where aneurysms might be expected to grow. In the group of rats studied for induction of cerebral aneurysms but not given Factor XIII, none of 11 bifurcations with or without aneurysms showed such intimal thickening. The results indicated that the proliferative response at the sites of aneurysm development was modified by exogenous Factor XIII.

We studied the elastic skeleton of major cerebral arteries in rats, monkeys, and one human using scanning electron microscopy after hot formic acid extraction followed by freeze-drying. For comparison, we also examined the thoracic aorta and femoral artery of rats. The cerebral arteries of rats had one distinct internal elastic lamina connected to the thin adventitia with sponge-like medial elastic tissue. This internal elastic lamina had fenestrations, which we found to be less frequent in cerebral arteries than in extracranial arteries, and fold-like protrusions into the lumen. This finding has not been recognized before. Such protrusions were more prominent in cerebral arteries than in extracerebral arteries. At the apical intimal pad, the internal elastic lamina appeared to be continuous, making a honeycomb-like structure. The folds and fenestrations were numerous at the apex. There were no essential differences among species. Our study shows that the internal elastic lamina is not a simple sheet but part of the complicated architecture of the elastic tissue of the vessel wall. These differences in the elastic skeleton, including fenestrations and fold-like structures, in various sites of different arteries may explain the development of various localized vascular diseases.

To analyze treatment results of supratentorial malignant gliomas in the megavoltage era, all the histologic specimens were reviewed and glioblastoma multiforme (GBM) was distinguished from anaplastic astrocytoma (AA) by the presence of necrosis. Among those who had completed radiotherapy and who had been followed for at least one year, 135 GBM and 43 AA patients were found. The median survival time (MST) after operation was 12 months for GBM and 18 months for AA. The 5-year survival rate was 0.9% for GBM and 18% for AA. The size of radiation field had little influence on survival time; MST was 12 months for GBM patients treated with a local field covering tumor plus less than 2 cm margin, 12 months for those treated with a generous field (2 cm or more margin), and 13 months for those treated to whole brain. Also for AA, whole brain radiation did not prolong survival. Initial relapse of GBM and AA developed within the irradiated volume in 86% of the cases treated with a generous field. Whole brain radiation seemed useless for the treatment of malignant gliomas. Survival time appeared to be dose-dependent; MST was 10, 13, and 16 months for GBM patients who received 45–57, 57–63, and 63–72 Gy, respectively. Extensive surgical resection was associated with a better prognosis in GBM. AA patients 60 years old or older had a poorer prognosis than younger patients, but age was not a significant prognostic factor for GBM. Chemotherapy appeared to prolong survival slightly without improving long-term survival. Currently, an accelerated hyperfractionation regimen is being tested in which 1.5 Gy is given twice a day up to 69 Gy. Preliminarily, this regimen had no acute or late toxicity and yielded a survival rate at least equivalent to the conventional regimen.

The clonal analysis in the ultrastructure of tumor-lymphocyte interaction was carried out in order to investigate the precise mechanism responsible for CTL-mediated cytolysis of tumor cells. A glioma-derived cell line (GI-1) and autologous tumor-specific cytotoxic T lymphocyte (CTL) clones were established. The CTL lines were composed of the morphologically homogeneous lymphocytes with intracytoplasmic electron-dense secretory granules. After the stimulation by GI-1, the size of the CTLs increased, and the intracytoplasmic organellas were developed. It was noted that the intracytoplasmic secretory granules markedly increased in number and size, and many of them exhibited an “immature” appearance. On the other hand, the tumor cells underwent a progressive degeneration. In contrast, the stimulation by other antigens caused only small morphological changes in the CTLs. It is suggested, therefore, that the secretory function of tumor-specific CTLs is activated by the stimulation of the specific antigen, and that soluble factors in the secretory granules in the CTLs may be closely associated with the mechanism of target Cell lysis.

The contents of glycogen and ATP in the major cerebral arteries were examined in dogs undergoing subarachnoid haemorrhage (SAH). SAH was produced by a single injection of autologous arterial blood (1 ml/kg body weight) into the cisterna magna. Vertebral angiograms showed biphasic basilar arterial narrowings after the injection of blood: Early arterial narrowing occurred immediately after the injection and continued for a few hours. Late arterial narrowing occurred from Day 1 to Day 14 of post-SAH period, and recovered to the normal level on Day 21 of post-SAH period. The content of glycogen in the large pial arteries significantly decreased from Day 1 to Day 14 and returned to the control level on Day 21. The content of ATP in the large pial arteries also decreased from Day 1 to Day 7 and returned to the control level on Day 14. These results show that energy stores in the major cerebral arteries might be diminished during late arterial narrowing.

Changes of calcitonin gene related-peptide (CGRP)- and vasoactive intestinal polypeptide (VIP)-like immunoreactivities (LI) in cerebrovascular nerve fibers on the dog basilar artery were immunohistochemically examined by using whole-mount preparations after single percutaneous injection of blood components into the cisterna magna. Blood components were prepared from autologous arterial blood. CGRP-and VIP-LI in cerebrovascular nerve fibers were highly suppressed after the injection of washed erythrocytes, but only moderately after the injection of platelet-rich or platelet-poor plasma. The results suggest that erythrocytes may suppress CGRP- and VIP-LI in cerebrovascular nerve fibers after subarachnoid hemorrhage.

To investigate the value of direct measurement of the rate constants by performing 18F-labeled fluorodeoxyglucose (FDG) studies of glucose consumption in human gliomas in vivo, a kinetic method with 3- and 4-parameter rate constant models for FDG uptake was used to analyze data from dynamic scans obtained by positron emission tomography after injection of FDG into 14 patients with glioma. The results were compared with those obtained by the autoradiographic method using 3- and 4-parameter rate constant models. There were no significant differences in the glucose consumption calculated by the four different methods both in the gliomas and in the contralateral intact cortex. It was found that the rate constant k4* could be neglected in calculation of glucose consumption in gliomas as well as in the contralateral intact cortex. The rate constant k3*, an index of hexokinase function, was higher in malignant gliomas than in benign gliomas and was close to that in the contralateral cortex. This study indicates that the 3-parameter autoradiographic method, which is the most common one used in clinical practice, is reliable for the calculation of glucose consumption in human gliomas. Furthermore, direct measurement of the regional rate constants for FDG by the kinetic method was found to be useful for evaluation of the biochemical and physiological characteristics of human gliomas in vivo.

A Moloney virus-induced T cell lymphoma, YAC-1, derived from A/Sn (H-2a) inbred mouse origin, was tested for hybrid resistance (HyR) after subcutaneous (s.c.) or intracerebral (i.c.) tumor cell inoculation into syngeneic and semi-syngeneic mice. The F1 hybrids (H-2a/b) between A/Sn and C57BL/6 mice more strongly resisted the s.c. inoculation of 106 and 5 × 105 cells than did syngeneic recipients. In contrast, no HyR to the i.c. inoculation of 104 and 103 cells was seen in the F1 hybrid mice. Natural killer (NK) cell activity was much higher in F1 hybrids than in syngeneic mice. 125I-iododeoxyuridine-labeled YAC-1 cells were more efficiently eliminated from the highly resistant F1 hybrids than from the parental strain in both 4 and 18 hour in vivo rejection assays via intravenous (i.v.) and s.c. injection, respectively. The remaining radioactivity of the brain, however, did not differ between these mice. Thus, there was a correlation between the in vivo resistance of F1 hybrid mice to challenge s.c. inoculation of parental tumors and their expression of lymphocyte-mediated natural cytotoxicity in vitro against those tumors. T cell depletion by thymectomy followed by irradiation and fetal liver reconstitution did not abrogate the s.c. HyR against YAC-1, whereas NK cell depletion by i.v. administration of anti-asialo-GM 1 antibodies resulted in the disappearance of the resistance. Furthermore, genotypic study segregating (A/Sn × C57BL/ 6) F1 × A/Sn backcross mice indicated that the s.c. HyR might be attributable primarily to heterozygosity within the H-2 complex. Taken together, it was suggested that HyR to an NK cellsensitive YAC-1 is mediated by an NK cell-dependent cytotoxic effector mechanism with H-2-linked genetic control against s.c. tumor grafts, while such an NK cell-mediated natural resistance does not operate in the brain.

The authors have investigated the relationship between oncogene (N-myc and c-src) expression and major histocompatibility complex (H-2 in the mouse) antigen gene expression at the molecular levels, by using mouse neuroblastoma sublines (NB-1 and NB-V). Fluorescence-activated cell sorter analysis showed that NB-1 cells exhibited positive expression to H-2 Kk, H-2 Dd, and beta-2-microglobulin, while NB-V cells were negative to all three antigens. It was found that dimethyl sulfoxide (DMSO) had a capacity to increase an H-2 class I antigen expression on NB-1 cells, whereas no change was observed on NB-V cells after DMSO treatment. Molecular analysis with deoxyribonucleic and ribonucleic acid (RNA) blot hybridization and immunoprecipitation revealed that the enhancement of H-2 antigen expression on NB-1 cells was modulated at the transcriptional control of the H-2 gene. In contrast, negative H-2 antigen expression on NB-V cells was caused by block at the level of glycosylation of the H-2 heavy chain, although an increase in messenger RNA of the H-2 gene was induced after DMSO treatment. There was neither amplification nor rearrangement of N-myc and c-src oncogenes in either neuroblastoma subline. Nuclear run-on transcription assay revealed that the N-myc gene was post-transcriptionally down-modulated by DMSO, whereas the c-src gene was transcriptionally up-regulated. It was thus suspected that N-myc and c-src might be directly associated with cellular proliferation and differentiation in neuronal tumors and that in vivo tumorigenicity could be regulated by the control mechanism of oncogene expression in relation to H-2 gene expression on tumor cells.

The authors report a case of cerebral metastasis from a spinal cord astrocytoma. The first metastatic tumor was controlled by radiation therapy. A second metastatic brain tumor was detected 2 years later, but attempts to control it through subtotal removal and chemotherapy failed. Metastasis from a spinal cord tumor to the brain is a rare event.

The in vivo spasmogenic activity of various blood components was examined in dogs. Each blood fraction was injected into the cisterna magna at 0.5 or 1.0 ml/kg body weight, after the removal of 0.5 ml/kg body weight of cerebrospinal fluid, and vertebral angiography was then performed. Whole blood induced both early and late arterial spasm. Platelet-rich and platelet-poor plasma produced only early spasm, and no arterial narrowing was observed on days 1, 3, and 7 after injection. On the contrary, intracisternal injection of washed red blood cells (0.5 ml/kg body weight) produced no arterial narrowing for 6 hours after injection and induced moderate arterial narrowing on days 1, 3, and 7 after injection. Hemolysate (a 10-gm/dl concentration of hemoglobin) produced prolonged monophasic arterial narrowing after injection. These results imply that red blood cells are required for late, prolonged arterial narrowing after experimental subarachnoid hemorrhage.

We report the results of 26 patients who underwent stent deployment for chronic total occlusion of proximal subclavian artery. From January 1998 to October 2005, 26 patients (18 male; mean age, 62.7 years, range 22 to 83 years), 28 lesions, underwent 29 procedures of stenting for chronic total occlusion of the proximal subclavian artery. Twenty-three patients had symptoms of claudication in their arm, no patients had subclavian steal syndrome. A brachial approach was used in 21 procedures, a femoral approach was used in five procedures, and combined femoral-brachial approach was required in three procedures. Primary stent deployment was success in 24 lesions (85.7%), and secondary procedure was success in one patient, totally 25 lesions (89.3%) were successfully treated by stenting. Procedure related complication occurred in four cases, including stent migration without symptoms in two procedures, hemianopsia on next day in a case, and TIA on unclear reason in one case. Permanent morbidity rate is 3.4% in procedure. Target lesion re-treatment required in three lesions, caused by subacute thrombosis, in-stent-restenosis, and dissection of the vessel by stent edge. The cases of subacute thrombosis and in-stent-restenosis were treated by re-PTA, and the case of dissection was treated by additional stenting. Secondary patency was 100%. We conclude that stenting for chronic total occlusion of subclavian arteries appears feasible and safe.

Objective: To evaluate possible applications of microsurgical extirpation to arteriovenous malformations (AVMs) involving the brainstem. Methods: We retrospectively reviewed clinical records of 25 patients with AVMs involving brainstems who were admitted to our institute from 1984 to 2004. We defined a brainstem AVM as an AVM in which some part was located within the brainstem. The main location of the nidus was classified into ventral midbrain (n = 3), dorsal midbrain (n = 10), pons (n = 5), cerebellopontine angle (n = 6), and medulla oblongata (n = 1). Bleeding risks from the AVMs were calculated, and applied treatment modalities, respectability, and clinical outcomes were analyzed. Results: The annual bleeding and rebleeding risks of brainstem AVMs were 15.1 and 14.2%, respectively. Total resection was successfully performed in 0 out of 3, 6 out of 10,2 out of 5,6 out of 6, and 0 out of 1 in each of the groups, respectively. Stereotactic radiosurgery was applied as a main treatment modality in three patients (two ventral midbrain AVMs and one pontine AVM), and after microsurgery in one patient with a medulla oblongata AVM. Microsurgery-related permanent neurological complications were observed in five patients (one postoperative bleeding, one hemiparesis, three hearing deterioration, one abducens nerve palsy). During a follow-up period of 8 years (range, 8 mo-15 yr), one patient with an untreated pontine AVM died owing to hemorrhage and one patient with a subtotally resected dorsal midbrain AVM died owing to an unknown etiology 4 years later. Conclusion: Surgical resection can be applied with considerable, but acceptable, morbidity and mortality in some groups of brainstem AVMs with hemorrhagic presentation, particularly dorsal midbrain and cerebellopontine angle types, in which most parts of the nidus located sub- or extrapially.

Background and Purpose— Status epilepticus and cerebral ischemia stimulate persistent neurogenesis in the adult brain, but both conditions cause neuronal damage. We determined whether spreading depression, a common epiphenomenon of these conditions, stimulates persistent neurogenesis. Methods— We analyzed the effect of KCl-induced spreading depression on persistent neurogenesis and the spatio-temporal distribution of cells exhibiting immunohistochemical markers for divided and early committed neurons (new neurons) in the adult rat brain. Results— After induction of spreading depression for 48 hours, the density of mitotic cells, divided cells, and new neurons in the subventricular zone increased at days 1 to 3, days 3 to 6, and day 6, respectively ( P P P Conclusions— Spreading depression has the potential to stimulate persistent neurogenesis or to produce ectopic new neuron-like cells.

Surgical and endovascular revascularization for ischemic cerebrovascular diseases (CVD) should be strictly indicated based on medical treatment. In this report, we describe current consensus and controversy in the treatment of ischemic CVD, and perspectives. 1) Local intra-arterial fibrinolytic therapy for acute cerebral embolism; intra-venous t-PA can be beneficial when given within 3 hours of stroke onset (NINDS), but many patients present later after stroke onset and alternative treatments are needed. Despite an increased frequency intracranial hemorrhage, treatment with intra-arterial proUK within 6 hours for MCA occlusion significantly improved clinical outcome at 90 days (mRS 40%25%, PROACT-II). MELT-Japan are going now and waiting for results. 2) Carotid stenting; Carotid angioplasty and stenting (CAS) has been proposed as an alternative to carotid endarterectomy (CEA) in those considered at high risk for CEA. SAPPHIRE study confirmed CAS is an excellent option for patients with coexisting coronary artery disease, congestive heart failure, and other comorbid conditions that make them poor candidates for CEA. Now, CREST in USA and CSSA in Europe are going for randomized trial compared with CEA and CAS in any risk for CEA patients. 3) Stenting for intracranial arteries; Stroke rates in patients with symptomatic intracranial stenosis may be high on medical therapy. Although there is no clinical evidence and appropriate devices for intracranial vessels, it seems to be a potentially effective in the future.

Expression of three heat shock proteins (HSPs), HSP70, HSP90, and immunoglobulin heavy chain binding protein (Bip) was examined in the developing rat retina using Northern blot analysis. The expression of the inducible form of HSP70 remained uniformly low throughout the perinatal period until P5 and increased rapidly at P7. On the other hand, the constitutive form of HSP70, HSP90, and Bip were expressed constitutively in the rat retina throughout the developmental stage except P3-P5, at which a transient decrease of the expression was observed. The increase of inducible HSP70 mRNA at P7 may correspond to the functional maturation of photoreception in the visual nervous system and may be one of the stress responses to photostimulation. The potential roles of each HSP during development of the rat visual system are discussed.

Preconditioning the rat brain with spreading depression for 48 h induces potent ischemic tolerance (infarct tolerance) after an interval of 12-15 days, consequently reducing the infarcted lesion size in the acute phase following focal cerebral ischemia. However, persistence of the morphological and functional neuroprotection has not yet been proven. We tested whether tolerance-derived neuroprotection against focal cerebral ischemia persists or merely delays the progress of cerebral infarction. Prolonged spreading depression was induced in mice by placing a depolarized focus with intracerebral microinfusion of KCl for 24 h; after intervals of 3, 6, 9 or 12 days, temporary focal ischemia was imposed. In the analysis of the infarcted lesion volume 24 h after ischemia, groups with 6 or 9 day interval demonstrated significantly smaller lesion volume compared to time-matched vehicle control group (P=0.002). Significant reduction in cerebral infarction was also observed at the chronic phase, namely 14 days after ischemia (33% reduction) (P=0.021) accompanied with less severe neurological deficits (38% reduction) (P=0.020). Using this technique, we also investigated if the mice with targeted disruption of a single BDNF allele (heterozygous BDNF-deficient mice) can gain the same potency of tolerance as the wild mice. In the result on infarcted lesion volumes following temporary focal ischemia, potent tolerance developed in the wild type (35% reduction) (P=0.007) but not in the heterozygous BDNF-deficient mice (

A 59-year-old female with a previous history of head injury presented with mild occipitalgia due to dolichoectasia of the middle cerebral artery (MCA). Initial examination by computed tomography and angiography using the usual projections suggested a terminal internal carotid artery saccular aneurysm. However, angiography by the reverse Waters view excluded a saccular aneurysm. Superselective angiography using a microcatheter revealed the complex tortuous course of the MCA due to dolichoectasia. She was discharged and has remained asymptomatic. Superselective angiography is extremely useful for the diagnosis of dolichoectasia localized in the MCA.

The temporary three-vessel occlusion (3VO) technique with a surgical approach for middle cerebral artery (MCA) produces consistent cerebral infarction in the neocortex in normotensive rats. The intraluminal thread-occlusion technique with an endovascular approach targeting the MCA occlusion (MCAO) is more widely used since it does not require complicated intracranial procedures. The aim of this study was to review the methods/models for MCAO stroke in normotensive rats and to evaluate a 3VO stroke model that provides consistent degrees and variance of cortical stroke injury for additional discussion. First, we analyzed a model with modified temporary 3VO technique requiring less complicated procedures than the temporary 3VO model, i.e., temporary occlusion of the bilateral common carotid arteries (CCAs) superimposed on a permanent occlusion of the MCA, in Sprague-Dawley rats or C57BL/6J mice. In the microvascular tissue (cerebral) perfusion study, significant reductions in regional cerebral perfusion during the 3VO accompanied a rapid return to baseline after release of the CCAs, showing that the technique induces temporary focal ischemia. The average sizes and variances of the neocortical infarction in this model, together with those in the other normotensive rat models caused by the 3VO technique in the literature, indicated a standard size and variance of infarcted lesion in the control groups relative to the specific ischemic period. However, stroke injuries in the neocortex induced by the thread occlusion technique showed greater variability with less consistent lesion sizes. Inclusion/exclusion criteria to avoid inappropriate cases with too mild (no/faint infarction) or too great (huge/fatal infarction) severity in the ischemic injury may differ between laboratories in the thread occlusion model.

Object. In their pursuit of a better substitute for dura mater in neurosurgical procedures, the authors review their experience with GM972. Methods. A newly developed synthetic dural substitute composed of bioabsorbable polymers (GM972) was placed in 53 patients during neurosurgical procedures. The handling properties of the material, surgical wound features, and findings of hematological, computerized tomography, and/or magnetic resonance imaging examinations were evaluated. The average follow-up period was 35.5 months. The handling properties and biocompatibility of this new dural substitute were highly satisfactory, and no significant complication was observed. In patients who underwent a second surgery performed more than 18 months after the initial operation, this new dural substitute was found to have been replaced by autologous collagenous tissue. Because of its bioabsorbability, chronic foreign body reactions to this synthetic dural substitute were negligible. Conclusions. In this report the authors support the effectiveness and safety of this bioabsorbable artificial dural substitute that provides a reduced risk of transmission of latent infection.

Molecular mechanisms in infarct tolerance, the consistently increased cerebral resistance to ischemic stroke within 12 days following repetitive cortical spreading depression (CSD), were analyzed by measuring brain derived neurotrophic factor (BDNF)-content in the neocortex in rats. The levels of total BDNF protein were significantly elevated from day 0 to 12, peaking on days 0 and 6 following CSD. In contrast, the BDNF-like immunoreactivity in neuronal nuclei observed by confocal laser-scanning microscopy linearly increased until day 12. This indicated that the upregulation of BDNF and subsequent intranuclear translocation of BDNF-like protein was a key feature in infarct tolerance. Furthermore, it was confirmed that continuous and prolonged intracerebral infusion of exogenous recombinant BDNF induced infarct tolerance with similar histological findings of enhanced nuclear immunoreactivity for BDNF following CSD.

Thrombin and the complement system are activated in vascular lesions during the process of atherosclerosis or pathologic proliferation of smooth muscle cells, and in the subarachnoid space during the development of cerebral vasospasm following subarachnoid hemorrhage (SAH). This article reviews the effects of a potent inhibitor of the complement system and/or thrombin on vascular neointimal formation in the carotid artery of rats, and the development of cerebral vasospasm following subarachnoid hemorrhage (SAH) in rabbits. Carotid balloon dilation injury induced in rats was treated with FUT-175 for 7 days. In rabbits, SAH was treated with FUT-175, or argatroban for 48 h. In addition, recombinant PDGF-BB was injected into the cisterna magna of normal rabbits to observe the calibers of the basilar arteries for 48 h. Neointimal formation after balloon injury was significantly reduced by the treatment with FUT-175. Development of cerebral vasospasm was prevented by FUT-175 or argatroban. In the histological examination, effective doses of FUT-175 or argatroban suppressed the expression of PDGF-BB in the neointimal lesions. Exogenous PDGF-BB resulted in delayed and prolonged vasoconstriction in normal basilar arteries. The complement system and/or thrombin activation following balloon dilation injury or SAH was demonstrated to play a critical role in the development of vascular lesion formation. In the cascade downstream of the protease activation, the production of PDGF-BB was indicated.

The potential of hypothermic brain protection for ischemic stroke has been demonstrated under laboratory conditions. This article reviews our recent progression understanding the efficacy and specific characteristics of prolonged mild hypothermia for ischemic stroke in rats. Using temporary or permanent focal ischemia models, the rats were treated by mild (33 °C) hypothermia at different schedules. The targeted mild hypothermia was applied only intra- or postischemia, or both periods in the temporary focal ischemia model. In permanent focal ischemia, mild hypothermia was achieved at the onset of ischemia, maintained for 2 h under general anesthesia and further maintained using a cold room for a total of 24 h. The infarcted lesion sizes and neurological function were analyzed for a maximum of 30 days following ischemia and compared to that of the normothermia group. In temporary focal ischemia, the infarcted lesion sizes with intraischemic hypothermia, postischemic hypothermia, or combined prolonged intra- and postischemic hypothermia, analyzed on day 2, were 159 ± 25, 141 ± 19, 76 ± 26 mm3, respectively. The values in the latter two groups were significantly smaller compared to that obtained under normothermia, 211 ± 19 mm3 (mean ± SEM, p< 0.05). The significant difference in lesion sizes and neurological deficits lasted only in the combined hypothermia group on day 30. In permanent focal ischemia, the infarcted lesion 88 ± 15 mm3 in the hypothermia group was significantly small compared to that in normothermia, 211 ± 19 mm3 on day 21 (p< 0.05). Mild hypothermia did suppress the development of cerebral infarction and neurological deficit in temporary or permanent focal ischemia. To obtain the maximum neuroprotection from mild hypothermia, acute and prolonged application of hypothermia are key factors.

Cerebral vasospasm after subarachnoid hemorrhage appears when infiltration of macrophages is prominent, however, a causal relationship between the vasospasm and infiltration of macrophages has not been elucidated. A potent vasoconstrictor endothelin is reported to be involved in the cerebral vasospasm, while the origin of the endothelin is unknown. We found and characterized the macrophage-induced constriction of cerebral artery via endothelin in a subarachnoid hemorrhage model. An injection of oxidized but not non-oxidized erythrocyte membranes induced an infiltration of macrophage and a cerebral vasospasm on the day 3. A simultaneous injection of macrophages along with the oxidized membranes induced a cerebral vasospasm immediately and the vasospasm was abolished by co-injection of endothelin-receptor antagonists (FR-139317 for ETAR or BQ-788 for ETBR). The direct vasoconstricting action of macrophage along with the oxidized membranes was confirmed with an isometric tension study. Macrophages preferentially recognized and interacted with the oxidized membranes. These data suggest that the infiltrated macrophage induces a cerebral vasospasm via endothelin after it’s activation by the interaction with oxidized erythrocyte menbranes.