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Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

Objective: We aimed to evaluate the feasibility of a one-day two-fraction Gamma Knife radiosurgery (GKRS) for brain metastases. Cases and methods: Ten cases with ten brain metastases (four cases of lung adenocarcinoma, one small cell lung carcinoma (SCLC), two renal cell carcinoma, one breast cancer, one esophageal carcinoma, and one bile duct carcinoma) were treated by one-day two-fraction (with an interval of more than six hours) GKRS under rigid skull frame fixation. Of the ten brain metastases, five lesions were in the frontal lobe, one in temporal, one in occipital, and three in the cerebellar hemisphere. The mean planning target volume (PTV) of the ten brain tumors was 7.8 ml (median, 8.0; range, 3.8 - 11.8). The ten targets of the mean prescription isodose volume (PIV) of 10.1 ml (median, 10.1; range, 4.4 - 15.9) were treated with a mean margin dose of 20.4 Gy (median, 20.5; range, 16.4 - 22) in two fractions. In five cases, other small brain metastases (one to seven tumors) were also treated simultaneously in a single fraction GKRS. The indication of two-fraction radiosurgery was large lesion size in eight, retreatment in three, the proximity of the motor area in three, and pre-existing perifocal edema symptom of dysarthria in two, nausea and vomiting in one, and dementia in one. Results: Eight cases were alive at the end of the follow-up period of one to nine months (median, 6). One patient with SCLC died four and a half months after GKRS, from aggressive regrowth of the treated frontal lesion after transient marked shrinkage. Another patient died four months after GKRS due to the progression of other brain tumors treated by single fraction GKRS at the same time. In nine of 10 cases, the size of the treated tumors was controlled until the end of the follow-up period or the patient’s death. In two cases, an additional GKRS was performed for newly developed brain metastases at distant locations at six months and five months after one-day two-fraction GKRS, respectively, and controlled at the end of the follow-up period. Conclusions: A relatively high dose may be safely delivered to large lesions, to those close to the important structures, or those with perifocal edema by one-day two-fraction radiosurgery. Local control was good except for a relapsed SCLC metastasis case. Evaluation in more cases with a longer follow-up period is necessary to determine definite indications and optimal prescription doses.

We previously reported the usefulness of three-dimensional (3D) CT angiography for perioperative evaluation of carotid endarterectomy (CEA). Calcification depicted well in the modality has also been studied pathologically. We have pointed out that the microscopically granular type might be relatively softer than the lump/luminar type and that this factor may affect the result of carotid angioplasty and stenting. The aim of the study was to determine the surgical option by analyzing hardness of calcification with calcium scores obtained by 3DCT angiography. Seventy carotid arteries were examined with 3DCT angiography and 35 plaques were extracted in CEA. Volume, Hounsfield units and calcium scores of calcified lesions were calculated and analyzed by a 3D workstation. Calcified lesions were classified into 4 groups according to their volume and Hounsfield units. Though large calcification tended to have a relatively bigger difference between maximum and mean CT values, the calcium score seemed to be plotted in proportion to overall hardness of calcification and to enable comprehensive evaluation, which might affect the choice for surgical treatments.

The expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) mRNA after traumatic brain injury in rats was investigated using an in situ hybridization technique, along with regulating gene p53 and stress response gene hsp70 mRNA levels. At 3 h postinjury, p21(WAF1/CIP1) mRNA was markedly increased in the cortex, white matter, thalamus, CA2, a part of CA1,3 and dentate gyrus of the injured side. Hybridization signals remained elevated at 6 h in injured cortex and hippocampus and returned to the baseline by 24 h post-insult. On the other hand, p53 mRNA induction was not observed in any brain sections throughout the post-injury time course. Slight expression of hsp70 mRNA was detected in the injured cortex 3-6 h following injury and this was similar to the temporary pattern of p21(WAF1/CIP1) mRNA expression. This study showed p21(WAF1/CIP1) mRNA to be transiently induced after traumatic brain injury, independent of p53, this possibly being an early stress response to protect cells by arresting them in the cycle and allow DNA repair.

The rat endovascular filament model has been utilized to study subarachnoid hemorrhage (SAH). Because the severity of the hemorrhage with this model has proven difficult to modulate, we attempted to vary the hemorrhage by modifying filament size, and compared this model to the blood injection method with regards to acute physiological responses and hemorrhage size. SAH was achieved using either a 3-0 or 4-0 filament, or by injecting 0.3 cc of autologous blood into the cisterna magna. Peak ICP elevations were lowest in the 4-0 filament group. CBF decreased acutely and rose from its nadir in all three models with the injection model demonstrating the earliest recovery. In the injection group, mean arterial blood pressure rose acutely and remained elevated, whereas in the 3-0 group, MABP rose transiently and in the 4-0 group it did not rise significantly. Histologically, there was less subarachnoid blood in the 4-0 group vs. the injection or 3-0 groups and a different distribution of blood in the two experimental models. Varying filament size provides a method to modulate the severity of SAH in the filament model. In addition, the rat endovascular filament and blood injection models produce different distribution of blood and physiological responses.

Expression of immediate early gene (IEG) mRNAs following traumatic brain injury in 3 different models-cryogenic injury, impact injury with craniotomy and impact injury without craniotomy-was investigated using in situ hybridization. Cryogenic brain injury resulted in c-fos and c-jun mRNA expression throughout the ipsilateral cortex, piriform cortex and dentate gyrus on the injured side, with peak at 30 min to 1 h post-injury. Impact injury with craniotomy was associated with hybridization signals in the same areas and also in the subcortical white matter or ependyma underlying the impact site at 30 min post-injury. The expression was rather more prolonged than with cryogenic injury. Impact injury without craniotomy induced the expression of both mRNAs throughout the ipsilateral cortex, piriform cortex and dentate gyrus at 30 min post-injury, but this was promptly attenuated by 1 h post-injury, except for bilateral elevation in the dentate gyrus. The present study, thus, demonstrated that regional and temporal expression of IEG mRNAs is influenced by the intensity, quality and manner of application of the insult. Differences in the expression of IEGs may alter the late response gene expression and affect the succeeding events.

The relationship between the expression of basic fibroblast growth factor (bFGF) messenger ribonucleic acid (mRNA) and protein, a potent mitogen for vascular smooth muscle cells in vivo, and administration of the angiotensin-converting enzyme inhibitor cilazapril, which suppresses smooth muscle cells proliferation in denuded arteries, was studied in spontaneously hypertensive rats using the in situ hybridization technique and immunohistochemical study. The effect of cilazapril on neointimal formation through modification of bFGF expression was evaluated using the increased tissue expression of the renin-angiotensin system in spontaneously hypertensive rats. Arterial injury was produced by using balloon catheter denudation in the left carotid artery of rats. The effects were evaluated 2 weeks later. bFGF mRNA and protein were observed only in the endothelial cells of sham-operated rats. bFGF mRNA and protein were observed in both endothelial cells and intimal smooth muscle cells in operated rats receiving only vehicle. Expression of bFGF mRNA and protein was suppressed in both endothelial cells and intimal smooth muscle cells of operated rats receiving cilazapril. These data suggest that cilazapril suppresses smooth muscle cell proliferation through modification of the expression of bFGF mRNA and bFGF protein in addition to other genes.

GLUTAMATE transporters play an important role in maintaining the extracellular glutamate concentration below the neurotoxic level. We investigated the expression of glutamate/aspartate transporter (GLAST) mRNA in the periventricular region of rats with kaolin- induced hydrocephalus by in situ hybridization (ISH). The density of GLAST mRNA-positive cells and the level of hybridization signals per positive cell significantly increased in the acute stage of hydrocephalus. We also demonstrated co-localization of GLAST mRNA and GFAP immunoreactivity in a single cell using the combined methods of ISH and immunohistochemistry. These findings suggest that GLAST is expressed in the reactive astrocytes of the periventricular area and regulates extracellular glutamate concentration after hydro- cephalic brain injury.

A 62-year-old male presented with glioblastoma multiforme in the left frontal lobe manifesting as motor aphasia, subsequent to a malignant lymphoma in the right orbit. He underwent subtotal removal of the right orbital mass presenting as right exophthalmos which was shown by histological examination to be non-Hodgkin's lymphoma. He received 30 Gy Lineac irradiation to the right orbit. His post-operative course was satisfactory. Magnetic resonance (MR) imaging with gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) 7 months later demonstrated a small spotty enhanced lesion in the left frontal lobe. He developed motor aphasia 1 year after irradiation. MR imaging disclosed an enhanced mass in the left frontal lobe, which was totally removed. Histological examination revealed glioblastoma multiforme. Patients with malignant lymphoma may develop a subsequent second malignant tumor. MR imaging with Gd-DTPA is quite useful for early detection of a second brain tumor.

BACKGROUND Although most of pituitary apoplexy occur spontaneous, some precipitating factors have been reported. We experienced two cases of pituitary apoplexy after a pituitary function test. METHODS In order to clarify the causal relation between the pituitary function test and apoplexy, we presented our two cases and reviewed 20 cases in the literature. RESULTS(Case 1) A 48-year-old man with a pituitary macroadenoma received an injection of 500μg thyrotropin-releasing hormone (TRH), 100μg gonadrotopin-releasing hormone (GnRH), and 0.1U/kg insulin as a preoperative test of pituitary function. Fifteen minutes later, he complained of diminished vision and headache. (Case 2) A 54-year-old man with a large cystic adenoma had an administration of 500μg TRH and 100μg GnRH. Ten minutes later, he complained of blurring of his left eye and headache. Although, in both cases, CT scans showed neither intratumoral hemorrhage nor infarction, the surgical specimen showed necrotic and hemorrhagic adenoma. The patients made excellent clinical recoveries after surgical decomposition Twenty-two reports including our two cases were reviewed in 15 cases (68%), TRH was associated with apoplexy events and seemed to be the agent most likely to have an etiologic role because of its vasoactive properties. Eighteen patients (82%) had pituitary macroadenoma with suprasellar extension. In 72% of 18 surgical cases, some recovery of visual function was obtained. CONCLUSIONS An apparent relationship between the test and the apoplexy events raises the possibility of the development of pituitary apoplexy after a pituitary function test. Unless there is a specific indication, pituitary function test should be avoided especially in patients with a large pituitary tumor.

Immediate early gene (IEG) mRNA induction by cryogenic injury was examined using an in situ hybridization approach and the results compared with the heat shock protein mRNA expression. Hybridization signals for c-fos and c-jun mRNA were found after 30 min in the ipsilateral cortex, the hippocampal dentate granule cells and the piriform cortex, c-jun mRNA was also detected in the contralateral dentate gyrus and the piriform cortex, but was less extensive. Return to baseline values was observed at the 24 h time point. Peak induction, with silver grains observed mainly over the neurons on emulsion autoradiograms, was demonstrated in all cases 30 min to 1 h post-injury. In contrast, only slight hsp70 mRNA expression by the neurons surrounding the cold-injured site could be detected by microautoradiography, at 6 h following the trauma. The results indicate that cryogenic brain injury induces IEGs in a similar way to mechanical modes of injury such as lateral fluid percussion, but that hsp70 mRNA is hardly expressed, implying the possible existence of differences in stress response pathways.

A 75-year-old female with chronic renal failure diagnosed as Wegener''s granulomatosis was receiving steroids and immunosuppressive agents when subarachnoid hemorrhage developed. Cerebral angiography showed a fusiform aneurysm arising from an angular branch of the left middle cerebral artery. Hemorrhage occurred and the aneurysm was excised by emergency surgery. Microscopic examination of the aneurysm revealed dense infiltration of hyphae identified as Aspergillus. She died of subsequent hemorrhage. Autopsy showed numerous Aspergillus hyphae in the lung. Fungal mycotic aneurysm should be considered in the differential diagnosis of an immunocompromised patient with subarachnoid hemorrhage.

Neurons and glial cells respond to extracellular hyperosmolarity by accumulating small organic solutes, called "osmolytes." Na + /myo-inositol is one of the major organic osmolytes in the brain and Na + /myo-inositol cotransporter (SMIT) regulates extracellular Na + /myo-inositol content. Subarachnoid hemorrhage (SAH) is an osmotic stress-inducing event of the brain. The expression of SMIT messenger ribonucleic acid (mRNA) and protein was investigated with in situ hybridization and immunohistochemistry in rat brains with SAH induced by endovascular perforation. SMIT riboprobe was raised from a 490-bp rat SMIT complementary deoxyribonucleic acid. Anti-SMIT antibody was raised in rabbits. SMIT mRNA was expressed strongly in the cortex, hippocampus, and hypothalamus of the perforated side at 6 to 24 hours after SAH. Mild upregulation was noted in the contralateral cortex, hippocampus, and hypothalamus. The ventral aspect of the pons showed mild upregulation. Microautoradiography and immunostaining showed SMIT expression mainly in the neurons, but also in some non-neural cells in the hippocampus. The present results indicate that diffuse osmotic stress occurs in the host brain after SAH.

Extracranial-intracranial (EC-IC) bypass surgery had been widely performed for the treatment of internal carotid artery occlusion. However, it is presently difficult to predict how the bypass flow will contribute to intracranial circulation. We examined intracranial hemodynamics by transcranial color-coded duplex sonography (TCCD) after superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and retrospectively studied the relationship between the postoperative contribution of the bypass flow and the preoperative collateral circulation and cerebrovascular perfusion status in 10 patients. Hemodynamics in the MCA detected by TCCD were classified into three patterns. In pattern A, perfusion of the whole MCA area is completely dependent on the bypass flow. In pattern B, perfusion of the M2 segment is dependent on the bypass flow, but perfusion of the M1 segment is independent of the bypass flow. In pattern C, perfusion of the whole MCA area is supplied by collateral flow and the bypass does not function efficiently. Preoperative absence of collateral flow via anterior communicating artery and cerebral perfusion status type 3 (reduced regional cerebral blood flow and regional cerebral vasoreactivity) seems to predict hemodynamic usefulness of the bypass flow after surgery. TCCD is an easy and noninvasive method for evaluating intracranial cerebral circulation after EC-IC bypass surgery.

We investigated expression of hsp70 and c-jun mRNA with in situ hybridization for evaluating hypothermia effect on the brain exposed to subarachnoid hemorrhage (SAH). SAH was induced in Wistar rats with endovascular perforation. Animals were divided arbitrarily into normothermic and hypothermic groups, and they were sacrificed at 3 h or 12 h after SAH. The SAH induced hsp70 and c-jun mRNAs in the cerebral cortex, hippocampus, thalamus, hypothalamus, and caudoputamen. Mild hypothermia depressed hsp70 mRNA expression in the cortex, thalamus, and hippocampus. The c-jun mRNA expression was reduced by hypothermia in the cortex, thalamus, and CA1 of the hippocampus. Based on these findings, we speculate that hypothermia protects the brain exposed to SAH by reducing this stress response. Although it is yet difficult to employ hypothermia in the clinical settings, this study suggests its utility to those patients sustaining severe subarachnoid hemorrhage.

Glial changes following traumatic injury to glial monolayers as well as to neuronal-glial co-culture systems in vitro were examined with a focus on the expression of mRNAs coding for the immediate early genes (IEG) c-fos, c-jun and zif/268, demonstrated using in situ hybridization. Glial cells along scratch wound lines extended cytoplasmic processes as early as 10 min post-injury and the whole wound was covered with gliosis by 24 h. For complete restoration in the case of glial cells co-cultured with neurons, this required 48 h. Induction of the three IEG mRNAs was eminent along the edges of scratch wound, peaking at 30-60 min post-injury and subsiding by 3 h. The peak expression of IEG mRNAs was delayed to 1-3 h post-injury and became undetectable at 6 h in neuronal-glial co-cultures. The data suggest that mechanical injury to glial cells causes gliosis and the expression of IEG mRNAs, which are suppressed by co-culture with neurons, indicating some influence of neuronal-glial interactions.

Apoptosis in neurons can be induced by mild cerebral ischemia. We developed a rat model of subarachnoid hemorrhage that caused mild ischemic stress to the brain and detected expression of apoptosis-related genes in the hippocampus. Intracranial carotid bifurcation of the rat was perforated by a 3–0 nylon and subarachnoid hemorrhage induced. The intracranial pressure rose immediately to a level similar to systemic arterial pressure for 30 s to 1 min and returned to baseline by 20 min. We detected mRNA expression of bax, bcl-2, bcl-x, ice, p53 and p21 (Waf1) using an in situ hybridization technique. With this model, about one-third of the CA1 neurons were TUNEL-positive at 48 h after perforation, and histological findings were compatible with apoptotic cell changes. The bax, bcl-2, and bcl-x mRNA were expressed transiently at CAl pyramidal neurons, with a peak at 12 h. The bax tended to be expressed for a longer period than bcl-2. The CA3 pyramidal neurons showed bax, bcl-2, and bcl-x mRNA expression as well, but transiently and with an intensity that was about half that at CAl. The ice mRNA, the key enzyme for protease cascade, was upregulated at CA1 neurons with a peak at 12–18 h. The p53 mRNA expression was transient with maximum levels at 12 h, indicating that p53 is located upstream of bax expression. The p2l(Waf1) expression, however, reached maximum levels at 48 h and lasted until 120 h, suggesting no relation to bax or bcl-2 expression. The results may relate to delayed ischemic neurological deficit, which is often observed as a result of subarachnoid hemorrhage and vasospasm.

No attention has been given to an influence of the intracranial pressure (ICP) elevation on the brain at the level of the gene. In the present study, we originally attempted to evaluate the molecular biological changes of the brain, especially the expression of c-fos mRNA as a marker of cellular response, caused by increased ICP. Our results confirm that the neurons and non-neuronal cells are well able to tolerate the stress of increased ICP at the level of the gene, under the condition that cerebral blood flow (CBF) is maintained. A severe increase in ICP, which reduces CBF, enhances the c-fos mRNA expression in a similar fashion as in a forebrain ischemia model, except in the choroid plexus.

To detect stress responses of the brain to subarachnoid hemorrhage (SAH), we investigated the expression of immediate early genes (IEGs) and hsp70 mRNA by in situ hybridization. Experimental SAH was produced in 49 rats by endovascular penetration. We also monitored the intracranial pressure (ICP) changes. The genes c-fos and c-jun were induced in the cerebral cortex, hippocampus and dentate gyrus in the penetrated side. mRNA coding for hsp70 was induced in the cerebral cortex, hippocampus, thalamus, hypothalamus and caudoputamen in the penetrated side and extended to the contralateral hemisphere. IEGs in the cerebral cortex were completely blocked by MK-801 pretreatment, but hsp70 mRNA was not. This suggests that the expression of IEGs correlates with spreading depression. The IEGs and hsp70 expression may reflect the severity of SAH impact and relate to the mechanisms of symptomatic vasospasm.

A 32-year-old male presented with progressive pure amnesia caused by astrocytoma invading the bilateral medial temporal lobes. Methionine positron emission tomography demonstrated the extent of tumor invasion well. His memory impairment was partially improved by treatment for the astrocytoma. Lesion of the bilateral hippocampus causes memory impairment, but pure memory loss without other associated neurological sign or deterioration of consciousness is rare in a case of cerebral neoplasm.

We have reported that basic fibroblast growth factor (bFGF) prevents retrograde degeneration of thalamic neurons after middle cerebral artery (MCA) occlusion. To identify the protective mechanism of bFGF, we examined bFGF mRNA expression in a model of transient focal ischemia with in situ hybridization. Compared to c-fos, c-jun, and hsp 70 mRNA expression, upregulation of the bFGF mRNA expression was delayed until 6 h after reperfusion. By 12 h, bFGF mRNA was markedly induced in the peri-infarcted cortex, cingulate cortex, and peri-infarcted white matter. At 24 h and 2 days the induction of bFGF mRNA in these regions persisted, and disappeared by 5 day. The quantitative assessment of bFGF mRNA expression revealed that optical density ratios of the cingulate gyrus and the caudoputamen were significantly higher at 12 h, 24 h, and 2 d after reperfusion than those in sham controls. Microscopic observation indicated bFGF mRNA signals were present in several types of cortical cells, including neurons and nonneuronal cells. Since intrinsic bFGF, released from the damaged tissue, can influence the healing response through receptors upregulated by injury, it is reasonable that this pattern of bFGF mRNA expression parallels the bFGFR mRNA expression previously reported.