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A 14 year-old boy developed infective endocarditis of the mitral valve caused by Methicillin-sensitive Staphylococcus aureus and became comatose. Isolated basilar artery dissection was initially observed on the 3rd day by magnetic resonance imaging (MRI), ie, it did not exist on day 1. He underwent successful urgent mitral valve repair on the 5th day because of highly mobile vegetations and a newly emerged brain infarction under optimal antibiotic administration. Postoperatively, he recovered well and the basilar artery dissection was found to have recovered on an MRI on the 25th day without any specific intervention. This clinical course indicated that intracranial artery dissection may occur as a complication of infective endocarditis and supports the importance of the careful evaluation of brain MRI in patients with infective endocarditis.

Endovascular recanalization for acute major cerebral artery occlusion is effective within a short time after symptom onset. However, its efficacy in the elderly remains unknown. We assessed the efficacy of our comprehensive stroke center's reduction of this time in 28 consecutive patients for elderly patients (defined as patients aged ≥75 years) with acute major cerebral artery occlusion treated with intravenous injection of tissue plasminogen activator, followed by thrombus retrieval by endovascular therapy. The patients were divided into groups according to whether they were treated before implementation of the time reduction measure (from January 2012 to May 2014) or after (from June 2014 to May 2015). The onset-to-door, onset-to-needle, onset-to-recanalization (O2R), door-to-image (D2I), door-to-needle (D2N), door-to-puncture (D2P), door-to-recanalization (D2R), and puncture-to-recanalization time intervals were compared between the two groups. There were 14 patients (including 8 elderly patients ≥80 years) before and 14 patients (including 10 elderly patients ≥80 years) after the time reduction measure. The mean duration of each of the following time intervals was significantly reduced after the time reduction measure (P < 0.05). To reduce the O2R time, the D2P time is the first time interval that can be reduced. At our center, conferences were regularly held to raise awareness among staff and make specific changes in the workflow, and overall time reduction was achieved. Similar results were obtained in elderly patients.

The presence or absence of the penumbra area is important when performing reperfusion therapy in patients with acute ischemic stroke. As a predictor of this penumbra area, magnetic resonance angiography (MRA)-diffusion-weighted imaging (DWI) mismatch is attracting attention. The usefulness of MRA-DWI mismatch (MDM) using the DWI-Alberta Stroke Program Early Computed Tomography Score (ASPECTS) in endovascular treatment (EVT) of patients with cerebral large vessel occlusion was evaluated.Of 1442 patients registered in the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Registry between July 1, 2010 and June 30, 2011 who presented to the hospital within 24 hours of the onset of acute cerebral infarction because of cerebral large vessel occlusion, 188 patients who had internal carotid artery or middle cerebral artery occlusion and achieved recanalization with EVT were included. Of these, 71 patients underwent intracranial EVT because intravenous recombinant tissue plasminogen activator therapy was ineffective. The associations between the presence or absence of MDM (MDM-positive [MDM-P], DWI-ASPECTS≥6; MDM-negative [MDM-N], DWI-ASPECTS6) and 90-day prognosis (modified Rankin Scale [mRS]) and symptomatic intracranial hemorrhage (sICH) were examined.Of the 188 patients analyzed, the time from symptom onset to admission was within 3 hours in 143 patients, 3-8 hours in 36 patients, and 8 hours or more in 9 patients. The time from the onset was within 3 hours in 118 patients in the MDM-P and 25 patients in the MDM-N cases. Favorable outcomes (mRS score≤2 at 90 days) were seen in 63 patients (53.4%) in the MDM-P group and 7 patients (28.0%) in the MDM-N group, showing a significantly more favorable clinical outcome in the MDM-P group (P=.027). The incidence of sICH was significantly lower in the MDM-P group (MDM-P group 3.4%, MDM-P group 20.0%; P=.009). The time from the onset was 3-8 hours in 29 patients in the MDM-P group and in 7 patients in the MDM-N group. Favorable outcomes were seen in 12 patients (41.4%) in the MDM-P group and 2 patients (28.6%) in the MDM-N group, with no significant difference between the 2 groups. No patients had sICH. The patients admitted 8 hours or more after the onset were all MDM-P. Five patients (55.6%) had a favorable outcome.This study demonstrated the safety and efficacy of EVT in MDM-P patients within 3 hours of symptom onset. Although the ratio of patients who had a favorable outcome was high in the MDM-P patients admitted 3-8 hours after the onset, the difference was not significant.

Background In patients who are not responsive to intravenous tissue plasminogen activator (IV t-PA), the present study aimed to report recanalization rates, the incidence of hemorrhagic transformation (HT), and clinical outcomes of additional endovascular therapy (AET), and to investigate the usefulness of magnetic resonance angiography–diffusion mismatch (MDM) in a selection of patients eligible for AET. Methods Fifty-eight patients who received IV t-PA therapy because of intracranial major artery occlusion between April 2007 and November 2010 were divided into 2 groups: 18 patients in the AET group and 21 patients in the IV t-PA nonresponders group. The remaining 19 patients were responders to IV t-PA and therefore not eligible for this study. Recanalization rates, HT incidence, and 3-month outcomes were assessed, and the relationship between MDM and clinical outcome was examined. Results A 3-month modified Rankin Scale (mRS) score of 0 to 3 was seen more frequently in the AET group (72% in the AET group v 29% in the nonresponder group; P = .01). Serious outcomes (3-month mRS of 5-6) were seen significantly less often in the AET group (17%) than in the nonresponder group (57%; P = .019). There were no differences in the incidence of HT. In the AET group, reappraisal considering MDM revealed a significantly higher rate of a 3-month mRS of 0 to 3 in the MDM-positive group compared to the MDM-negative group (86% v 25%, respectively; P = .044). Serious outcomes were observed significantly less frequently in the MDM-positive group compared to the MDM-negative group (0% v 75%, respectively; P = .005). Conclusions AET for nonresponders to IV t-PA was safe, improved recanalization rates, and led to better prognoses. MDM was a very good predictor of improved prognosis in a selection of eligible patients for AET after IV t-PA.

Background We retrospectively analyzed factors related to the outcomes of patients with basilar artery occlusion. Methods Twenty-eight patients with basilar artery occlusion admitted to our hospital within 24 hours after onset between April 2007 and December 2010 were included. We investigated parameters related to outcome, such as coexisting disease, clinical type, clinical severity at admission, the site of occlusion and the infarction lesion, the collateral flow from posterior communicating artery, therapy, and time to therapy after onset. Results Of 28 patients with basilar artery occlusion, good outcomes occurred in 6 patients (21%) and poor outcomes occurred in 22 patients (79%). Clinical severity on admission was significantly different between the 2 groups. Three of 5 patients with percutaneous transluminal angioplasty achieved recanalization. Two of 3 cases with recanalization resulted in poor outcomes. Conclusions Clinical severity on admission was the determinant factor of functional prognosis in patients with basilar artery occlusion.

Background We evaluated whether clinical–diffusion mismatch (CDM) or magnetic resonance angiography (MRA)–diffusion mismatch (MDM) is useful in detecting diffusion–perfusion mismatch (DPM) in hyperacute cerebral infarction within 3 hours after stroke onset. Methods Among patients with cerebral infarction who arrived within 3 hours after stroke onset at our hospital between May 2007 and December 2010, we included 21 patients (16 men and 5 women; mean age 70 ± 7.8 years) with cerebral infarction of the anterior circulation, and in whom magnetic resonance imaging (diffusion-weighted imaging)/MRA and computed tomograpic perfusion of the head were performed at the time of arrival. DPM-positive status was defined as a difference between DWI abnormal signal area and mean transit time prolongation area (≥20% on visual assessment). CDM-positive status was defined as a National Institute of Health Stroke Scale score ≥8 and DWI–Alberta Stroke Program Early CT Score (ASPECTS) ≥8. MDM-positive status was defined as a major artery lesion and DWI-ASPECTS ≥6. Results Ten of 21 patients had DPM. In all DPM-positive patients, MRA revealed a major artery lesion. Of the 10 DPM-positive patients, 6 were CDM-positive. CDM detected DPM with a sensitivity of 60% and a specificity of 64%. The positive likelihood ratio was 1.65. Of the 10 DPM-positive patients, all were MDM-positive. MDM detected DPM with a sensitivity of 100% and a specificity of 82%. The positive likelihood ratio was 5.5. Conclusions In hyperacute cerebral infarction within 3 hours after onset, MDM, as compared with CDM, was able to detect DPM with higher sensitivity and specificity. This suggests that MDM is more reflective of DPM.

Secondary degeneration of the mesencephalic substantia nigra after cerebral infarction is widely known to occur in animal experiments, but has yet to be sufficiently investigated in human cerebral infarction. This study investigated the background and features of patients exhibiting secondary degeneration of the mesencephalic substantia nigra. The subjects comprised 43 patients admitted to our hospital for cerebral infarction between April 2007 and October 2010 showing secondary degeneration of the mesencephalic substantia nigra on cranial magnetic resonance imaging (MRI). We investigated clinical disease type, location of vascular occlusion, lesion site, and time from onset of symptoms to lesion identification by MRI. The clinical disease type was cardiogenic embolism in 29 patients (67%), atheromatous embolism (artery to artery) in 8 patients (19%), embolism (origin unknown) in 2 patients (5%), infarction after coil embolization for internal carotid aneurysm in 1 patient (2%), arterial dissection in 2 patients (5%), and vasculitis due to Takayasu disease in 1 patient (2%). Magnetic resonance angiography (MRA) identified the occluded vessel as the internal carotid artery in 19 patients (44%), the middle cerebral artery (M1) in 20 patients (47%), and the middle cerebral artery (M2) in 3 patients (7%); MRA was not performed in 1 patient (2%). The cerebral infarctions were striatal in 7 patients (16%) and striatal and cortical in 36 patients (84%). Hyperintense regions in the mesencephalic substantia nigra were observed in all patients after 7-28 days (mean, 13.3 days) on diffusion-weighted imaging or fluid-attenuated inversion recovery and T2-weighted MRI. Most patients with secondary degeneration of the substantia nigra demonstrated clinical disease comprising vascular occlusion of the internal carotid artery or the neighborhood of the middle cerebral artery, which was envisaged to cause a sudden drop in brain circulation across a wide area. Striatal infarctions were observed in all patients. Secondary degeneration of the substantia nigra appeared at 1-4 weeks after onset and disappeared after several months.

Background Clinical features of medullary infarction were compared between patients with lateral medullary infarction and medial medullary infarction Methods Thirty-seven patients with medullary infarction (29 with lateral medullary infarction and 8 with medial medullary infarction) who were admitted to our center between April 1, 2007 and March 31, 2010 were examined. Background factors, neurologic signs and symptoms, imaging findings, cause of disease, and outcomes were assessed for patients with lateral and those with medial medullary infarction. Results Examination of the clinical symptoms and neurologic findings suggested that among patients with medial medullary infarction, few demonstrated all of the symptoms of Dejerine syndrome at onset, and many had lesions that were difficult to locate based only on neurologic findings. Both lateral and medial medullary infarction were frequently caused by atherothrombosis. However, cerebral artery dissection was observed in 31% of patients with lateral medullary infarction and 12.5% of those with medial medullary infarction. In 13% of patients with lateral and 37% of patients with medial medullary infarction, magnetic resonance imaging diffusion-weighted images on the day of onset did not show abnormalities, and the second set of diffusion-weighted images confirmed infarction lesions. For lateral medullary infarction, a more rostral lesion location was correlated with a poorer 90-day outcome. For medial medullary infarction, a more dorsal lesion location was correlated with a poorer 90-day outcome. Conclusions The diagnosis rate of medullary infarction using imaging examinations at onset—particularly medial medullary infarction—is not necessarily high. The imaging examinations need to be repeated for patients who are suspected to have medullary infarction based on neurologic signs and symptoms.

Background and objective Cervicocephalic arterial dissection can cause both ischemic stroke and hemorrhagic stroke. However, spontaneous cervicocephalic arterial dissection presenting only with headache and neck pain has rarely been reported. The clinical features of patients with spontaneous cervicocephalic arterial dissection presenting only with headache and neck pain were investigated. Methods The subjects were seven patients with spontaneous cervicocephalic arterial dissection with headache and neck pain alone who were admitted to our hospital during the past 3 years. The clinical features of these patients were investigated. The diagnosis of arterial dissection was based on the criteria of the Strategies Against Stroke Study for Young Adults in Japan. Results The age of the patients (3 males, 4 females) ranged from 35 to 79 (mean, 51.0 ± 16.2) years. Six patients had vertebral artery dissection, one had internal carotid artery dissection, and one had an association of vertebral and internal carotid artery dissection. With the exception of one patient, the headache and neck pain were unilateral. All patients with vertebral artery dissection complained of posterior cervical or occipital pain. In the cases of internal carotid artery dissection, one patient complained of temporal pain, and one patient with co-existing vertebral artery dissection complained of posterior cervical pain. The mode of onset was acute in five patients, thunderclap in one, and gradual and progressive in one. The pain was severe in all cases. Five patients complained of continuous pain, while two had intermittent pain. The quality of the pain was described as throbbing by five patients and constrictive by two. The headache and neck pain persisted for 1 week or longer in six of the seven patients. Conclusion Cervicocephalic arterial dissection should be suspected when patients complain of intense unilateral posterior cervical and occipital pain or temporal pain.

Therapeutic results with respect to lesion size were analyzed and compared in patients with hyperacute cerebral infarction with and without major artery lesions on magnetic resonance angiography (MRA) and in those who did and did not receive intravenous (IV) tissue plasminogen activator (t-PA). Of the patients with cerebral infarction who visited the hospital within 3 hours of onset between April 2007 and September 2009, 127 patients with cerebral infarction in the anterior circulation region in whom head magnetic resonance imaging (diffusion-weighted imaging [DWI]) or MRA was performed (81 men and 46 women; mean age, 71 ± 11 years) were enrolled. Major artery lesions (+) were defined as internal carotid artery occlusion and middle cerebral artery (M1/M2 segment) occlusion and ≥50% stenosis. Based on the presence or absence of major artery lesions and the size of DWI lesions, the subjects were divided into 3 groups: MRA-DWI mismatch (+) group [major artery lesion (+) and DWI-ASPECTS ≥6], MRA-DWI mismatch (-) group [major artery lesion (+) and DWI-ASPECTS6], and major artery lesion (-) group. IV t-PA was given to 21 of the 64 patients in the MRA-DWI mismatch (+) group, to 1 of the 24 patients in the MRA-DWI mismatch (-) group, and to 9 of the 39 patients in the major artery lesion (-) group. In the MRA-DWI mismatch (+) group (n = 64), the median National Institutes of Health Stroke Scale (NIHSS) score on admission was higher in t-PA-treated patients than in t-PA-untreated patients (15 vs 11). The modified Rankin scale (mRS) score at day 90 after onset was more favorable in t-PA-treated patients (0-2 in 10 patients [48%] and 3-6 in 11 patients [52%]) than in t-PA-untreated patients (0-2 in 12 patients [28%] and 3-6 in 31 patients [72%]). After adjusting for admission NIHSS score, there was a significant difference in outcome (mRS score) between t-PA-treated patients (0-2 in 10 patients [48%] and 3-6 in 11 patients [52%]) and t-PA-untreated patients (0-2 in 3 patients [9%] and 3-6 in 29 patients [91%]) (P = .002). In the MRA-DWI mismatch (-) group (n = 24), mRS scores at day 90 after onset were poor in both t-PA-treated (3-6 in 1 patient [100%]) and t-PA-untreated patients (0-2 in 1 patient [4%] and 3-6 in 22 patients [96%]). In the major artery lesion (-) group (n = 39), mRS scores at day 90 after onset were favorable in both t-PA-treated (0-2 in 9 patients [100%]) and t-PA-untreated patients (0-2 in 28 patients [93%] and 3-6 in 2 patients [7%]). When comparing major artery lesions in the MRA-DWI mismatch (+) group, outcomes were more favorable in patients with M1/M2 segment lesions who received t-PA than in those who did not receive t-PA. In the MRA-DWI mismatch (+) group, the prognosis was significantly better for t-PA-treated patients than for t-PA-untreated patients, suggesting that IV t-PA is indicated in patients with MRA-DWI mismatch.

The inhibitory response to clopidogrel considerably varies among individuals and clopidogrel resistance is a risk factor for thrombotic events in patients with cardiovascular disease. Based on the platelet aggregation evaluated by the VerifyNow P2Y12 Assay, the present study investigated clopidogrel resistance and the effect of cilostazol addition.We measured the ability of 20 µM ADP to aggregate platelets using the VerifyNow P2Y12 Assay. Clopidogrel resistance was defined as % inhibition of20% in this assay.We examined 77 patients (53 men and 24 women, aged 65.8 ± 9.9 years) with ischemic stroke or carotid artery stenting who received clopidogrel (75 mg) for7 days at our hospital between October 2009 and March 2010. For 62 patients (42 men and 20 women, aged 65.3 ± 9.9 years) 75 mg clopidogrel alone was administered (clopidogrel only group); the other 15 patients (11 men and 4 women, aged 67.9 ± 9.9 years) received 75 mg of clopidogrel plus 100 or 200 mg of cilostazol (cilostazol combination group).Clopidogrel resistance was identified in 18 (29%) of the 62 patients in the clopidogrel only group. The percent inhibition was significantly higher in the cilostazol combination group than in the clopidogrel only group (41.7 ± 28.0% vs. 64.9 ± 22.7%, p=0.005). None of the patients in the cilostazol combination group had % inhibition of20%.Clopidogrel resistance developed in 29% of patients given clopidogrel alone. The addition of cilostazol to clopidogrel may have intensified platelet inhibition.

The clinical symptoms of Takayasu's arteritis (TA), which mainly affects the aorta and major aortic branches, vary widely depending on the site and degree of arterial lesions. We present herein the case of a young man whose initial symptom was pulmonary artery occlusion and who manifested TA 6 years later as cerebral embolism. Angiography confirmed bilateral common carotid artery (CCA) occlusion and a well-developed collateral circulation. The stump of the occluded CCA has both proximal and distal ends. The possibility of emboli from the occluded CCA (distal stump) seems to be the most probable explanation, as turbulent flow was detected at distal stump on color Doppler sonography. The carotid stump can be a potential source of emboli in TA as well as in atherosclerosis.

Background Patent foramen ovale (PFO) can cause ischemic stroke because of paradoxical embolism. Autopsy studies have shown that the prevalence of PFO is 25% in whites or blacks. However, there is a paucity of data on the prevalence of PFO in Asians. The aim of this study was to clarify the prevalence of PFO in the Japanese population. Methods and results We reviewed 52,717 autopsy reports, which were collected and edited by the Japanese Society of Pathology from 2009 to 2012. Next, we inspected consecutive 103 formalin-fixed specimens that had already been examined by certified pathologists from 2009 to 2013 to find PFO and atrial septal aneurysm (ASA). ASA was defined as ≥10 mm protrusion of the septum into the left or the right atrium. In the database of the Japanese Society of Pathology, the incidence of PFO was 0.08% (43/52,717). Inspection of heart specimens disclosed that the prevalence of PFO was 13.6% (14/103). None of the PFO cases was reported at the original autopsy. PFO was more frequently found in the subjects with ASA (50%) than in those without ASA (9.7%) (P=0.004). Conclusions PFO is under-reported in autopsy reports. Re-evaluation of heart specimens disclosed that the prevalence of PFO was 13.6%. The prevalence was lower than reported in the past.

This study examines the alteration of oligodendrocyte progenitor cells (OPCs), mature oligodendrocytes (OLGs) and myelination after focal ischemia in the rat brain. Adult male Sprague-Dawley rats were subjected to 90-min occlusion of the middle cerebral artery, followed by reperfusion time of up to 2 weeks. The infarct core showed a rapid and progressive decrease in the number of OPCs, OLGs, as well as the myelin density after 48 h of recirculation. The peri-infarct area exhibited a moderate reduction in the number of OLGs and the myelin density with a slight increase in the number of OPCs at 48 h of recirculation. Subsequently, a steady increase in the number of OPCs and a gradual recovery of the number of OLGs were noted in the peri-infarct area, which were accompanied by a gradual restoration of the myelin density, resulting in almost complete recovery of myelin density at 2 weeks of recirculation. OPCs in the peri-infarct area showed characteristic morphological changes such as mitotic figures, monopolar or bipolar shapes, and hypertrophied cell bodies and processes, all indicating active cell proliferation and migration. These findings suggest that the upregulation of OPCs may contribute to replenishment of OLGs and resultant remyelination in the peri-infarct area after ischemic insult.

A 60-year-old man was admitted to our hospital after being found at his home in a comatose state. Cerebrospinal fluid and blood cultures were positive for Streptococcus pneumoniae. Brain magnetic resonance imaging (MRI) revealed sinusitis in the sphenoid sinus. Computed tomography demonstrated the presence of multiple air pockets in the basilar cistern, and we diagnosed pneumococcal meningitis complicated with pneumocephalus. Multiple cerebral infarctions were found on brain MRI after admission. In this case, pneumocephalus was secondary to pneumococcal meningitis due to sinusitis on admission, and multiple cerebral infarctions after admission. We demonstrated that early diagnosis is required for the successful treatment of pneumococcal meningitis.

Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase (PKA) is an essential step in cyclic AMP-mediated intracellular signal transduction. This binding is, however, rapidly inhibited in the acute phase of cerebral ischemia, indicating that the signal transduction via PKA is very vulnerable to ischemia, although this signal pathway is very important for neuronal survival in the brain. Several lines of evidence suggest that the activation of voltage-sensitive Na + and Ca 2+ channels is an important mediator of acute ischemic brain damage. In the present study, therefore, we examined the effect of a novel Na + and Ca 2+ channel blocker, NS-7 (4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride), on changes in the binding activity of PKA to cyclic AMP in permanent focal cerebral ischemia, which was induced by occlusion of the middle cerebral artery by the intraluminal suture method for 5 h in the rat. NS-7 (1 mg/kg) or saline was intravenously infused 5 min after occlusion. The binding activity of PKA to cyclic AMP and local cerebral blood flow were assessed by the in vitro [ 3 H]cyclic AMP binding and the [ 14 C]iodoantipyrine methods, respectively. NS-7 significantly suppressed inhibition of the binding activity of PKA to cyclic AMP in the ischemic regions such as the frontal and parietal cortices and the medial region of the caudate-putamen without affecting cerebral blood flow or arterial blood pressure. Infarct area measured in the brain slices stained with cresyl violet was significantly smaller in animals treated with NS-7 than in those treated with saline. Blockade of voltage-sensitive Na + and Ca 2+ channels by NS-7 was expected to reduce ischemia-induced depolarization and thus prevent a massive formation of free radicals, which is known to inhibit the binding activity of PKA to cyclic AMP. These data clearly indicate that NS-7 provides very efficient neuroprotection in the acute phase of cerebral ischemia, and sustains the normal function of PKA.

The endoplasmic reticulum (ER) is thought to play important roles in various neurological diseases via multifactorial and complex mechanisms. The Ire1-mediated signal is part of one ER signaling pathways; the signal induces the expression of an ER-resident protein, Bip/GRP78, and is thought to be involved in cell death under ER stress. In this study, we examined time-dependent Bip expression after transient middle cerebral artery occlusion and characterized the Bip-positive cells. Ire1- mediated molecules, Bip, were rapidly up-regulated in the ischemic area after 3.5 h recirculation. Their immunoreactivity continued to increase until 24-48 h. Immunofluorescence staining revealed Bip up-regulation in ischemic neurons, which were TUNEL positive. Our studies suggest that the Ire1-mediated signal might be associated with ischemic neuronal damage.

Expression of interleukin-6 (IL-6), a neurotrophic cytokine, is up-regulated after cerebral ischemia, but the underlying mechanism of the up-regulation remains unclear. NS-7 is a novel blocker of voltage-sensitive Ca 2+ and Na + channels and is known to reduce cerebral damage by ischemia. The present study was undertaken to examine the association between increases in intracellular Ca 2+ concentration induced by membrane depolarization and IL-6 induction. IL-6 expression in rat brain was investigated by immunohistochemistry and Western blot analysis following 3.5-48 h of reperfusion after 1.5 h of occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was injected i.v. 5 min after the start of reperfusion. The saline group showed clear IL-6 expression in various cortical regions, which peaked at 24 h of reperfusion. By contrast, IL-6 expression was significantly suppressed in the NS-7 group throughout the reperfusion period. Microglia activation was also reduced in the NS-7 group. These findings suggest that IL-6 expression may be up-regulated by the increased intracellular Ca 2+ concentration triggered by membrane depolarization after cerebral ischemia.

NS-7 is a novel blocker of voltage-sensitive Ca(2+) and Na(+) channels, and it significantly reduces infarct size after occlusion of the middle cerebral artery. Persistent activation of cyclic AMP response element binding protein (CREB), which can be induced by increase in intracellular Ca(2+) concentrations or other second messengers, has recently been found to be closely associated with neuronal survival in cerebral ischemia. The present study was therefore undertaken to evaluate the neuroprotective effects of NS-7 by analyzing changes in CREB phosphorylation in a focal cerebral ischemia model. CREB phosphorylation in the brain of rats was investigated immunohistochemically at 3.5-48-h recirculation after 1. 5-h occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was intravenously injected 5 min after the start of recirculation. The NS-7 group showed significantly milder activation of CREB phosphorylation in various cortical regions after 3.5 h of recirculation than the saline group. The inner border zone of ischemia in the NS-7 group subsequently exhibited a moderate, but persistent, increase in number of phosphorylated CREB-positive neurons with no apparent histological damage. By contrast, the saline group displayed a marked, but only transient, increase in number of immunopositive neurons in this border zone after 3.5 h of recirculation, and this was followed by clear suppression of CREB phosphorylation and subsequent loss of normal neurons. These findings suggest that: (1) the marked enhancement of CREB phosphorylation in the acute post-ischemic phase may be triggered largely by an influx of calcium ions as a result of activation of the voltage-sensitive Ca(2+) and Na(+) channels; and that (2) the neuroprotective effects of NS-7 may be accompanied by persistent activation of CREB phosphorylation in the inner border zone of ischemia.

Phosphorylation of the DNA-binding transcription factor, cyclic AMP response element binding protein (CREB), was immunohistochemically examined in rat brain hippocampal CA1 in order to examine the ischemic vulnerability of this region from the viewpoint of CREB activation. The rat brain had been subjected to 90-min focal ischemia followed by various periods of recirculation. Focal ischemia was induced by occlusion of the middle cerebral artery using the intraluminal suture method. CA1 pyramidal neurons in the sham animals showed definite immunoreactivity with anti-CREB antibody, which binds to both unphosphorylated and phosphorylated CREB, while reactivity with anti-phosphorylated CREB antibody was barely detectable in these neurons. In contrast, at 3.5 h of recirculation, a significant increase in the number of phosphorylated CREB-positive neurons was noted in the CA1 on both sides, and the increase continued until 48 h of recirculation with a tendency for gradual decline. At each period, the ischemic side showed a more marked increase in the number of immunoreactive cells as compared to the nonischemic side. Cresyl violet staining revealed CA1 pyramidal neurons to be maintained intact until 14 day of recirculation, at which time CREB phosphorylation has returned to the control level. Transient global ischemia is known to induce only mild CREB phosphorylation in the CA1 followed by a frank neuronal loss in this region. These data suggest that CREB phosphorylation can be persistently activated in CA1 neurons after focal ischemia and that this phenomenon may be closely associated with protection of these neurons.

Although interleukin-6 (IL-6) has various neuroprotective effects against cerebral ischemia, the topographic distribution and cellular source of IL-6 after cerebral ischemia remain unclear. In the current study, the localization of IL-6 protein was immunohistochemically examined in rats after 3.5, 12, 24, and 48 hours of reperfusion after 1.5 hours of middle cerebral artery occlusion. Middle cerebral artery occlusion was induced by the intraluminal suture method. The specificity of the anti–IL-6 antibody used in the current study was confirmed by Western blot analysis and an immunoabsorption test. To identify the cellular source, lectin histochemical study and immunohistochemical study with microtubule-associated protein-2, ED1, and glial fibrillary acidic protein also were carried out. The sham group did not show any clear IL-6 immunoreactivity. After 3.5 hours of reperfusion, IL-6 immunoreactivity was first detected on the reperfused side, and it was upregulated, especially in the periinfarct region, after 24 hours of reperfusion. Also, IL-6 was expressed after 3.5 hours of reperfusion in the contralateral cerebral cortex and bilateral hippocampi. Double staining showed that the cells containing IL-6 were neurons and round-type microglia, not astrocytes. The current findings suggest that IL-6 expression in ischemically threatened neurons and reactive microglia is closely associated with brain tissue neuroprotective mechanisms against cerebral ischemia.

Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase is an essential step in cyclic AMP-mediated intracellular signal transduction. In the present study, the binding capacity of cyclic AMP-dependent protein kinase for cyclic AMP was examined by autoradiography with local cerebral blood flow in focal cerebral ischemia in the rat, which was induced by occlusion of the middle cerebral artery using the intraluminal suture method. The binding capacity of cyclic AMP-dependent protein kinase and local cerebral blood flow were assessed by the in vitro [ 3 H]cyclic AMP binding and the [ 14 C]iodoantipyrine methods, respectively. At 3 h of occlusion, a significant reduction in the binding of cyclic AMP-dependent protein kinase to cyclic AMP was already noted in the lateral region of the caudate–putamen and the parietal cortex. Between three and five hours of occlusion, the area with reduced cyclic AMP binding was significantly expanded to the peri-ischemic regions including the frontal cortex and the medial region of the caudate–putamen. The threshold in local cerebral blood flow for reduced cyclic AMP binding was clearly noted at 5 h of ischemia, and was 45 ml/100 g per min in the cerebral cortices, and 38 ml/100 g per min in the caudate–putamen, respectively. No threshold was noted at 3 h of ischemia, since cyclic AMP binding showed a large variation ranging from reduced to normal values even when local cerebral blood flow was below 20 ml/100 g per min. Recirculation for 3.5 h following 1.5 h of ischemia restored the normal cyclic AMP binding in the cerebral cortices, but failed to normalize cyclic AMP binding in the caudate–putamen despite good recovery of local cerebral blood flow. Western blot analysis suggested that this reduction in cyclic AMP binding was not due to loss or degradation of the subunit protein of cyclic AMP-dependent protein kinase, and may therefore have resulted from conformational changes in the protein. A significant increase in cyclic AMP binding was noted after recirculation in the non-ischemic regions such as the frontal and the cingulate cortices on the occluded side and in the contralateral cortices. These data indicate that cyclic AMP-mediated signal transduction in the brain tissue may be very susceptible to ischemic stress, and the region of disrupted signal transduction may expand progressively from the ischemic core to peri-ischemic regions in the acute phase of ischemia. Such impairment of signal transduction may not be restored in the caudate–putamen even when cerebral circulation is fully recovered after short-term ischemia, suggesting that a regional vulnerability to ischemic stress may also exist in cyclic AMP-mediated signal transduction. A significant increase in cyclic AMP binding after recirculation in regions outside of ischemic area may be closely related with the protective mechanisms of brain tissue, since cyclic AMP has been reported to exert various neuroprotective actions.

The phosphorylation of cAMP response element binding protein (CREB) in the rat brain was examined immunohistochemically at 3.5 h, 12 h, 24 h and 48 h of recirculation after focal ischemia induced by occlusion of the middle cerebral artery for 1.5 h. Brain sections were stained with affinity purified anti-phosphorylated CREB antibody. The ischemic core revealed a significant, but transient increase in number of phosphorylated CREB-positive cells at 3.5 h of recirculation, followed by a rapid decrease during the subsequent period. In the peri-ischemia area, the number of phosphorylated CREB-positive cells showed a more marked increase as compared to that in the ischemic core at 3.5 h of recirculation, and the increase continued until 48 h of recirculation with a tendency for gradual decline. Persistent enhancement of CREB phosphorylation may thus be closely related to the neuronal viability and neuroprotective mechanisms, whereas rapid disappearance of CREB phosphorylation may clearly precede neuronal death.

Markedly increased interleukin-6 (IL-6) mRNA levels occur in experimental cerebral ischemia, although the protein production and cellular sources of IL-6 remain unclear. We examined the cellular localization of IL-6 protein in gerbil brain following transient forebrain ischemia employing immunohistochemistry and Western blot analysis. The ischemia/recirculation groups revealed distinct IL-6 immunoreactivity predominantly in cortical and hippocampal neurons after 3 hours to 3 days recirculation. At 12 h recirculation, the IL-6 expression declined specifically in the hippocampus CA1. Microglia, but not activated astrocytes, also expressed IL-6 immunoreactivity. The sham group showed no apparent immunoreactivity. IL-6 protein may thus be expressed mainly in neurons following transient forebrain ischemia. Its transient decline in the CA1 at 12 h recirculation could reflect the specific vulnerability of this region.

Phosphorylation of cyclic AMP response element binding protein (CREB) is one of the most important mechanisms controlling various gene transcriptions. In the present study, the phosphorylation of CREB was examined immunohistochemically at 24 h of recirculation following 1.5 h of middle cerebral artery occlusion (MCAO) in rats. MCAO was induced by the intraluminal suture method. The infarct core revealed a significant reduction in the number of immunoreactive cells with the anti-phosphorylated CREB and with the anti-CREB antibody, which binds to both unphosphorylated and phosphorylated CREB. In contrast, the peri-infarct area exhibited a marked increase in the number of immunopositive cells as well as in the intensity of nuclear staining with each antibody, so that almost all of the cells expressing CREB demonstrated phosphorylation of CREB. On the other hand, about half of the CREB immunopositive cells reacted weakly with the anti-phosphorylated CREB antibody in the sham group. These findings indicated that the expression as well as phosphorylation of CREB protein was significantly activated in the regions surrounding the infarct area. Since phosphorylation of CREB has recently been implicated in signal transductions that promote the survival and differentiation of neurons, the present data suggest that tissue repair mechanisms may be markedly activated in the peri-infarct area.

The binding capacity of FK506 binding protein (FKBP) was examined after 2-h hemispheric ischemia in the gerbil brain in order to clarify the precise mechanism of the neuroprotective effects of FK506. Firstly, the FK506 binding was evaluated in vitro in the normal gerbil brain using 1 nM [ 3 H]dihydro-FK506 as a specific ligand. FK506 binding sites were distributed in a rather homogeneous manner, although the greatest binding was noted in the hippocampus CA1. Secondly, Scatchard analysis demonstrated that the binding sites of FK506 could be composed of two components in each brain region. Thirdly, 18 Mongolian gerbils were divided into two groups: an ischemia group ( n =12) and a sham group ( n =6). The right common carotid artery was ligated to induce hemispheric ischemia for 2 h in the ischemia group. The local cerebral blood flow was measured at the end of the experiment by the [ 14 C]iodoantipyrine method. The ligated animals with levels of local cerebral blood flow in the lateral nuclei of the thalamus of less than 50 ml/100 g/min were utilized as the ischemia group ( n =6) for further data analysis. No significant differences in FK506 binding between the ischemia and sham groups were observed in any regions. The above data indicate that the binding capacity of FKBP tends to remain normal during 2-h ischemia, suggesting that FK506 may exert its neuroprotective effects through its binding to FKBP in the brain during the early phase of cerebral ischemia.

To determine the difference in cerebral hemodynamics between Moyamoya disease and atherosclerotic occlusion of the major cerebral arterial trunks, we measured local cerebral blood flow (CBF) and local CO 2 reactivity (CO 2 R) by xenon-enhanced computed tomography (CT). A total of 11 adult patients with Moyamoya disease (mean age, 39.6±7.8 years) and eight patients with atherosclerotic occlusion of the major arterial trunks (mean age, 62.4±15.4 years) were studied. Regions of interest were frontal, temporal and occipital cortex, caudate, putamen and thalamus in each hemisphere. In patients with Moyamoya disease, local CBF values in the internal carotid artery territory (frontal and temporal cortex, caudate, putamen) were significantly higher than those in the occluded side of patients with atherosclerotic occlusion. Local CO 2 R values in the caudate and putamen were significantly higher than those in the occluded side of patients with atherosclerotic occlusion. These results suggest that the cerebral hemodynamics of Moyamoya disease differ from those of atherosclerotic occlusion of the major cerebral arterial trunks, and may be a result of the abundant collateral circulation through basal `Moyamoya' vessels.

Ryanodine receptors located on the sarcoplasmic or endoplasmic reticulum, play an important role in the regulation of the intracellular Ca2+ level via the mechanism of Ca(2+)-induced Ca2+ release (CICR). Perturbation of intracellular Ca2+ regulation has been considered to be one of the most important mechanisms underlying acute ischemic neuronal damage. The ryanodine binding, an indicator of intracellular channels of CICR, and local cerebral blood flow (LCBF) were therefore examined at 15 min post-ischemia in the gerbil brain. The autoradiographic method developed in our laboratory enabled us to determine both parameters within the same brain. Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. LCBF was measured at the end of the experiment using [14C]iodoantipyrine method. The ryanodine binding was evaluated autoradiographically in vitro using [3H] ryanodine. A group of gerbils who underwent a sham procedure served as controls. LCBF was found to be significantly decreased in most cerebral regions on the occluded side. In contrast, a significant reduction in ryanodine binding was noted only in the hippocampus CA1 on the occluded side. Taken together, these findings indicate that the CICR in the hippocampus CA1 may be especially susceptible to acute ischemic stress, and be closely associated with the pathophysiological mechanisms of the selective vulnerability of this region.

A 55-year-old man presented with vertigo, nystagmus, and gait ataxia followed by left hemiparesis (Opalski syndrome). T2-weighted magnetic resonance imaging revealed vascular compression of the left lateral side of the medulla oblongata by the left vertebral artery. On diffusion tensor imaging, the level of fractional anisotropy (FA) in the left corticospinal fibers caudal to the pyramidal decussation was lower than that observed in the right corticospinal fibers. Opalski syndrome caused by vascular compression is very rare. This is the first reported case of Opalski syndrome that was imaged on FA.

We describe unusual delayed recurrent episodes of ischemic stroke in a patient with initial good recovery from pneumococcal meningitis due to progressive arterial stenosis for over 3 months. We postulate that any of the following may have been responsible for his condition: widespread cerebral vasculopathy due to the effects of purulent material bathing the base of the brain, an immune-mediated para-infectious condition, or a rebound effect of the primary inflammatory reaction that was initially suppressed by dexamethasone. This case demonstrates that progressive arterial stenosis can evolve months after bacterial meningitis and should be recognized as a potential vascular complication.

Background This was a retrospective analysis of factors related to recanalization after hyperacute recombinant tissue-plasminogen activator (rt-PA) infusion therapy in patients with middle cerebral artery occlusion. Methods Of the 50 patients (39 males and 11 females; mean age 70 ± 11 years) with cerebral infarction who were able to undergo diffusion-weighted magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) of the head within 24 hours of starting rt-PA infusion therapy while hospitalized at our center between April 2007 and October 2010, 23 patients (18 males and 5 females; mean age 71 ± 9.4 years) with hyperacute cerebral infarction with findings of obstruction in the proximal segment of the middle cerebral artery (MCA-M1) served as subjects. Results Of the 23 patients with MCA occlusion, 13 (57%) were recanalized. Analysis of factors related to recanalization revealed a significant difference ( P = .019) for obesity (body mass index >25 kg/m 2 ), with significantly more obese patients in the nonrecanalized group than in the recanalized group. The study revealed no significant differences in other factors between the 2 groups. Conclusions The results suggest that obesity may be involved in recanalization after hyperacute rt-PA infusion therapy in patients with MCA occlusion.

Patent foramen ovale (PFO) is an important etiology of ischemic stroke in young adults. We investigated factors contributing to recurrent ischemic stroke in patients with PFO. Subjects comprised 47 patients (mean age, 56.8 ± 14.2 years; range 23–74 years) with ischemic stroke due to PFO who were admitted to our hospital between April 2007 and February 2011. Mean duration of follow-up was 34.5 ± 13 months. Recurrence occurred in 11 cases. Annual recurrence rate was 23.4%. We investigated relationships between recurrence of ischemic stroke and size of PFO (large, >4 mm; medium, 2–3.9 mm; small

In recent years, patient selection for intravenous tissue plasminogen activator (t-PA) therapy based on clinical-diffusion mismatch (CDM) has been closely examined. We investigated the relationship between prognosis and CDM in patients with hyperacute cerebral infarction within 3 hours of onset and compared CDM with diffusion-perfusion mismatch (DPM). Of 122 patients with hyperacute cerebral infarction who visited the hospital within 3 hours of onset between April 2007 and November 2008, 85 patients with cerebral infarction in the anterior circulation who underwent head magnetic resonance imaging diffusion-weighted imaging (DWI)/magnetic resonance angiography (MRA) (51 men and 34 women; average age, 74 ± 10 years) were enrolled. Seventeen of these patients underwent CT perfusion imaging. CDM-positive cases were those with a National Institute of Health Stroke Scale (NIHSS) score ≥ 8 and a DWI-Alberta Stroke Program Early CT Score (DWI-ASPECTS) ≥ 8; CDM-negative cases were those with an NIHSS score ≥ 8 and an ASPECTS-DWI < 8. The other patients were classified as belonging to the NIHSS score < 8 group. Of the 32 CDM-positive cases, 10 received t-PA infusion. These patients had markedly higher modified Rankin Scale scores 90 days after onset compared with the 22 patients who did not receive t-PA infusion. The 8 CDM-positive cases included 4 DPM-positive cases and 4 DPM-negative cases, and a discrepancy was confirmed between CDM and DPM. In all DPM-positive cases, MRA confirmed lesions in major intracranial arteries. CDM may enable more accurate prediction of outcomes in patients with hyperacute cerebral infarction. In addition, the combination of CDM findings and MRA findings (stenosis or occlusion in major intracranial arteries) may be an alternative to DPM for determining the indications for IV t-PA therapy in patients with hyperacute cerebral infarction.

We report our experience in carotid stenting via the transbrachial approach in patients with anomalous origin of the left common carotid artery, the so-called bovine arch, in which both the right common carotid artery and the left common carotid artery arise from the brachiocephalic artery. Via percutaneous access to the right brachial artery, a 6Fr Shuttle sheath is advanced into the aortic arch to cannulate the left common carotid artery. A Guardwire distal-protection balloon is positioned within the left internal carotid artery distal to the stenosis. The lesion is dilated, followed by satisfactory deployment and dilation of a 6Fr Precise stent. Carotid stenting via the brachial artery in bovine arch appears feasible as an alternative to standard femoral access.

The Eustachian valve (EV) is an embryological remnant of the inferior vena cava valve that prenatally directs the oxygenated blood from inferior vena cava across the patent foramen ovale (PFO) into systemic circulation. We present a 30-year-old man with PFO whose prominent EV initiated spontaneous right-to-left shunt without Valsalva maneuver and promoted paradoxical embolism. Even when the persistence of EV is prominent in adult, it has been considered to be benign finding in the absence of the associated cardiac anomalies. EV should be considered as an adjunctive risk factor for paradoxical embolism in patients with PFO.

Background and Purpose —Iba1 is a novel calcium-binding protein and is specifically expressed in microglia in the brain. It has been suggested that Iba1 plays an important role in regulation of the function of microglia. In the present study we examined time-dependent Iba1 expression after transient middle cerebral artery occlusion and characterized microglial activation in various brain regions. Methods —Rat middle cerebral artery occlusion was induced by the intraluminal filament technique. After 1.5 hours of transient ischemia, Iba1 expression was examined by immunohistochemical and immunoblot analyses. The microglial activation in association with ischemic severity was characterized by double immunostaining with other specific markers. Results —In the peri-ischemic area, heavily Iba1 immunoreactive cells rapidly appeared at 3.5 hours after reperfusion. Immunoreactivity was further increased and peaked at 7 days. In the ischemic core, round Iba1-positive cells, which may be blood-borne monocytes, appeared from 24 hours and reached a peak at 4 to 7 days. Double immunostaining revealed that activated microglia in the peri-ischemic area upregulated Iba1 expression but were negative for the macrophage marker ED1. ED1-positive cells were clearly restricted to the ischemic core. Conclusions —These findings suggest the following: (1) Iba1 expression may be associated with microglial activation in ischemic brain, and Iba1 immunostaining can be useful to evaluate the pathophysiological roles of activated microglia in ischemic injury. (2) Expression of ED1 antigen is strictly restricted to severe ischemic damage, whereas activated microglia in the peri-ischemic area showed Iba1 upregulation without ED1. Therefore, microglia may exhibit difference of antigenicity in the severity of ischemic brain injury.

This study examines the alteration of oligodendrocyte progenitor cells which express membrane NG2 chondroitin sulfate proteoglycan after focal ischemia in the rat brain. Adult male Sprague-Dawley rats were subjected to 90 min occlusion of the middle cerebral artery, followed by reperfusion time of up to 2 weeks. The distribution and morphological changes in NG2-positive oligodendrocyte progenitor cells were immunohistochemically examined. Stellate-shaped NG2-positive cells with multiple branched processes were detected in both the gray and white matter of normal brain. After 2 weeks of reperfusion, NG2-positive cells in the area surrounding the infarction site (peri-infarct area) clearly showed enlarged cell bodies with hypertrophied processes. These stained strongly for NG2. Although the number of NG2-positive cells was increased significantly in the peri-infarct area, it decreased markedly in the infarct core compared to controls. Double immunostaining revealed that these NG2-positive cells were neither astrocytes nor microglia, but NG2-positive oligodendrocyte progenitor cells. These progenitor cells are known to differentiate into oligodendrocytes. As such, this upregulation of NG2 expression may be an adaptive mechanism attempting to remyelinate rat brain tissue after ischemic insult. Only further study will elucidate this hypothesis.

JAK-STAT is the major downstream signal pathway of interleukin-6 (IL-6) cytokine family and is regulated by Tyr705 phosphorylation of Stat3. The present study examined the extent and the localization of phosphorylated Stat3 protein in brain tissue after focal ischemia in rats. The localizations of unphosphorylated and phosphorylated Stat3 were immunohistochemically examined in rats after 0.5 to 168 h of reperfusion following 1.5 h of middle cerebral artery occlusion (MCAO), induced by the intraluminal suture method. Absolute phosphorylated Stat3 immunoreactive cell counts were made in the cerebral cortex (ischemic core, peri-ischemia region, and contralareral cortex) and lateral striatal regions on both the ischemic and the contralateral sides. Stat3 protein was localized diffusely in cortical and striatal neurons in the sham-operated animals. Although weak Stat3 staining was detected in damaged neurons in the ischemic region, activated microglia, astrocytes, and endothelial cells clearly expressed Stat3 in this region. On the other hand, the sham group showed no phosphorylated Stat3 immunoreactivity. Phosphorylated Stat3 immunoreactivity was first detected in neurons after 3.5 h of reperfusion in each cortical and striatal region. Thereafter, Stat3 phosphorylation was marked in neurons in the peri-infarct region, peaked at 24 h, and then gradually declined throughout the reperfusion period. Endothelial cells expressed phosphorylated Stat3 in the ischemic core at 48 h of reperfusion. To identify the cellular source of phosphorylated Stat3, lectin histochemical study and immunohistochemical study with anti-microtubule-associated proten-2 and anti-glial fibrillary acidic protein antibodies were carried out. Double-staining immunohistochemistry with these cellular makers revealed phosphorylated Stat3 to be present in neurons, but in neither astrocytes nor microglia/macrophages. These results were also confirmed be western blot analysis. The present results indicate that Stat3 activation occurs in neurons and endothelial cells only during post-ischemic reperfusion despite widespread expression of IL-6 cytokines.

Phosphorylation of the DNA-binding transcription factor, cyclic AMP response element binding protein, has recently been suggested to provide neuroprotective signals in times of cellular stress. Medium-sized striatal neurons are among the cells that are most vulnerable to ischemic stress in the brain. In the present study, phosphorylation of cyclic AMP response element binding protein was immunohistochemically evaluated in rat striatum in order to examine the ischemic vulnerability of each striatal region from the standpoint of cyclic AMP response element binding protein. Rats were subjected to 90-min focal cerebral ischemia followed by various periods of recirculation. Focal ischemia was induced by occlusion of the middle cerebral artery by the intraluminal suture method. Local cerebral blood flow measured by the 14C-iodoantipyrine method in the lateral and the medial striatal regions during occlusion was 5.0±7.1 and 42.5±8.1 ml/100 g/min, respectively. Cerebral blood flow in each region was restored to the control level during the recirculation period. The lateral and the medial regions of the striatum in the sham animals showed hardly any immunoreactivity with the specific antibody against phosphorylated cyclic AMP response element binding protein. By contrast, at 3.5 h of recirculation, a number of phosphorylated cyclic AMP response element binding protein-positive neurons were detected in the medial striatal region on the occluded side, and the increase in the number of immunopositive cells continued until two weeks of recirculation with gradual decline. The lateral striatal region on the ischemic side showed only a mild increase in phosphorylated cyclic AMP response element binding protein-positive cells at 3.5 h of recirculation, and the immunoreactivity rapidly disappeared during the subsequent recirculation period. Appreciable increase in immunoreactive cells was also noted in the contralateral striatum during the early phase of recirculation, and this increase seemed to be associated with spontaneous circling movements of the animals. Cresyl Violet staining revealed that striatal neurons in the medial region remained intact until two weeks of recirculation, whereas neurons in the lateral striatal region soon showed ischemic damage, followed by complete neuronal loss, and evolution of a frank infarct. Immunoreactivity for bcl-2, apoptosis-suppressive protein, was clearly detected in many neurons in the medial striatal region, but no such immunoreactivity was detected in the lateral striatal region. These findings suggest that persistently activated phosphorylation of cyclic AMP response element binding protein in the striatum during post-ischemic recirculation may be closely associated with protection of striatal neurons on the ischemic side, while it may be associated with spontaneous circling movements on the contralateral side.

The cytokine leukemia inhibitory factor (LIF) modulates neuronal function during development and promotes neuronal survival after peripheral nerve injury, but little is known about LIF expression after cerebral ischemia. In the present study, the localization of LIF protein was immunohistochemically examined in rats after 3.5, 12, 24, 48, and 96 hours of reperfusion following 1.5 hours of middle cerebral artery occlusion (MCAO) induced by the intraluminal suture method. Double-staining immunohistochemistry with microtubule-associated protein-2 (MAP2), glial fibrillary acidic protein (GFAP), lectin histochemistry, and interleukin (IL) 6 was also performed. The sham group and immunosorption test did not show any clear LIF immunoreactivity. Definite LIF immunoreactivity was first detected after 12 hours of reperfusion in each of the brain regions examined: ischemic core, periinfarct region, and contralateral cortex. However, expression of LIF was most prominent in the periinfarct region at each time point, peaked at 24 hours, and then gradually declined until 96 hours of reperfusion. Some LIF-positive neurons in the periinfarct region expressed IL-6. At 96 hours of reperfusion, GFAP-labeled astrocytes around the infarct core also expressed LIF protein. Induction of LIF mRNA and protein was also confirmed by reverse transcription polymerase chain reaction and western blot analysis, respectively. These findings suggest that LIF expression in ischemically threatened neurons may reflect a repair or defense mechanism against the ischemic insult.

We examined whether or not nitration of tyrosine residues takes place in the ischemic and postischemic reperfused brain. The nitration of tyrosine residues to produce nitrotyrosine is a sensitive marker elicited by peroxynitrite, a powerful oxidant formed by the reaction of nitric oxide (NO) with superoxide. Mongolian gerbils were subjected to 60 min ischemia induced by occlusion of the right common carotid artery (ischemia group), to 30 min recirculation following 60 min ischemia (reperfusion group) or to sham surgery (sham group). Immunohistochemical staining with polyclonal anti-nitrotyrosine antibody revealed the widespread and distinct occurrence of nitrotyrosine in cortical neurons on the reperfused side of the brain in the reperfusion group, while only partial or weak immunoreactivity was noted on the contralateral side. On the other hand, nitrotyrosine was not detected in the brain of the ischemia and sham groups. These findings suggest that nitration of tyrosine residues in various proteins may be closely associated with reperfusion injury of the brain.

ALTERATIONS of [ 3 H]cyclic AMP (cAMP) binding, an indicator of the binding activity of particulate cyclic AMP-dependent protein kinase (PKA), were examined after 15 and 30 min of ischemia in the gerbil brain. Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. Significant reductions in cAMP binding were noted only in the dendritic subfields of the hippocampus CAI such as the strata oriens, radiatum and lacunosum-moleculare, on the ischemic side after 15 min of ischemia. After 30min ischemia cAMP binding was significantly decreased not only in each dendritic subfield of the hippocampus CA1, but also in the layer of pyramidal cell bodies (stratum pyramidale) on the occluded side; other brain regions such as the hippocampus CA3, dentate gyrus and cerebral cortices revealed no significant changes in cAMP binding. These findings suggest that derangement of PKA may begin in the dendritic subfields of the hippocampus CA1 after as little as 15 min of severe ischemia, and proceed centrally to the neuronal cell bodies of the hippocampus CAI.

We examined the effects of FK506, a specific inhibitor of calcineurin, on the binding capacity of cyclic AMP-dependent protein kinase (cAMP-DPK) in gerbils subjected to 2-h cerebral hemispheric ischemia. FK506 (0.1 mg/kg) was infused intravenously at 15 min prior to the induction of ischemia by common carotid artery occlusion. The binding capacity of cAMP-DPK was evaluated by autoradiographic analysis of the cAMP binding, and cerebral blood flow (CBF) was measured by the [14C] iodoantipyrine method. In the sham-operated gerbils, FK506 significantly increased mean arterial blood pressure and tended to decrease CBF, suggesting that FK506 may constrict systemic blood vessels as well as cerebral blood vessels. On the other hand, cAMP binding was not altered by FK506 in the sham-operated gerbils. In the ischemia group of gerbils, FK506 prevented any significant reduction of cAMP binding in the hippocampus CA1 and cerebral cortices on the ischemic side, whereas it exerted no significant influence on the cAMP binding of the nonischemic side. The values of CBF were comparable between the vehicle-treated gerbils and FK506-treated gerbils in the ischemic regions. Preservation of cAMP binding indicates that intracellular signal transduction via cAMP-DPK can be maintained by FK506 despite ischemia, suggesting that this agent may be beneficial for reducing ischemic tissue damage.

Local cerebral blood flow (CBF) measured by xenon-enhanced CT was correlated with the clinical findings in 21 patients with motor neuron disease (mean +/- SD age, 60 +/- 10 years). In 11 patients, CBF was also measured after intravenous injection of 2 mg thyrotropin releasing hormone (TRH). There were no significant differences in CBF of the cerebral cortex, basal ganglia, thalamus, and subcortical white matter with respect to age, duration of illness, or presence (n = 9) or absence (n = 12) of bulbar palsy. In patients with upper motor neuron disturbance (n = 10), however, local CBF in the frontal cortex was significantly lower (p < 0.05) than in those without it (n = 11). Within the frontal cortex, CBF reduction was marked in the upper posterolateral part (p < 0.05) that included the motor and premotor areas. Intravenous administration of TRH did not significantly alter the local CBF in any of the brain regions examined. An additional patient with motor neuron disease and severe dementia showed marked CBF reduction in the frontal lobe, which was in common with but much greater than the reduction in those exhibiting subcortical dementia (e.g., progressive supranuclear palsy). We conclude that in motor neuron disease patients with upper motor neuron involvement, the selective reduction of CBF in brain regions that include primary motor and premotor areas may reflect functional disturbance or neuronal degeneration in these regions. The ameliorating effect of TRH in patients with motor neuron disease, if any, appears not to be related to increases in local CBF or activation of brain function.

A 63-year-old man presented with aphasia. A computed tomographic scan of the head revealed hemorrhagic infarction in the left temporal lobe. Magnetic resonance venography (MRV) revealed no flow from the straight sinus and left transverse sinus to the sigmoid sinus, indicating cerebral venous sinus thrombosis (CVST). Because of rapidly deteriorating consciousness despite heparin infusion, neuroendovascular therapy was performed, recanalization was achieved, and the level of consciousness improved. In Western countries, neuroendovascular therapy is often aggressively performed in patients with worsening symptoms despite anticoagulation. However, in Japan, such reports are extremely rare. We recommend neuroendovascular therapy for deep CVST resistant to anticoagulant therapy.