Increased Piezo1 expression in myofibroblasts in patients with symptomatic carotid atherosclerotic plaques undergoing carotid endarterectomy: A pilot study.

OBJECTIVES: We aimed to investigate Piezo1 expression in myofibroblasts in symptomatic and asymptomatic patients undergoing carotid endarterectomy and its relationship with atherosclerotic plaque formation. METHODS: This cross-sectional study analyzed carotid plaques of 17 randomly selected patients who underwent carotid endarterectomy from May 2015 to August 2017. In total, 51 sections (the most stenotic lesion, and the sections 5-mm proximal and distal) stained with hematoxylin-eosin and elastica-Masson were examined. Immunohistochemistry was performed using antibodies to Piezo1. The Piezo1 score of a section was calculated semiquantitatively, averaged across 30 randomly selected myofibroblasts in the fibrous cap of the plaque. RESULTS: Of 17 patients (mean age: 74.2 ± 7.1 years), 15 were men, 9 had diabetes mellitus, and 13 had hypertension. Symptomatic patients had higher mean Piezo1 score than asymptomatic patients (1.78 ± 0.23 vs 1.34 ± 0.17, p < .001). Univariate linear regression analyses suggested an association between plaque rupture, thin-cap fibroatheroma and microcalcifications and the Piezo1 score (p = .001, .008, and 0.003, respectively). CONCLUSIONS: Increased Piezo1 expression of myofibroblasts may be associated with atherosclerotic carotid plaque instability. Further study is warranted to support this finding.

Cerebral Aneurysms with Internal Carotid Artery Agenesis: A Unique Case Similar to Moyamoya Disease and Literature Review.

Internal carotid artery (ICA) agenesis/aplasia is occasionally accompanied with cerebral aneurysms caused by hemodynamic stress. If the aneurysms are located around the circle of Willis, they are managed with clipping or coil embolization. Herein, we report a case of ICA agenesis with perforating artery aneurysms treated successfully with revascularization. Moreover, a literature review of ICA agenesis with cerebral aneurysms was performed to compare with the current case. We conducted a literature review using data from PubMed. A secondary search was also performed by reviewing the references of each article previously searched. In our case, the aneurysms shrank and disappeared after direct and indirect bypass surgeries, and indirect bypass developed as in moyamoya disease (MMD). The epidemiological and clinical features of aneurysms accompanied with ICA agenesis were identified via a literature review. Aneurysms with ICA agenesis categorized as type F based on the Lie classification system, or referred to as rete mirabile, are occasionally located in an untreatable site; hence, they cannot be treated with clipping or coil embolization. Moreover, results showed that previous studies did not use revascularization for the treatment of aneurysm. In conclusion, if an aneurysm with ICA agenesis is difficult to approach directly or via an endovascular procedure, revascularization can be a treatment option.

Subarachnoid Hemorrhage with Progressive Cerebral Steno-Occlusive Disease: Report of 2 Cases.

Nontraumatic nonaneurysmal subarachnoid hemorrhage (SAH) is a rare condition. Among them, SAH with cerebral steno-occlusive disease is quite rare. Moreover there has been no report of SAH patient who had been diagnosed with steno-occlusive disease since before. We here report 2 cases of nontraumatic nonaneurysmal convexity SAH who originally had progressive cerebral steno-occlusive disease. Case 1, a woman in her 40s who had diagnosed left internal carotid artery (ICA) stenosis 6 years before complained of headache. She was diagnosed SAH and progressive ICA stenosis, then performed revascularization. Case 2, a woman in her 40s who had diagnosed right ICA stenosis 7 months before complained of headache. She was diagnosed with SAH and ICA occlusion. These 2 cases suggested that progressive cerebral steno-occlusive disease lead to SAH due to collapse of their fragile pial anastomoses.

Monitoring Corticocortical Evoked Potentials During Intracranial Vascular Surgery.

BACKGROUND: Monitoring of corticocortical evoked potentials (CCEPs) during brain tumor surgery of patients under anesthesia was recently reported to be effective in assisting in preservation of speech function. The aim of this study was to investigate whether CCEPs can be reproducibly measured between the frontal and temporal lobes during standard intracranial vascular surgery under general anesthesia; whether dynamic changes in CCEPs caused by reduced focal cerebral blood flow can be measured; and whether CCEPs can be used to monitor speech function, particularly associated with the left side of the brain. METHODS: We monitored CCEPs during 58 vascular surgeries (42 clipping procedures; 15 bypasses, 1 of which overlapped with clipping; and 2 hematoma removals from the left frontal and temporal lobe) at Kashiwaba Neurosurgical Hospital from October 2016 to January 2018. RESULTS: CCEPs could be reproducibly and routinely monitored in bilateral vascular surgeries. None of the patients experienced any postoperative symptoms or showed any ischemic lesions on postoperative magnetic resonance imaging; however, 5 patients temporarily demonstrated reduced CCEPs intraoperatively that were caused by transient obstructions of blood flow. Motor evoked potentials and somatosensory evoked potentials were simultaneously monitored intraoperatively and did not show any changes. CONCLUSIONS: The results of our pilot study show that CCEPs can be routinely monitored during bilateral intracranial vascular surgery and that they are sensitive to ischemia. CCEPs on the left side could serve as unique intraoperative monitoring of speech function under anesthesia.

Stabilization of symptomatic carotid atherosclerotic plaques by statins: a clinico-pathological analysis.

Human and animal studies have revealed a stabilization of atherosclerotic plaques by statins. However, the stabilization of human carotid plaques has not been thoroughly described pathologically. This analysis explored the relationship between statin therapy and plaque stability in carotid endarterectomy (CEA) specimens. We analyzed specimens harvested between May 2015 and February 2017, from 79 consecutive patients presenting with > 70% carotid artery stenoses, of whom 66 were untreated (group 1) and 13 treated (group 2) with a statin. Immunohistochemistry was performed, using an endothelial specific antibody to CD31, CD34 and platelet derived growth factor receptor-ß. The prevalence of plaque ruptures (P = 0.009), lumen thrombi (P = 0.009), inflammatory cells (P = 0.008), intraplaque hemorrhages (P = 0.030) and intraplaque microvessels (P < 0.001) was significantly lower in group 2 than in group 1. Among 66 patients presenting with strokes and infarct sizes > 1.0 cm3 on magnetic resonance imaging, the mean infarct volume was significantly smaller (P = 0.031) in group 2 (4.2 ± 2.5 cm3) than in group 1 (8.2 ± 7.1 cm3). The difference in mean concentration of low-density lipoprotein cholesterol between group 1 (121 ± 32 mg/dl) and group 2 (105 ± 37 mg/dl) was non-significant (P = 0.118). This analysis of plaques harvested from patients undergoing CEA suggests that statin therapy mitigates the plaque instability, which, in patients presenting with strokes, might decrease infarct volume.

Pathological Quantification of Carotid Artery Plaque Instability in Patients Undergoing Carotid Endarterectomy.

BACKGROUND: Unstable atherosclerotic carotid plaques cause cerebral thromboemboli and ischemic events. However, this instability has not been pathologically quantified, so we sought to quantify it in patients undergoing carotid endarterectomy (CEA).Methods and Results:Carotid plaques were collected during CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. The specimens were stained with hematoxylin-eosin and elastica-Masson. Immunohistochemistry was performed using an endothelial-specific antibody to CD31, CD34 and PDGFRß. The histopathological characteristics of the plaques were studied. By multiple-variable logistic regression analysis, plaque instability correlated with the presence of plaque rupture [odds ratio (OR), 9.75; P=0.013], minimum fibrous cap thickness (OR per 10 µm 0.70; P=0.025), presence of microcalcifications in the fibrous cap (OR 7.82; P=0.022) and intraplaque microvessels (OR 1.91; P=0.043). Receiver-operating characteristics analyses showed that these factors combined into a single score diagnosed symptomatic carotid plaques in patients with carotid artery stenosis with a high level of accuracy (area under the curve 0.92; 95% confidence interval 0.85-0.99 vs. asymptomatic). CONCLUSIONS: This analysis of carotid plaque instability strongly suggested that the diagnostic scoring of carotid plaque instability improves the understanding and treatment of carotid artery disease in patients undergoing CEA.

Sonographic Detection of Abnormal Plaque Motion of the Carotid Artery: Its Usefulness in Diagnosing High-Risk Lesions Ranging from Plaque Rupture to Ulcer Formation.

We investigated the feasibility of using sonography of abnormal plaque motion to diagnose high-risk carotid lesions ranging from plaque rupture to ulcer formation. Fifty consecutive carotid arteries of 49 patients (71 ± 7 y, 37 males) who underwent carotid endarterectomy were investigated by carotid sonography to find a plaque concavity (sonographic ulcer [SU]), fine trembling motion inside the plaque (FTMI) and systolic retractive motion of the plaque surface (SRMS). Plaque rupture or ulcer, necrotic core and intra-plaque hemorrhage were determined at carotid endarterectomy. Twenty-two SUs, 41 cases of FTMI and 20 cases of SRMS were detected by carotid sonography. The sensitivity and specificity of SU in diagnosing plaque rupture or ulcer at carotid endarterectomy were 48% and 90%, and those of FTMI were 93% and 60%. Plaques with SRMS more frequently had both a necrotic core and intra-plaque hemorrhage than those without SRMS (80% vs. 30%, p = 0.0005). Abnormal plaque motion detected by carotid sonography is useful in detecting a ruptured or ulcerated plaque with a necrotic core and/or hemorrhage.

Diagnostic impact of baseline cerebral blood flow in patients with acute ischemic stroke prior to intravenous recombinant tissue plasminogen activator therapy.

OBJECTIVE: To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). METHODS: We measured baseline cerebral blood flow (CBF) using technetium-99m-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38-93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. RESULTS: Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08±0.08 (n=3) and 0.3±0.15 (n=49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5±9.5% (n=3) and 0.43±0.87% (n=49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. CONCLUSION: These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy.

Spontaneous echo contrast and thrombus formation at the carotid bifurcation after carotid endarterectomy.

Spontaneous echo contrast (SEC) consists of numerous microechoes swirling in the cardiovascular lumen and is usually seen during blood stasis in dysfunctional left atrium. However, SEC and consecutive local thrombus formation at the carotid artery early after carotid endarterectomy (CEA) have not been reported. This study retrospectively investigated the clinical importance and therapeutic strategy of postoperative SEC and thrombus formation in 113 consecutive patients who underwent CEA between 2001 and 2009. Ultrasonography was routinely performed preoperatively, intraoperatively, and 1 day and 1 week after the operation. If SEC and/or thrombus was detected at any time after the operation, follow-up ultrasonography was performed at short intervals, once a week for inpatients and once every 1-2 months for outpatients. Eight of the 113 patients (7%) had SEC after the operation from Day 1 to 12 (mean 7.2 days), and 6 of these 8 patients developed local de novo thrombus formation at the site of SEC from Day 6 to 33 (mean 14.7 days). The maximum luminal narrowing by the thrombi were 26-62% (mean 37%). After administering anticoagulant therapy, all thrombi disappeared from Day 13 to 190 (mean 57 days) from CEA. SEC seen after CEA is highly associated with consecutive local thrombus formation. Postoperative geometric blood stasis with the absence of intima may be the causative factor for its development.

Identification of high-risk carotid artery stenosis: motion of intraplaque contents detected using B-mode ultrasonography.

OBJECT: Identification of the risk of rupture and vulnerability of arterial plaque is not yet clearly understood. The aim of this study was to assess the clinical features of the motion of intraplaque contents (MIC) detected by B-mode ultrasonography. The MIC is characterized by the peculiar movement of the intraplaque contents that is not synchronized with the heartbeat; however, the movement of the carotid artery (CA) wall depends on the heartbeat. METHODS: From January 2008 to November 2010, 1798 consecutive patients with transient ischemic attacks (TIAs) or acute ischemic stroke underwent CA ultrasonography for the examination of the MIC. Patients with CA stenosis greater than 50% were followed up until they underwent carotid endarterectomy or CA angioplasty and stent placement. If neither of these procedures were used, the patients were followed up at 90 days. Chi-square and Mann-Whitney tests were performed to compare the categorical and continuous demographic data and risk factors. The effect of the MIC on the rate of recurrent cerebral ischemia was examined using Kaplan-Meier and univariate Cox regression analyses. RESULTS: One hundred and fifteen patients had CA stenosis greater than 50%. Among these 115 patients, 58 with a total of 59 CA stenoses had MIC. Twenty-four recurrent ischemic events were associated with MIC, whereas only 6 such events occurred in the absence of MIC. The MIC decreased event-free survival (log-rank test = 15.8, p < 0.001); univariate Cox analysis confirmed that MIC increased the risk of a recurrent ischemic event (HR 5.12, 95% CI 2.08-12.58; p < 0.001). CONCLUSIONS: The MIC is one of the findings of vulnerable plaques. The MIC is more useful in predicting the recurrence of TIAs or ischemic events in patients with symptomatic CA stenosis.

New criteria for the sonographic diagnosis of a plaque ulcer in the extracranial carotid artery.

OBJECTIVE: The diagnostic power of carotid sonography in detecting plaque ulcers may be inadequate when using the conventional criteria. We aimed to evaluate the usefulness of new criteria that we devised through a preliminary analysis of 50 endarterectomy cases before the present series. SUBJECTS AND METHODS: Thirty carotid arteries of 30 consecutive patients who underwent endarterectomy (28 men; age range, 46-83 years) were studied. In the long- and short-axis B-mode images of carotid arteries, the concavity of the plaque surface and the surface echo intensity were carefully investigated. The conventional criteria stipulate a concavity larger than 2 × 2 mm with a well-defined back wall and flow reversal within the recess. Our new criteria specify a concavity in the plaque with the basal border echo weaker than that of the adjacent plaque surface, regardless of size. The final diagnosis was based on surgical and histologic findings. RESULTS: Among the 30 carotid arteries, 14 arteries had 14 ulcers at surgery. Seventeen concavities were detected by sonography, and 12 of them, including six smaller than 2 × 2 mm, were truly ulcers. Two concavities with an echo intensity of the basal border equal to or greater than that of the adjacent surface were not true ulcers. Only two of 14 ulcers were not detected by sonography. The sensitivity and specificity of the conventional criteria were 35.7% and 75.0%, respectively, and those of our new criteria were 85.7% and 81.3%, respectively. CONCLUSION: Our new criteria for the sonographic diagnosis of plaque ulcer are more useful than the conventional ones.

Effects of cyclosporin A administration on gene expression in rat brain.

PRIMARY OBJECTIVE: The immunosuppressant cyclosporin A (CsA) is reported to have a strong anti-ischemic effect. Although this neuroprotective effect is speculated to be related to the blockade of a mitochondrial permeability transition pore (mPTP), the underlying molecular mechanism remains to be elucidated. This study focused on the effect of CsA on transcriptional regulation in brain cells. METHODS: CsA and a control substance were injected into rat brains and purified extracted mRNA. Both mRNAs were compared using a cDNA subtraction technique. RESULTS: Nine significantly up-regulated genes and seven significantly down-regulated genes were detected following CsA administration. All of the up-regulated genes are neurotrophic or reported to have roles in regeneration of brain tissue. Among the down-regulated genes, three are known to be detrimental to neuronal cells and are also reported to facilitate the pathology of Alzheimer's disease (AD) and four genes are related to oxidative metabolism. CONCLUSIONS: Strong immunosuppression would present as a side-effect during CsA use as a neuroprotectant. The results of this study will help to discriminate between the CsA immunosuppressive effect and the neuroprotective effect at the molecular level and may lead to the development of new conceptual and pharmacological tools.

Cilostazol may suppress restenosis and new contralateral carotid artery stenosis after carotid endarterectomy.

Carotid artery restenosis is a serious complication following carotid endarterectomy (CEA), so preventative management of the risk factors is important. The present study investigated the potential of cilostazol, a mediator of vascular stabilization as well as inhibitor of platelet aggregation, to suppress restenosis on the ipsilateral carotid artery and new plaque development on the contralateral carotid artery. Eighty-two patients treated by CEA were divided into two groups according to the postoperative antiplatelet aggregation drugs into the cilostazol and other groups. Patients were periodically examined for recurrence of the plaque on the ipsilateral side, development of plaque on the contralateral side, and the bilateral intermedia thicknesses measured by ultrasonographic examination for up to 6 years. Restenosis and development of the contralateral plaque were not detected in any patients in the cilostazol group, whereas such changes were found in seven patients in the other group. Cilostazol might be effective to inhibit the growth mechanism of plaque.

Cilostazol may prevent cerebral vasospasm following subarachnoid hemorrhage.

Cilostazol is an antiplatelet aggregation inhibitor drug associated with increased cerebral blood flow and inflammation suppression. This study evaluated administration of cilostazol to prevent cerebral vasospasm following subarachnoid hemorrhage (SAH) in 50 patients treated surgically from December 2004 to November 2006. All patients, excluding those with Hunt and Kosnik grade 5 or who had undergone late surgery, were classified into two groups: 26 patients who received 200 mg/day cilostazol from postoperative day 1 to day 14 and 24 control patients. The frequency and the degree of cerebral vasospasm, occurrence of ischemic lesion, and clinical symptoms due to vasospasm were compared between the two groups. The appearance of severe vasospasm on angiography, persistent symptomatic spasm, and new cerebral infarction due to vasospasm demonstrated by neuroimaging were apparently lower in the cilostazol group than in the control group, suggesting that cilostazol may significantly suppress cerebral vasospasm following SAH.

Prevalence and clinical importance of spontaneous echo contrast within the carotid artery in patients with ischemic cerebrovascular disease.

OBJECTIVE: Spontaneous echo contrast (SEC) is composed of numerous microechoes swirling in the cardiovascular lumen, usually appearing during blood stasis. This study aimed to clarify the clinical importance of SEC in the carotid artery (CA) in patients with ischemic cerebrovascular disease (ICVD). METHODS: In 264 CAs of 132 consecutive patients with ICVD and in 40 CAs of 20 healthy control subjects, SEC was classified as none, faint, or dense, and CA abnormalities, including plaque, plaque ulcer, mural thrombus, and internal CA stenosis, were assessed with 10-MHz sonography. RESULTS: The overall prevalence of SEC was greater in CAs of patients with ICVD (164/264 [62%]) than in CAs of control subjects (6/40 [15%]; P < .0001). Dense SEC was more specifically detected in CAs of ICVD with the prevalence of 81 (31%) of 264, which was greater than that of controls (1/40 [3%]; P = .0002). Dense SEC was more frequently detected in CAs with plaque (38/98 [39%]) than in those without (43/166 [26%]; P = .0285), in CA plaque with ulcerative lesions (7/10 [70%]) than in those without (31/88 [35%]; P = .0325), in CA plaque with a thrombus (11/12 [92%]) than in those without (27/86 [31%]; P < .0001), and in CAs with severe stenosis (11/13 [85%]) than in those with mild stenosis (25/75 [33%]; P = .0005) and in those without stenosis (45/176 [26%]; P < .0001). CONCLUSIONS: Dense SEC was frequently observed in CAs of patients with ICVD, especially in those with local atheromatous lesions, although the influence of systemic factors could not be excluded. Dense SEC within a CA may be a marker of ICVD.

Stepwise revascularization for prevention of postoperative hyperperfusion.

Abrupt normalization of cerebral blood flow (CBF) after surgical procedures to improve excessive cerebral hypoperfusion can cause irreversible brain parenchymal damage. Such hyperperfusion, which is caused by inflow at normal blood pressure into maximally dilated fine vessels, is an important complication following carotid endarterectomy (CEA). Strict control of blood pressure in the perioperative period can prevent this complication except in a few patients, who have severe cerebral hypoperfusion and poor cerebrovascular reserve due to extremely severe stenosis of the ipsilateral or the bilateral carotid arteries, for which CEA is indicated. The requirement for improved CBF and the risk of postoperative hyperperfusion conflict in the pathogenesis of these patients. We tried to prevent abrupt improvement in perfusion by attempting gradual restoration of CBF. Superficial temporal artery-middle cerebral artery anastomosis was first performed to improve the poor cerebrovascular reserve by allowing insufficient blood flow. A few weeks later, CEA was performed to completely restore CBF. This surgical approach obtained good results without postoperative problems in four patients. The indications of this surgical management and efficacy of stepwise restoration of CBF to prevent postoperative hyperperfusion depend on careful preoperative evaluation of perfusion studies.

Evaluation of carotid distal pressure for prevention of hyperperfusion after carotid endarterectomy.

BACKGROUND: Sometimes preoperative cerebral misery perfusion induces an occurrence of hyperperfusion after carotid endarterectomy (CEA). We intraoperatively measured carotid proximal and distal pressures and evaluated their role in predicting hyperperfusion. METHODS: Twenty-one sites with an indication of CEA were preoperatively assessed based on the bilateral perfusional state of the cerebral blood flow (CBF) and delta CBF by single photon emission computed tomography (SPECT). Postoperative SPECT was performed immediately and on the fifth day after surgery. The distal and proximal pressures were intraoperatively measured through an internal shunt tube, and the evaluated relationship against hyperperfusion was shown on postoperative SPECT. RESULTS: Despite strict control of blood pressure, 7 patients postoperatively showed hyperperfusion on SPECT and 2 of them had transient neurological symptoms. The distal pressure was significantly different between the postoperative hyperperfusion group and the normal one; however, proximal pressure and the difference between proximal and distal pressures were not significantly different. In the hyperperfusion group, delta pressure was apparently higher, and delta CBF and distal pressure were significantly lower than those of the normal group. CONCLUSION: Intraoperative measurement of distal pressure as well as preoperative estimation of the cerebrovascular perfusion and the reserve is of importance in predicting postoperative hyperperfusion.

FK506 reduces infarct volume due to permanent focal cerebral ischemia by maintaining BAD turnover and inhibiting cytochrome c release.

It has been reported that immunosuppressant FK506 inhibited ischemic neuronal injury in forebrain ischemia or transient focal cerebral ischemia, but the mechanisms of the neuroprotective effect have not been clarified. In permanent focal cerebral ischemia, we investigated whether FK506 caused remission of brain infarction, and how mechanism was concerned. Male Balb/c mice were subjected to permanent middle cerebral artery (MCA) occlusion. They were treated with 1.0 or 3.0 mg/kg FK506 or vehicle 30 min before ischemia. Infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) method after 24 h. Cytochrome c release from mitochondria was evaluated by Western blotting and immunocytochemistry after ischemia. Simultaneously, the immunoreactivity of total and phosphorylated BAD was also studied using immunocytochemistry. We demonstrated that pretreatment with 3.0 mg/kg FK506 salvaged the tissue damage in the infarct rim and significantly reduced infarct volume to 75.5% (P<0.05), and FK506 inhibited cytochrome c release on 6 h after ischemia for Western blot analysis (P<0.05). Immunocytochemical study showed that permanent MCA occlusion increased the amount of cytochrome c and total BAD in the cytosol, but not phosphorylated BAD, in the ischemic core and the infarct rim as early as 1 h after ischemia, and FK506 inhibited the increases in the infarct rim. The results suggest that FK506 may, at least in part, ameliorate tissue damage due to permanent focal cerebral ischemia in the infarct rim through maintaining BAD turnover and inhibiting cytochrome c release from mitochondria.

Repeated thrombus formation immediately following carotid endarterectomy.

A 56-year-old male presented with thrombus formation manifesting as cerebral embolic infarction suspected to be caused by hemostasis at the carotid bifurcation, not by the intimal abnormalities or hematological disorders. Thrombus repeatedly and reproducibly appeared at the same area in spite of carotid endarterectomy (CEA). Ultrasonography demonstrated a stenotic lesion of the cervical carotid bifurcation. Medical treatment reduced the stenosis, but the thrombus was repeatedly formed at the same area of the cervical carotid bifurcation. CEA was performed. Histological examination of the specimen found only the underlying thin intima consisting of mild fibrous atheromatic change without ulceration or vascular dissection. Ultrasonography following CEA showed reduced blood flow, indicating hemostasis, and moyamoya appearance in that area. The thrombus had recurred in spite of the medical treatment with anti-platelet agent. This repeated thrombus was gradually dissolved and reduced with anticoagulant therapy. Thrombus causing cerebral embolic stroke and originating at the cervical carotid bifurcation is usually due to the intimal atherosclerotic change such as ulcer formation or vascular dissection. The thrombus in this case was probably formed by hemostasis at the cervical carotid bifurcation and CEA was not effective to prevent recurrence.

NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia.

Stroke is the third leading cause of death in the US, with a prevalence of 750,000 patients per year, and a social cost estimated at $50 billion. Current therapeutics are targeted at restoring blood flow rather than on preventing the actual mechanisms associated with neuronal cell death. Here, we show that, following transient (2 h) middle cerebral artery occlusion (tMCAO) in male, Wistar rats, neuronal damage determined using MAP-2 staining increased progressively after the tMCAO. Notably, such neuronal degeneration was first associated with a decrease in p-Akt in both the focus and penumbra of the infarct region and, later with an increase in cytosolic cytochrome C levels in cortical neurons in the infarct area. These findings implicate that Akt alterations and consequent release of cytochrome C are involved in neuronal death. To further address this issue, NXY-059 (disodium 4-[(tert.-butylimino)methyl]benzene-1,3-disulfonate N-oxide) administered i.v. (30 mg/kg bolus, followed by 30 mg/kg/h infusion for up to 24 h), commencing 1 h after reperfusion, not only prevented the increase in infarct area but also attenuated the postreperfusion increase in neuronal cytosolic cytochrome C and the postperfusion decrease in neuronal p-Akt. Thus, NXY-059, by preventing mitochondrial cytochrome C release by maintaining activation of the Akt pathway, appears to protect neurons from damage after ischemia.