田中 亮太

A 41-year-old male with a history of human immunodeficiency virus (HIV) infection developed motor aphasia, dysarthria, and right hemiparesis. A magnetic resonance imaging scan of the brain revealed a cerebral infarction in the territory of the left middle cerebral artery. The laboratory data showed decreased levels of protein S and protein C. Transesophageal contrast-enhanced echocardiography revealed a patent foramen ovale (PFO). Prothrombotic states, such as protein S and C deficiency, have been reported in HIV-infected patients. In addition, previous studies have reported prothrombotic states to be risk factors for PFO-related cerebral infarction. An association between combined protein S and C deficiency caused by HIV infection and PFO-related cerebral infarction was suggested in our patient. © 2013 Elsevier B.V. All rights reserved.

Objective: We aimed to explore the association between abnormal glucose metabolism such as diabetes, prediabetes, and short-term prognosis in patients with acute ischemic stroke. Methods: Of 242 consecutive acute ischemic stroke patients, a 75-g oral glucose tolerance test was administered to 116 patients without previously diagnosed diabetes. One hundred forty patients were classified into diabetes, 52 patients were prediabetes (impaired glucose tolerance or impaired fasting glucose or both), and 50 patients were normal glucose tolerance (NGT). The association between each glycemic status and early neurological deterioration (END; increase in the NIH Stroke Scale (NIHSS) of >= 2 points during the first 14 days after admission) or poor short-term outcome (30-day modified Ranking Scale [mRS] score 2-6) was evaluated. Results: In multivariable analysis, the risk of END was significantly higher in the diabetes group than in the NGT group (ORs = 11354; 95% CI, 1.492-86.415; p = 0.019), even after adjustment for possible confounding factors (ORs = 12.769; 95% Cl, 1.361-119.763; p = 0.026). Similar but insignificant associations were observed between prediabetes and NGT groups (ORs = 6.369; 95% Cl, 0.735-55.177; p = 0.093). The risk of poor outcome (30-day mRS 2-6) was significantly higher in the diabetes group (ORs = 3.667; 95% CI, 1.834-7.334; p < 0.001) than in the NGT group, even after adjusting for confounding factors (ORs = 3.340; 95% Cl, 1.361-8.195; p = 0.008). Similar but insignificant associations were observed between prediabetes and NGT groups (ORs = 2.058; 95% Cl, 0.916-4.623; p = 0.08). Conclusion: In our patient population, both diabetes and prediabetes were associated with a poor early prognosis after acute ischemic stroke. (C) 2013 Elsevier B.V. All rights reserved.

Glutamate plays a central role in brain physiology and pathology. The involvement of excitatory amino acid transporters (EAATs) in neurodegenerative disorders including acute stroke has been widely studied, but little is known about the role of glial glutamate transporters in white matter injury after chronic cerebral hypoperfusion. The present study evaluated the expression of glial (EAAT1 and EAAT2) and neuronal (EAAT3) glutamate transporters in subcortical white matter and cortex, before and 3-28. days after the ligation of bilateral common carotid arteries (LBCCA) in rat brain. K-B staining showed a gradual increase of demyelination in white matter after ischemia, while there was no cortical involvement. Between 3 and 7. days after LBCCA, a significant increase in EAAT2 protein levels was observed in the ischemic brain and the number of EAAT2-positive cells also significantly increased both in the cortical and white matter lesions. EAAT2 was detected in glial-fibrillary acidic protein (GFAP)-positive astrocytes in both the cortex and white matter, but not in neuronal and oligodendroglial cells. EAAT1 was slightly elevated after ischemia only in the white matter, but EAAT3 was at almost similar levels both in the cortex and white matter after ischemia. A significant increase in EAAT2 expression level was also noted in the deep white matter of chronic human ischemic brain tissue compared to the control group. Our findings suggest important roles for up-regulated EAAT2 in chronic brain ischemia especially in the regulation of high-affinity of extracellular glutamate and minimization of white matter damage. © 2013 IBRO.

Although challenging, neuroprotective therapies for ischemic stroke remain an interesting strategy for countering ischemic injury and suppressing brain tissue damage. Among potential neuroprotective molecules, heat shock protein 27 (HSP27) is a strong cell death suppressor. To assess the neuroprotective effects of HSP27 in a mouse model of transient middle cerebral artery occlusion, we purified a "physiological" HSP27 (hHSP27) from normal human lymphocytes. hHSP27 differed from recombinant HSP27 in that it formed dimeric, tetrameric, and multimeric complexes, was phosphorylated, and contained small amounts of ab-crystallin and HSP20. Mice received intravenous injections of hHSP27 following focal cerebral ischemia. Infarct volume, neurological deficit scores, physiological parameters, and immunohistochemical analyses were evaluated 24 h after reperfusion. Intravenous injections of hHSP27 1 h after reperfusion significantly reduced infarct size and improved neurological deficits. Injected hHSP27 was localized in neurons on the ischemic side of the brain. hHSP27 suppressed neuronal cell death resulting from cytochrome c-mediated caspase activation, oxidative stress, and inflammatory responses. Recombinant HSP27 (rHSP27), which was artificially expressed and purified from Escherichia coli, and dephosphorylated hHSP27 did not have brain protective effects, suggesting that the phosphorylation of hHSP27 may be important for neuroprotection after ischemic insults. The present study suggests that hHSP27 with posttranslational modifications provided neuroprotection against ischemia/reperfusion injury and that the protection was mediated through the inhibition of apoptosis, oxidative stress, and inflammation. Intravenously injected human HSP27 should be explored for the treatment of acute ischemic strokes.

One-third of patients with acute ischemic stroke develop early neurologic worsening, which is associated with increased mortality and long-term functional disability. We investigated the predictive factors for neurologic deterioration in patients with acute ischemic stroke within 1 week of onset. We retrospectively investigated 643 patients who were admitted within 2 days of acute ischemic stroke between April 2007 and March 2010. Neurologic deterioration was defined as an increase of 4 points or more in the National Institutes of Health Stroke Scale (NIHSS) score within 1 week of admission. We retrieved data on demographic and clinical characteristics, medications, and stroke subtypes. Out of 537 patients, deterioration was noted in 64 patients (11.9%; deterioration group). Multivariate analysis identified history of myocardial infarction (P < .001), NIHSS score >= 8 at onset (P < .001), high leukocyte count (P = .035), low-density lipoprotein cholesterol >= 140 mg/dL (P = .002), and hemoglobin A1c >= 7% (P = .006) as significant factors associated with deterioration. Branch atheromatous disease was more frequent in the deterioration group, and >90% of patients with deterioration either were discharged to nursing home care or died. Multivariate analysis of magnetic resonance imaging findings identified internal carotid/middle cerebral artery occlusion (each P < .001), striate capsular infarction (P = .030), pontine infarction (P = .047), and lesion size of 15-30 mm (P = .011) as independent factors associated with deterioration. Stroke patients with a high low-density lipoprotein level, high hemoglobin A1c level on admission, a history of myocardial infarction, and high NIHSS score are at high risk for neurologic deterioration. Patients with multiple risk factors for deterioration can benefit most from intensive monitoring.

Phosphodiesterase (PDE) exists in the cardiovascular system, adipose tissue and platelets, and its inhibition increases the cellular levels of cAMP, which could activate cAMP-responsive element binding protein (pCREB). The present study was designed to map the expression of PDE3A/B in the forebrain and define the time course of PDE3 expression in the ischemic boundary zone after ischemia. The number of PDE3A-positive cells (neurons and endothelial cells) remained unchanged, while PDE3B-positive cells gradually increased after ischemia/reperfusion. In the corpus callosum, PDE3B was expressed in oligodendrocytes, oligodendrocyte progenitor cells, and astrocytes. PDE3B-expressing astrocytes showed gradual increase after ischemia/reperfusion. In the cortex, the majority of PDE3B-expressing cells before ischemia were neurons, though few were astrocytes. Ischemic insult resulted in gradual increase in PDE3B-expressing astrocytes and neurons, with larger increase in astrocytes. Expression of brain derived neurotrophic factor (BDNF) and B-cell leukemia/lymphoma 2 protein (Bcl-2) was detected in pCREB-positive cells, not in PDE3B-positive cells. Our results demonstrated that ischemic insult increased PDE3B expression, but not PDE3A, and changed the number and type of cells in a time-dependent manner. The variation of PDE3B-expression in the brain might play a crucial pathophysiological role, and regulation of PDE3B production might protect against ischemic brain damage. (C) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

The ratio of low- (LDL-C) to high- (HDL-C) density lipoprotein cholesterol serves as a positive predictor of atherosclerosis including coronary artery disease. We assessed the contribution of the LDL-C/HDL-C ratio to atheromatous aortic plaques (AAPs) in patients with unexplained ischemic stroke. One hundred thirty-seven patients (age, 65 +/- 14 years; 87 male) with ischemic stroke underwent transesophageal echocardiography (TEE) and enrolled to the study. Patients were classified based on TEE findings: (1) AAPs<4 mm in thickness; (2) AAPs >= 4 mm; and (3) mobile or ulcerated aortic plaques (MUAPs). We assessed clinical characteristics and biochemical findings, and investigated the relationship between AAPs and the LDL-C/HDL-C ratio of stroke patients. 84 (61%) patients had AAPs<4 mm, 29 (21%) had AAPs >= 4 mm, and 24 (18%) had MUAPs. Older age (OR: 1.18; 95% CI: 1.08 to 130; p = 0.001), and LDL-C/HDL-C ratio (OR: 2.94; 95% CI: 1.10 to 7.87; p = 0.032) were significantly associated with MUAPs. The incidence of MUAPs substantially increased in patients with LDL-C/HDL-C ratios of >223 (p<0.001) when the ratios were divided into quartiles. The LDL-C/HDL-C ratio was closely associated with MUAPs. An elevated LDL-C/HDL-C ratio could be a positive predictor of aortogenic brain embolism. (c) 2013 Elsevier B.V. All rights reserved.

The purpose of the present study was to evaluate the contributions of embolic etiologies, patent foramen ovale (PFO) and atrial septal aneurysm (ASA) to the pathogenesis of ischemic stroke in patients with antiphospholipid syndrome (APS). We performed transesophageal echocardiography (TEE) examination for consecutive stroke patients who had been diagnosed with APS (APS group) to detect potential embolic sources. APS was diagnosed based on the modified Sapporo criteria. The control stroke group comprised age- and sex-matched cryptogenic stroke patients undergoing TEE. We assessed and compared the clinical characteristics and TEE findings between stroke patients with APS and control stroke groups. Among 582 patients, nine patients (nine women; mean age, 50 +/- A 18 years) were classified into the APS group. In 137 patients undergoing TEE, 41 age-matched female stroke patients were recruited to the control stroke group. Prevalences of PFO and ASA were significantly higher in the APS group than in the control stroke group (89 vs. 41 %, p = 0.027; 67 vs. 20 %, p = 0.015, respectively). Multiple logistic regression analysis showed that PFO (odds ratio (OR), 13.71; 95 % confidence interval (CI), 1.01-185.62; p = 0.049) and ASA (OR, 8.06; 95 % CI, 1.17-55.59; p = 0.034) were independently associated with the APS group. PFO and ASA were strongly associated with the APS group, and could thus represent potential embolic sources in ischemic stroke patients with APS.

We herein report the fourth case of cerebral infarction, concomitant with hemorrhagic shock, in English literature. A 33-year-old male, who had been diagnosed with schizophrenia and given a prescription for Olanzapine, was discovered with multiple self-inflicted bleeding cuts on his wrist. On arrival, he was in hemorrhagic shock without verbal responsiveness, but his vital signs were normalized following infusion of Lactate Ringer's solution. The neuroradiological studies revealed multiple cerebral ischemic lesions without any vascular abnormality. He was diagnosed with speech apraxia, motor aphasia, and dysgraphia, due to multiple cerebral infarctions. As there was no obvious causative factor with regard to the occurrence of cerebral infarction in the patient, the hypoperfusion due to hemorrhagic shock, and the thromboembolic tendency due to Olanzapine, might have acted together to lead to the patient's cerebral ischemia.

Background: Mobile or ulcerated aortic plaques (MUAPs) on transesophageal echocardiography (TEE) can cause aortogenic brain embolism. Aortic arch calcification (AoAC) on chest X-ray represents systemic atherosclerosis. This study focused on AoAC on chest X-ray and its link with atheromatous aortic plaques (AAPs) on TEE in stroke patients. The aim of the present study was to assess the relationship between AoAC and AAPs in unexplained stroke patients. Methods: A total of 178 patients (mean age: 64 +/- 15 years; 115 males) with ischemic stroke who underwent TEE were enrolled. The patients were classified based on TEE findings: (1) AAPs <4 mm; (2) AAPs >= 4 mm, and (3) MUAPs. The extent of AoAC on chest X-ray was divided into 4 grades (0-3). Clinical characteristics including AoAC were compared among the 3 groups. Multiple logistic regression analysis was performed to identify the independent factors associated with MUAPs. An original diagnostic criterion was defined as a potential indicator of MUAPs in unexplained stroke patients. Results: 104 (58%) patients had AAPs <4 mm, 46 (26%) had AAPs >= 4 mm, and 28 (16%) had MUAPs. Older age (OR: 1.14; 95% CI: 1.06-1.24; p = 0.001), AoAC (OR: 2.35; 95% CI: 1.30-4.24; p = 0.005), and multiple infarctions in multiple vascular territories (VTs) demonstrated on diffusion-weighted imaging (DWI) (OR: 2.58; 95% CI: 1.35-4.92; p = 0.004) were independently associated with MUAPs. The CAM score was defined as consisting of the degree of AoAC (0-3 points), age (= 70 years: 1 point), and DWI findings (multiple infarctions in 1 VT: 1 point; 2 VTs: 2 points; more than 3 VTs: 3 points). The prevalence of MUAPs was substantially increased in patients with medium risk (CAM score 3-4, OR: 7.68; 95% CI: 2.89-20.44; p < 0.001) and high risk (CAM score 5-7, OR: 20.63; 95% CI: 5.12-83.06; p < 0.001). Conclusions: Older age, advanced AoAC, and multiple infarctions in multiple VTs are associated with aortogenic brain embolism. The CAM score can be useful for the diagnosis of aortogenic brain embolism. Copyright (C) 2013 S. Karger AG, Basel

Cerebral infarcts associated with hypercoagulability in malignant tumors have been well recognized. However, reports on cerebral infarcts in patients with a benign gynecologic tumor, such as adenomyosis, are extremely limited. We report the cases of 4 patients with adenomyosis and cerebral infarcts, all without obvious evidence of conventional causes of cerebral infarcts. Brain magnetic resonance imaging revealed multiple cerebral infarcts in both cortical and subcortical areas in all the patients and in different arterial territories in 3 patients. Two patients also had systemic embolism in the fingers or kidneys. One patient had thrombi in the brachiocephalic trunk and left subclavian artery. The levels of coagulation markers were elevated in the acute phase of cerebral infarcts. Although cerebral infarcts might be uncommon in adenomyosis patients, these patients might be potentially at risk of developing cerebral infarcts associated with hypercoagulability related to increased mucinous tumor marker levels, menstruation-related coagulopathy, or increased tissue factor expression levels. Additional study is required to determine the mechanism underlying the development of cerebral infarcts in adenomyosis; however, physicians need to pay particular attention to those who have hypercoagulability with adenomyosis among middle-aged women.

Cerebral air embolism (CAE) is a rare neurologic complication that can occur in patients undergoing various medical procedures or trauma. CAE can sometimes result in death caused by severe brain edema. In spite of these implications, the pathophysiologic mechanisms and radiologic features of fatal CAE remain to be elucidated. In this case report, a patient with carcinomatous pleuritis lost consciousness and developed quadriplegia and had generalized seizures during intrathoracic lavage. Serial computed tomography (CT) revealed the presence of air in intracranial blood vessels following severe brain edema; these are typically observed on the CT scans of patients with fatal CAE. Diffusion-weighted imaging (DWI) of the brain obtained at 24 hours after the onset of CAE revealed scattered cortical gyriform high signal intensity often observed in CAE cases, whereas the apparent diffusion coefficient and T2-weighted imaging revealed diffuse hyperintensity in the subcortical deep white matter, indicating vasogenic edema. Our case showed predominant vasogenic edema rather than cortical ischemic changes in the subcortical deep white matter area. These findings indicate that diffuse subcortical vasogenic edema could be the main cause of mortality in fatal CAE.

Background: There is a general agreement that the stroke prevention benefit of antihypertensive agents is mainly based on their blood pressure lowering properties. The aim of this retrospective study was to assess the benefits of angiotensin type 1 receptor blockers (ARBs) used before the onset of ischemic stroke. Methods: Data were obtained between April 2007 and March 2009 using the discharge statistics of the neurologic service at Juntendo hospital. We retrieved the demographic and clinical characteristics of stroke patients and functional status upon discharge assessed by the modified Rankin Scale (mRS) and Barthel index (BI). Results: We enrolled 151 patients. Patients treated with ARBs were less often treated with a calcium channel blocker (CaB)/angiotensin-converting enzyme inhibitor (ACEI). They often had diabetes and showed better outcomes than the non-ARB group. Logistic regression analysis indicated that in patients with a mRS score of 0 to 2, older age (P < .007) was associated with severe outcomes, while the factor of pretreatment with ARB (P < .014) was associated with better outcomes. For patients with BI scores of more than 75, older age (P < .015) and large artery atherosclerosis (P < .035) were associated with severe outcomes. Logistic regression analysis identified the factor of pretreatment with ARB (P < .020) to be associated with better outcomes. Conclusions: ARB is widely used in patients with hypertension and cardiovascular disease, and our results further support this indication.

In Parkinson's disease (PD), nonmotor symptoms manifest before motor symptoms. In this report, we present a remarkable case of a semiprofessional painter with PD whose painting style dramatically changed from abstract painting to realism before he developed motor, psychiatric, and autonomic nerve disorders. This case suggests that certain types of visual creativity may be impaired in the very early, presymptomatic stages of PD.

Economy class stroke syndrome is a cardiovascular complication associated with long periods of travel, only a few cases have been reported after long drives, however. The patient, a 62-year-old professional driver, had driven a truck for 2 days with minimal rest. While driving, he noted left foot paresis and numbness, along with geographical disorientation. Magnetic resonance imaging of the brain revealed multiple cerebral embolisms in the bilateral cerebral hemisphere. The only complications representing a stroke risk in this patient were a patent foramen ovale and an anterior septal aneurysm, as detected by transesophageal echocardiography. The patient was diagnosed with paradoxical cerebral embolism following his long drive. This case report examines the paradoxical cerebral emboli documented in a patient following a long period of driving.

A 57-year-old woman suffered sudden onset of thunderclap headache after exposure to phenylpropanolamine (PPA), and subsequently developed posterior reversible encephalopathy syndrome (PRES) complicated by occipital intracranial hemorrhage (ICH) with cerebral vasoconstriction. PPA is well known to be associated with ICH and vasoconstriction, but this case illustrates the association with PRES. The danger of exposure to PPA and subsequent adverse events is quite low at present, but we must consider the possibility of exposure to medical agents in patients with repeated severe headache who have no organic disorder.

Cardiac tumor is a rare, but clinically important source of cerebral embolism. We report a case of metastatic chondrosarcoma in the left atrium with multiple cerebral emboli. A computed tomography scan of the chest revealed a large mass in the left atrium and pulmonary vein. The patient underwent heart surgery to remove the metastatic chondrosarcoma in the left atrium, to prevent the formation of further systemic emboli and possible sudden death. The cardiac tumor resection was successful, and the patient was discharged from the hospital without any handicap. This is a rare case of metastatic cardiac tumor that was a source of emboli into the brain and was eradicated.

Evidence suggests that neurogenesis occurs in the adult mammalian brain, and that various stimuli, for example, ischemia/hypoxia, enhance the generation of neural progenitor cells in the subventricular zone (SVZ) and their migration into the olfactory bulb. In a mouse stroke model, focal ischemia results in activation of neural progenitor cells followed by their migration into the ischemic lesion. The present study assessed the in vivo effects of cilostazol, a type 3 phosphodiesterase inhibitor known to activate the cAMP-responsive element binding protein (CREB) signaling, on neurogenesis in the ipsilateral SVZ and peri-infarct area in a mouse model of transient middle cerebral artery occlusion. Mice were divided into sham operated (n=12), vehicle- (n=18) and cilostazol-treated (n=18) groups. Sections stained for 5-bromodeoxyuridine (BrdU) and several neuronal and a glial markers were analyzed at post-ischemia days 1, 3 and 7. Cilostazol reduced brain ischemic volume (P&lt 0.05) and induced earlier recovery of neurologic deficit (P&lt 0.05). Cilostazol significantly increased the density of BrdU-positive newly-formed cells in the SVZ compared with the vehicle group without ischemia. Increased density of doublecortin (DCX)-positive and BrdU/DCX-double positive neural progenitor cells was noted in the ipsilateral SVZ and peri-infarct area at 3 and 7 days after focal ischemia compared with the vehicle group (P&lt 0.05). Cilostazol increased DCX-positive phosphorylated CREB (pCREB)-expressing neural progenitor cells, and increased brain derived neurotrophic factor (BDNF)-expressing astrocytes in the ipsilateral SVZ and peri-infarct area. The results indicated that cilostazol enhanced neural progenitor cell generation in both ipsilateral SVZ and peri-infarct area through CREB-mediated signaling pathway after focal ischemia. © 2010 IBRO.

Background: The aim of this study was to identify the relevant clinical backgrounds for anterior circulation territory infarctions (ACTI) and posterior circulation territory infarctions (PCTI). Methods: Data were obtained from April 1995 to May 2005 discharge statistics of the neurologic service in our hospital. The infarctions were divided into anterior circulation territory and posterior circulation territory by computed tomography and magnetic resonance imaging, and we examined clinical backgrounds for small vessel disease, large artery disease, and cardioembolism (CE). Results: A total of 1089 cases were ACTI and 430 were PCTI. Male/female ratio was 1.75 for ACTI and 2.67 for PCTI (P <.05). The mean age was 69.1 years for ACTI and 65.9 years for PCTI (P <.001). Multiple logistic regression analysis showed that significant contributed clinical backgrounds for small vessel disease were age and hyperlipidemia in ACTI. Those for large artery disease were male sex and history of cerebrovascular disease in PCTI. Those for CE were age and atrial fibrillation in ACTI; and diabetes, hypertension, hyperlipidemia, and smoking in PCTI. Those for all cerebral infarctions were age and atrial fibrillation in ACTI; and male sex, diabetes, and hypertension in PCTI. Conclusion: This study showed differences in clinical backgrounds between ACTI and PCTI. Moreover, PCTI were closely related to the conventional vascular risk factors even in CE.

Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 299-310; doi: 10.1038/jcbfm.2009.210; published online 14 October 2009

Background: The purpose of the present study was to assess the contribution of embolic etiologies, patent foramen ovale (PFO) and atrial septal aneurysm (ASA), to cerebral white matter lesions (WMLs) in ischemic stroke patients. Methods: Patients with acute ischemic stroke who underwent transesophageal echocardiography were prospectively studied to investigate the relationships between the prevalence of PFO and ASA and the degree of WMLs. The patients were classified into four groups based on transesophageal echocardiography findings: (1) the PFO group (patients having PFO but not ASA); (2) the ASA group (patients having ASA but not PFO); (3) the PFO-ASA group (patients having both PFO and ASA), and (4) the non-septal abnormalities group (non-SA group, patients with neither PFO nor ASA). Based on MRI findings, the patients were also subdivided into grades 0, 1, 2, and 3 according to the Fazekas classification. Results: 115 patients (age, 69 +/- 11 years; 41 females) were enrolled; 49 (43%) were in the PFO group, 4 (3%) were in the ASA group, 23 (20%) were in the PFO-ASA group, and 39 (34%) were in the non-SA group. The PFO-ASA group had significantly increased WMLs compared to the other three groups (p = 0.004). On multiple logistic regression analysis, the coexistence of PFO and ASA was significantly associated with the degree of WMLs (odds ratio: 2.40; 95% confidence interval: 1.11-5.17; p = 0.026) when the PFO-ASA and non-SA groups were compared. Conclusions: The coexistence of PFO with ASA could play an important pathogenic role in WML severity. Copyright (c) 2010 S. Karger AG, Basel

This study was designed to examine the effect of adrenomedullin deficiency on cerebral infarction and the relationship between adrenomedullin and cyclic AMP-protein kinase A pathway in regulating reactive oxygen species (ROS). Adrenomedullin heterozygous and wild-type mice were subjected to 60-mins focal ischemia. We used adrenomedullin heterozygous mice because adrenomedullin homozygotes die in utero. Infarct volume, neurologic deficit scores, and immunohistochemical analyses were evaluated at several time points after ischemia. The infarct volume and neurologic deficit scores were significantly worse in adrenomedullin heterozygous mice. Significant accumulation of inducible nitric oxide, oxidative DNA damage, and lipid peroxidation was noted after reperfusion in adrenomedullin heterozygous mice. Treatment of wild-type mice with H89, a protein kinase A inhibitor, resulted in increased infarct size, and worsening of neurologic deficit score and other parameters to levels comparable to those of adrenomedullin heterozygous mice. In contrast, cilostazol, which increases cyclic AMP, rescued neurologic deficit and ROS accumulation in adrenomedullin heterozygous mice. This study showed that adrenomedullin downregulation results in increase in ROS after transient focal ischemia in mice. The results also indicated that adrenomedullin has an important function against ischemic injury through the cyclic AMP-protein kinase A pathway. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1769-1779; doi:10.1038/jcbfm.2009.92; published online 1 July 2009

Various stimuli, such as ischemia/hypoxia enhance newborn cell survival in the subventricular zone and their migration tangentially in chains toward the olfactory bulb. The present study assessed the fate of newborn neurons from subventricular zone to olfactory bulb under conditions of chronic cerebral hypoperfusion, and examined the role of cAMP-responsive element binding protein signaling on the survival of these neurons by using cilostazol, a potent inhibitor of type III phosphodiesterase. Rats underwent bilateral common carotid artery ligation. They were divided into sham-operated (n=70), vehicle- (n=70), and type III phosphodiesterase inhibitor-treated (n=70) groups. Immunohistochemically-stained section for 5-bromodeoxyuridine and a series of neuronal and glial markers were analyzed at days 7, 14, 21 and 28 after hypoperfusion. The reduction of olfactory bulb size gradually progressed in the vehicle group (P&lt 0.05), but not in the sham-operated and type III phosphodiesterase inhibitor-treated group. The subventricular zone of the vehicle-treated rats contained significantly larger numbers of newborn neuroblasts after hypoperfusion, compared with sham-operated rats (P&lt 0.05), but significantly lower numbers in the rostral migratory stream and olfactory bulb (P&lt 0.05). Treatment of rats with type III phosphodiesterase inhibitor increased the number of neuroblasts and enhanced the survival and differentiation of cells (P&lt 0.05). Phosphorylated cAMP-responsive element binding protein within neuroblasts was markedly decreased in the subventricular zone, rostral migratory stream, and olfactory bulb of vehicle-treated rats (P&lt 0.05), but treatment with type III phosphodiesterase inhibitor resulted in recovery of this expression throughout hypoperfusion, leading to enhanced neurogenesis (P&lt 0.05). These effects were abrogated by protein kinase A and C inhibitor. Our results indicated that cAMP-responsive element binding protein signaling is a key mediator of neurogenesis after prolonged hypoperfusion and provide the basis for new regenerative therapies for ischemic brain injury. © 2009 IBRO.

A multicenter randomized clinical trial demonstrated that acute ischemic stroke patients treated with edaravone, a scavenger of hydroxyl radicals, had significant functional improvement. We tested the hypothesis that edaravone has protective effects against white matter lesions (WML) and endothelial injury, using a rat chronic hypoperfusion model. Adult Wistar rats underwent ligation of bilateral common carotid artery (LBCCA) and were divided into the edaravone group (injected once only immediately after LBCCA [n=39, ED1] and injected on three consecutive days [n=39, ED3]), the vehicle group (n=39), and the sham group (n=15). Cerebral blood flow, Morris water maze performance, footprint test for locomotor function, immunohistochemical analyses and Western blot analysis were performed before and after LBCCA. The ED3 group upregulated endothelial nitric oxide synthase and attenuated Evans Blue extravasation at day 3 after LBCCA (P&lt 0.05). Edaravone markedly suppressed accumulation of 4-hydroxy-2-nonenal-modified protein and 8-hydroxy-deoxyguanosine (P&lt 0.01), and loss of oligodendrocytes (P&lt 0.05) in the cerebral white matter at days 3, 7, 14, 21 and 28 after LBCCA. These results were more evident in the ED3 group. Moreover, at day 21 after LBCCA, spatial memory but not motor function, and axonal damage were significantly improved by three-time treatment of edaravone (P&lt 0.05). Our results indicated that 3-day treatment with edaravone provides protection against WML through endothelial protection and free radical scavenging and suggested that edaravone is potentially useful for the treatment of cognitive impairment. © 2009 IBRO.

Phosphorylated tau (p-tau) is the principal component of neurofibrillary tangles, a pathological hallmark, and likely plays a neurotoxic role in tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We subjected brains from autopsy cases of AD, PSP, and CBD to a variety of immunohistochemical, immunoblotting, and pull-down assays. In this study, we show that excitatory amino acid transporter 2 (EAAT2) preferentially interacted with phosphorylated tau and was localized in neurofibrillary tangles in the brains of such patients. These results strongly indicate that EAAT2 acts in tauopathy-related neurodegeneration, and abnormalities in glutamate transport play an important role in the pathogenesis of tauopathies. Structured summary: MINT-7148349, MINT-7148361:TAU (uniprotkb:P10636) physically interacts (MI:0914) with EAAT2 (uniprotkb:P43004) by pull-down (MI:0096). MINT-7148372, MINT-7148384:TAU (uniprotkb:P10636) physically interacts (MI:0914) with EAAT2 (uniprotkb:P43004) by anti bait coimmunoprecipitation (MI:0006). © 2009 Federation of European Biochemical Societies.

Phosphorylated tau (p-tau) is the principal component of neurofibrillary tangles, a pathological hallmark, and likely plays a neurotoxic role in tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We subjected brains from autopsy cases of AD, PSP, and CBD to a variety of immunohistochemical, immunoblotting, and pull-down assays. In this study, we show that excitatory amino acid transporter 2 (EAAT2) preferentially interacted with phosphorylated tau and was localized in neurofibrillary tangles in the brains of such patients. These results strongly indicate that EAAT2 acts in tauopathy-related neurodegeneration, and abnormalities in glutamate transport play an important role in the pathogenesis of tauopathies. Structured summary: MINT-7148349, MINT-7148361: TAU (uniprotkb: P10636) physically interacts (MI: 0914) with EAAT2 (uniprotkb: P43004) by pull-down (MI: 0096) MINT-7148372, MINT-7148384: TAU (uniprotkb: P10636) physically interacts (MI: 0914) with EAAT2 (uniprotkb: P43004) by anti bait coimmunoprecipitation (MI: 0006) (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Background and Purpose-The purpose was to assess the prevalence of disorders of glucose metabolism and insulin resistance in Japanese ischemic stroke patients with no history of diabetes by performing 75-gram oral glucose tolerance test (OGTT). Methods-We recruited 427 ischemic stroke patients (atherothrombotic infarction, n = 220; lacunar infarction, n = 125; cardioembolic infarction, n = 82). OGTT was used to evaluate disorders of glucose metabolism in stroke patients without previously known diabetes (n=113). We investigated the relationships among the prevalence of abnormal glucose metabolism, ischemic stroke subtypes, and the prevalence of insulin resistance using homeostasis model assessment for insulin resistance and immunoreactive insulin at 120 minutes after glucose loading (IRI(120)). Results-OGTT identified the presence of disorders of glucose metabolism in 62.8% of ischemic stroke patients without previously known diabetes, including diabetes (24.8%) and impaired glucose tolerance (lone impaired glucose tolerance and impaired fasting glucose plus impaired glucose tolerance, 34.5%). The prevalence of newly diagnosed diabetes and impaired glucose tolerance was the highest in the atherothrombotic infarction group (68.9%). The highest values of homeostasis model assessment for insulin resistance and immunoreactive insulin at 120 minutes after glucose loading were found in atherothrombotic infarction patients with abnormal glucose tolerance. Conclusions-In this study, a significantly large percentage of Japanese patients with ischemic stroke and no history of diabetes were found to have disorders of glucose metabolism by OGTT. Impaired glucose tolerance and insulin resistance could play an important pathogenic role in the development of atherothrombotic infarction. (Stroke. 2009;40:1289-1295.)

Pneumonia is a common complication with the highest attributable proportion of deaths in patients with stroke. Cilostazol is a potent type III phosphodiesterase inhibitor, approved as an anti-platelet aggregation agent. The present study was designed to determine the protective mechanism of cilostazol against post-stroke pneumonia using a rat chronic cerebral hypoperfusion model. Rats were subjected to bilateral common carotid artery ligation (LBCCA) and divided randomly into the vehicle group (n=72) and cilostazol group (n=72). Rats of each group were sacrificed at baseline and at days 14, 28 and 42 after LBCCA. Cilostazol significantly improved the swallowing reflex by shortening the latency to elicited swallowing and increasing the numbers of swallows (P&lt 0.05) at 14 days of hypoperfusion. It also decreased the numbers of bacterial colonies grown in cultures from homogenized lungs. Cilostazol markedly upregulated cyclic AMP responsive element binding protein (CREB) phosphorylation, increased tyrosine hydroxylase (TH) expression in the substantial nigra, and maintained dopamine (84.7±2.3 vs. 79.2±4.1% control P=0.0512) and substance P levels (86.6±7.9 vs. 73.9±6.5% control P&lt 0.05) in the striatum, compared with the vehicle group. Our results indicate that cilostazol improves the swallowing reflex by enhancing the expression of TH through the CREB phosphorylation signaling pathway, and suggest that cilostazol could be useful in preventing pneumonia in the chronic stage of stroke. © 2009 IBRO.

Adult-onset type II citrullinemia (CTLN2) is a hereditary metabolic disorder characterized by highly elevated plasma citrulline and ammonia. Recent studies have identified the "citrin gene" (SLC25A13) as the causative gene for CTLN2. Various neurobehavioral symptoms seen in this disease, such as unconsciousness, disorientation, abnormal behavior, and epilepsy, are thought to be caused by encephalopathy mostly due to hyperammonemia. A 47-year-old woman presented with repeated unconsciousness and abnormal behavior. The high plasma anmonia level was not always associated with her neurobehavioral symptoms (unconsciousness, disorientation, abnormal behavior, and epilepsy), but paroxysmal EEG discharges were invariably associated with these symptoms. Her symptoms and abnormal EEG discharges were sometimes treated with diazepam simultaneously. Based on these findings, we considered that her symptoms were caused by nonconvulsive status epilepticus (NCSE). Until date, neurobehavioral symptoms of CTLN2 are considered to be caused by hyperammonemia or other metabolic factors. We suggest that encephalopathy of CTLN2 is caused not only by hyperammonemia but also by NCSE. Therefore, repeated EEG monitoring is recommended in the follow up of patients with CTLN2.

This study assessed the time course of angiotensin (Ang) II type 1 and type 2 receptor expression after 60 min of ischemia/reperfusion in mice treated with a nonhypotensive dose of valsartan, an angiotensin II type 1 receptor antagonist. We also examined the potential neuroprotective mechanisms mediated by angiotensin II type 2 receptor. Mice were divided into two groups (n = 64, each): valsartan-treated and control, vehicle groups. Infarct volume and neurological deficit scores were evaluated at several time points after ischemia, while immunohistochemical analyses were performed at serial time points after reperfusion. Valsartan significantly reduced the infarct volume and improved the neurological deficit scores (P < 0.05). Both angiotensin II type 1 and type 2 receptors were upregulated at 24 h and peaked at 72 h with type I receptors dominating in the ischemic penumbra of the vehicle group. Interestingly, angiotensin II type 2 receptor expression levels were significantly higher in the valsartan group than vehicle controls (P < 0.001). Moreover, angiotensin II type 2 receptor upregulated phosphosignal transducer and activator of transcription-3, and B-cell lymphoma protein-2 (P < 0.05). Our results indicated that angiotensin II type 2 receptor has antiapoptotic activity by activating the B-cell lymphoma protein-2 via the janus kinase/signal transducer and activator of transcription signaling pathway. (c) 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Background and Purpose - White matter lesions contribute to cognitive impairment in poststroke patients. The present study was designed to assess the neuroprotective mechanisms of cilostazol, a potent inhibitor of type III phosphodiesterase, through signaling pathways that lead to activation of transcription factor cAMP-responsive element binding protein (CREB) phosphorylation using rat chronic cerebral hypoperfusion model. Methods - Rats underwent bilateral common carotid artery ligation. They were divided into the cilostazol group (n = 80) and the vehicle (control) group (n = 80). Performance at the Morris water maze task and immunohistochemistry for 4-hydroxy-2-nonenal (HNE), glutathione-S-transferase-pi (GST-pi), ionized calcium-binding adaptor molecule 1, phosphorylated CREB (p-CREB), Bcl-2, and cyclooxygenase-2 (COX-2) were analyzed at baseline and at 3, 7, 14, 21, and 28 days after hypoperfusion. Result - Cilostazol significantly improved spatial learning memory (6.8 +/- 2.3 seconds; P < 0.05) at 7 days after hypoperfusion. Cilostazol markedly suppressed accumulation of HNE-modified protein and loss of GST-pi-positive oligodendrocytes in the cerebral white matter during the early period after hypoperfusion (P < 0.05). Cilostazol upregulated p-CREB and Bcl-2 (P < 0.05), increased COX-2 expression, and reduced microglial activation in the early period of hypoperfusion. Conclusion - Our results indicate that cilostazol exerts a brain- protective effect through the CREB phosphorylation pathway leading to upregulation of Bcl-2 and COX-2 expressions and suggest that cilostazol is potentially useful for the treatment of cognitive impairment in poststroke patients.

Cerebral ischemia induces the expression of several growth factors and cytokines, which protect neurons against ischemic insults. Recent studies showed that granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect through the signaling pathway for the antiapoptotic cascade. The current study was designed to assess the neuroprotective mechanisms of G-CSF in ischemia/reperfusion injury using bone marrow chimera mice known to express enhanced green fluorescent protein (EGFP). Mice were subjected to ischemia/reperfusion and divided into two groups: those treated with G-CSF (G-CSF group) and vehicle (control group) (n=35 in each group). Immunohistochemistry and immunoblotting for antiapoptotic protein, nitrotyrosine, and inducible nitrate oxide synthase ( iNOS) were performed. G-CSF significantly reduced stroke volume (34%, P < 0.006). G-CSF upregulated Stat3, pStat3, and Bcl-2 (P < 0.05), and suppressed iNOS and nitrotyrosine expression. In EGFP chimera mice, G-CSF decreased the migration of Iba-1/EGFP-positive bone marrow-derived monocytes/macrophages and increased intrinsic microglia/macrophages at ischemic penumbra (P < 0.05), suggesting that bone marrow-derived monocytes/macrophages are not involved in GCSF-induced reduction of ischemic injury size. Our study indicated that G-CSF exerts a neuroprotective effect through the direct activation of antiapoptotic pathway, and suggested that G-CSF is important for expansion of the therapeutic time window in patients with cerebral ischemia.

Background: The purpose of this study was to assess the influence of clusters of risk factors on the incidence of echolucent carotid plaque in stroke patients. Methods: A retrospective analysis of 413 stroke patients who had undergone carotid ultrasonography was performed. High-resolution B-mode ultrasonography was used to evaluate the characteristics of carotid plaque. We investigated the relationships between the incidence of echolucent carotid plaque and clustering of risk factors (hypertension, diabetes mellitus and hyperlipidemia) and stroke subtypes and transient ischemic attack (TIA). Results: Echolucent plaques were present in 10.5% of patients free of risk factors, in 18.8% with a single risk factor (NS), in 27.7% with two risk factors (p < 0.01) and in 50.0% with three risk factors (p < 0.001), and were significantly more common in patients with multiple risk factors (odds ratio 1.79; 95% CI, 1.05-3.06; p = 0.045). Echolucent plaques were observed in 41.2% of patients with atherothrombotic infarction, in 17.6% with lacunar infarction, in 11.5% with cardioembolic stroke, and in 25.0% with TIA, and were significantly more common in patients with atherothrombotic infarction than in those with lacunar infarction or cardioembolic stroke (p < 0.001), or in those with TIA (p < 0.05). Conclusions: The clustering of risk factors increased the incidence of echolucent carotid plaque. Patients with multiple risk factors were at increased risk of echolucent plaque, and these had a significant relationship with atherothrombotic infarction compared with other stroke subtypes and TIA. Copyright (c) 2006 S. Karger AG, Basel.