Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016966.89226.67
S. Chrissobolis, C. Sobey
Background and Purpose— The structurally related, inwardly rectifying K+ (KIR) channel and the ATP-sensitive K+ (KATP) channel are important modulators of cerebral artery tone. Although protein kinase C (PKC) activators have been shown to inhibit these channels with the use of patch-clamp electrophysiology, effects of PKC on K+ channel function in intact cerebral blood vessels are unknown. We therefore tested whether pharmacological alteration of PKC activity affects cerebral vasodilator responses to KIR and/or KATP channel activators in vivo. Methods— We measured changes in basilar artery diameter using a cranial window preparation in anesthetized rats. In addition, intracellular recordings of smooth muscle membrane potential were made in isolated basilar arteries. Results— K+ (5 to 15 mmol/L) and aprikalim (1 to 10 &mgr;mol/L) each elicited reproducible vasodilatation. The PKC activator phorbol-12,13-dibutyrate (PdBu) (50 nmol/L) inhibited responses to K+ (by 40% to 55%) and aprikalim (by 40% to 70%), whereas responses to papaverine were unaffected. The PKC inhibitor calphostin C (0.1 &mgr;mol/L) augmented responses to K+ (by 2- to 3-fold) and aprikalim (2-fold) but not papaverine. In addition, K+ (5 mmol/L) and aprikalim (3 &mgr;mol/L) each hyperpolarized the basilar artery. PdBu inhibited these responses to aprikalim by 45% but had no effect on K+-induced hyperpolarization. Conclusions— These data suggest that both basal and stimulated PKC activity inhibit KIR and KATP channel–mediated cerebral vasodilatation in vivo. The inhibitory effect on KATP channel–mediated vasodilatation occurs at least partly by inhibition of hyperpolarization mediated by KATP channels. PKC inhibits K+-induced vasodilatation without affecting hyperpolarization, suggesting that the inhibitory effect of PKC on vasodilator responses to K+ does not involve altered KIR channel function.
{"title":"Inhibitory Effects of Protein Kinase C on Inwardly Rectifying K+- and ATP-Sensitive K+ Channel-Mediated Responses of the Basilar Artery","authors":"S. Chrissobolis, C. Sobey","doi":"10.1161/01.STR.0000016966.89226.67","DOIUrl":"https://doi.org/10.1161/01.STR.0000016966.89226.67","url":null,"abstract":"Background and Purpose— The structurally related, inwardly rectifying K+ (KIR) channel and the ATP-sensitive K+ (KATP) channel are important modulators of cerebral artery tone. Although protein kinase C (PKC) activators have been shown to inhibit these channels with the use of patch-clamp electrophysiology, effects of PKC on K+ channel function in intact cerebral blood vessels are unknown. We therefore tested whether pharmacological alteration of PKC activity affects cerebral vasodilator responses to KIR and/or KATP channel activators in vivo. Methods— We measured changes in basilar artery diameter using a cranial window preparation in anesthetized rats. In addition, intracellular recordings of smooth muscle membrane potential were made in isolated basilar arteries. Results— K+ (5 to 15 mmol/L) and aprikalim (1 to 10 &mgr;mol/L) each elicited reproducible vasodilatation. The PKC activator phorbol-12,13-dibutyrate (PdBu) (50 nmol/L) inhibited responses to K+ (by 40% to 55%) and aprikalim (by 40% to 70%), whereas responses to papaverine were unaffected. The PKC inhibitor calphostin C (0.1 &mgr;mol/L) augmented responses to K+ (by 2- to 3-fold) and aprikalim (2-fold) but not papaverine. In addition, K+ (5 mmol/L) and aprikalim (3 &mgr;mol/L) each hyperpolarized the basilar artery. PdBu inhibited these responses to aprikalim by 45% but had no effect on K+-induced hyperpolarization. Conclusions— These data suggest that both basal and stimulated PKC activity inhibit KIR and KATP channel–mediated cerebral vasodilatation in vivo. The inhibitory effect on KATP channel–mediated vasodilatation occurs at least partly by inhibition of hyperpolarization mediated by KATP channels. PKC inhibits K+-induced vasodilatation without affecting hyperpolarization, suggesting that the inhibitory effect of PKC on vasodilator responses to K+ does not involve altered KIR channel function.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"43 1","pages":"1692-1697"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76491948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016326.78014.FE
W. Steinke, S. Ley
Background and Purpose— Severe motor deficits are the predominant cause of long-term disability in stroke patients. In particular, progressive hemiparesis in the initial stage after stroke onset is frequently devastating. Therefore, we attempted to define the population at risk with respect to the presumed pathogenesis. Methods— Among 941 stroke patients hospitalized during a 3-year period, 92 patients (41 men, 51 women; mean age, 68 years) had a severe motor deficit (<25 of 42 points on the 7 motor items of the European Stroke Scale) resulting from brain infarcts. Risk factors, neurological examinations, comprehensive diagnostic tests, and therapy were documented. The study population was separated into patients with (group A) and without (group B) progressive motor deficits. Progression was defined as a further decrease of at least 5 points on the initial European Stroke Scale motor score during the first 5 days after stroke onset. Results— Of the 92 patients, 23.9% had significant worsening of motor function with a decrease in the mean European Stroke Scale motor score from 20.3 to 12.9 points (P <0.01). Infarcts in group A patients were subcortical in 59.1%, whereas most infarcts were cortical in group B (61.4%, P <0.05). Progressive hemiparesis was also significantly associated with lacunar stroke (group A:, 59.1%; group B, 24.3%;P <0.01). With regard to risk factors, diagnostic studies, and neuroimaging, small-vessel disease was the predominant presumed cause of stroke in group A (63.6%, P <0.01), whereas infarcts in group B patients were frequently caused by embolism from cardiac or undetermined sources (61.4%, P <0.01). Prevalence of high-grade carotid stenosis was not significantly different between groups A and B; however, subtotal stenoses and complete internal carotid artery occlusions were found only among patients without progressive motor deficits. Conclusions— Lacunar stroke caused by small-vessel disease is the major cause of progressive motor deficits, probably because of stepwise occlusion of the branches of small penetrating arteries.
{"title":"Lacunar Stroke Is the Major Cause of Progressive Motor Deficits","authors":"W. Steinke, S. Ley","doi":"10.1161/01.STR.0000016326.78014.FE","DOIUrl":"https://doi.org/10.1161/01.STR.0000016326.78014.FE","url":null,"abstract":"Background and Purpose— Severe motor deficits are the predominant cause of long-term disability in stroke patients. In particular, progressive hemiparesis in the initial stage after stroke onset is frequently devastating. Therefore, we attempted to define the population at risk with respect to the presumed pathogenesis. Methods— Among 941 stroke patients hospitalized during a 3-year period, 92 patients (41 men, 51 women; mean age, 68 years) had a severe motor deficit (<25 of 42 points on the 7 motor items of the European Stroke Scale) resulting from brain infarcts. Risk factors, neurological examinations, comprehensive diagnostic tests, and therapy were documented. The study population was separated into patients with (group A) and without (group B) progressive motor deficits. Progression was defined as a further decrease of at least 5 points on the initial European Stroke Scale motor score during the first 5 days after stroke onset. Results— Of the 92 patients, 23.9% had significant worsening of motor function with a decrease in the mean European Stroke Scale motor score from 20.3 to 12.9 points (P <0.01). Infarcts in group A patients were subcortical in 59.1%, whereas most infarcts were cortical in group B (61.4%, P <0.05). Progressive hemiparesis was also significantly associated with lacunar stroke (group A:, 59.1%; group B, 24.3%;P <0.01). With regard to risk factors, diagnostic studies, and neuroimaging, small-vessel disease was the predominant presumed cause of stroke in group A (63.6%, P <0.01), whereas infarcts in group B patients were frequently caused by embolism from cardiac or undetermined sources (61.4%, P <0.01). Prevalence of high-grade carotid stenosis was not significantly different between groups A and B; however, subtotal stenoses and complete internal carotid artery occlusions were found only among patients without progressive motor deficits. Conclusions— Lacunar stroke caused by small-vessel disease is the major cause of progressive motor deficits, probably because of stepwise occlusion of the branches of small penetrating arteries.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"28 10 1","pages":"1510-1516"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82718150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000017219.83330.FF
R. Gerlach, Fabian Tölle, A. Raabe, M. Zimmermann, A. Siegemund, V. Seifert
Background and Purpose— The functional integrity of the hemostatic system is a prerequisite for the safe performance of neurosurgical procedures. To monitor the individual coagulation capacity of each patient, standard tests are effective to detect deficiencies involving the generation of fibrin. However, fibrin clot strength depends primarily on coagulation factor XIII, which cross-links fibrin monomers and enhances clot resistance against fibrinolysis. Therefore, factor XIII is functionally involved in both the hemostatic and fibrinolytic systems. The objective of this prospective study was to determine the incidence and clinical relevance of perioperative decreased factor XIII with respect to standard coagulation parameters and the occurrence of postoperative hematoma. Methods— In 876 patients, 910 neurosurgical procedures were performed. Prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen, and factor XIII were tested in each patient preoperatively and postoperatively. Results— Postoperative intracranial hematoma (defined as requiring surgical evacuation) occurred after 39 (4.3%) of 910 surgical procedures. Patients with postoperative hematoma had significantly lower factor XIII and fibrinogen levels preoperatively and postoperatively than patients without hematoma. In patients with postoperative hematoma, PT and platelets differed significantly only postoperatively, whereas PTT was different neither preoperatively nor postoperatively. Of the 39 patients with a postoperative hematoma, 13 (33.3%) had a postoperative factor XIII <60% compared with 61 (7%) of 867 patients without hematoma (P <0.01, Fisher’s exact test). The relative risk of developing a postoperative hematoma is therefore increased 6.4-fold in patients with postoperative factor XIII <60%. The risk is increased 12-fold in patients who additionally have postoperative decreased fibrinogen levels (<1.5 g/L) and 9-fold in patients with platelet count <150×109/L and factor XIII <60%. Conclusions— This is the first prospective study that demonstrates the association of decreased perioperative factor XIII with an increased risk of postoperative hematoma in neurosurgical patients. The risk is further increased in those patients with low factor XIII and additional abnormalities of fibrinogen, PT, platelets, and PTT. Factor XIII testing and specific replacement, as accepted for other clotting factors, may reduce the risk of postoperative hematoma.
{"title":"Increased Risk for Postoperative Hemorrhage After Intracranial Surgery in Patients With Decreased Factor XIII Activity: Implications of a Prospective Study","authors":"R. Gerlach, Fabian Tölle, A. Raabe, M. Zimmermann, A. Siegemund, V. Seifert","doi":"10.1161/01.STR.0000017219.83330.FF","DOIUrl":"https://doi.org/10.1161/01.STR.0000017219.83330.FF","url":null,"abstract":"Background and Purpose— The functional integrity of the hemostatic system is a prerequisite for the safe performance of neurosurgical procedures. To monitor the individual coagulation capacity of each patient, standard tests are effective to detect deficiencies involving the generation of fibrin. However, fibrin clot strength depends primarily on coagulation factor XIII, which cross-links fibrin monomers and enhances clot resistance against fibrinolysis. Therefore, factor XIII is functionally involved in both the hemostatic and fibrinolytic systems. The objective of this prospective study was to determine the incidence and clinical relevance of perioperative decreased factor XIII with respect to standard coagulation parameters and the occurrence of postoperative hematoma. Methods— In 876 patients, 910 neurosurgical procedures were performed. Prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen, and factor XIII were tested in each patient preoperatively and postoperatively. Results— Postoperative intracranial hematoma (defined as requiring surgical evacuation) occurred after 39 (4.3%) of 910 surgical procedures. Patients with postoperative hematoma had significantly lower factor XIII and fibrinogen levels preoperatively and postoperatively than patients without hematoma. In patients with postoperative hematoma, PT and platelets differed significantly only postoperatively, whereas PTT was different neither preoperatively nor postoperatively. Of the 39 patients with a postoperative hematoma, 13 (33.3%) had a postoperative factor XIII <60% compared with 61 (7%) of 867 patients without hematoma (P <0.01, Fisher’s exact test). The relative risk of developing a postoperative hematoma is therefore increased 6.4-fold in patients with postoperative factor XIII <60%. The risk is increased 12-fold in patients who additionally have postoperative decreased fibrinogen levels (<1.5 g/L) and 9-fold in patients with platelet count <150×109/L and factor XIII <60%. Conclusions— This is the first prospective study that demonstrates the association of decreased perioperative factor XIII with an increased risk of postoperative hematoma in neurosurgical patients. The risk is further increased in those patients with low factor XIII and additional abnormalities of fibrinogen, PT, platelets, and PTT. Factor XIII testing and specific replacement, as accepted for other clotting factors, may reduce the risk of postoperative hematoma.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"10 26 1","pages":"1618-1623"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82877515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016961.01086.94
K. Yonemura, K. Kimura, K. Minematsu, M. Uchino, Takenori Yamaguchi
Background and Purpose— A small centrum ovale infarct (SCOI), caused by occlusion of the white matter medullary arteries, is often equated with a lacunar infarct. We sought to clarify the clinical characteristics of a SCOI visualized by diffusion-weighted MRI (DWI) compared with those of a small basal ganglia infarct (SBGI). Methods— Patients with a SCOI (SCOI group; n=38) or SBGI (SBGI group; n=68) ≤15 mm in diameter on conventional MRI and DWI were selected from 582 consecutive patients with acute ischemic stroke. Sex, age, neurological symptoms, vascular risk factors, emboligenic heart disease, arterial occlusive disease in the ipsilateral carotid system, and recurrent stroke within the initial 30 days were compared between the 2 groups. Results— Only 47% of SCOIs but 87% of SBGIs could be identified with the use of conventional MRI, whereas DWI could detect them all. Age, sex, and vascular risk factors were not significantly different between the 2 groups. The SCOI group had more frequently an abrupt onset of symptoms (63% versus 26%;P =0.0002), emboligenic heart diseases (34% versus 12%;P =0.0054), occlusive carotid and/or middle cerebral artery diseases (53% versus 19%;P =0.0004), and recurrent stroke (13% versus 1%;P =0.0216) but less frequently a classic lacunar syndrome (50% versus 81%;P =0.0009) than the SBGI group. On a multivariate analysis, both arterial and heart diseases were independently associated with the SCOI group. Conclusions— Symptomatic SCOIs detected by DWI may be associated with large-vessel and heart diseases and should be distinguished from lacunar infarcts.
背景和目的:由髓质动脉白质阻塞引起的小卵圆心梗死(SCOI)通常等同于腔隙性梗死。我们试图澄清扩散加权MRI (DWI)显示的SCOI与小基底神经节梗死(SBGI)的临床特征。方法:SCOI患者(SCOI组;n=38)或SBGI组(SBGI组;选取582例连续急性缺血性脑卒中患者，常规MRI和DWI上直径≤15 mm (n=68)。比较两组患者的性别、年龄、神经系统症状、血管危险因素、栓塞性心脏病、同侧颈动脉系统动脉闭塞性疾病、30天内卒中复发情况。结果-使用常规MRI只能识别47%的scoi和87%的sbgi，而DWI可以检测到所有scoi。两组患者年龄、性别、血管危险因素差异无统计学意义。与SBGI组相比，SCOI组更频繁地出现突发性症状(63%对26%，P =0.0002)、栓塞性心脏病(34%对12%，P =0.0054)、颈动脉和/或大脑中动脉闭塞性疾病(53%对19%，P =0.0004)和复发性中风(13%对1%，P =0.0216)，但典型腔隙综合征的发生率较低(50%对81%，P =0.0009)。在多变量分析中，动脉和心脏疾病都与SCOI组独立相关。结论:DWI检测到的症状性scoi可能与大血管和心脏疾病有关，应与腔隙性梗死区分开。
{"title":"Small Centrum Ovale Infarcts on Diffusion-Weighted Magnetic Resonance Imaging","authors":"K. Yonemura, K. Kimura, K. Minematsu, M. Uchino, Takenori Yamaguchi","doi":"10.1161/01.STR.0000016961.01086.94","DOIUrl":"https://doi.org/10.1161/01.STR.0000016961.01086.94","url":null,"abstract":"Background and Purpose— A small centrum ovale infarct (SCOI), caused by occlusion of the white matter medullary arteries, is often equated with a lacunar infarct. We sought to clarify the clinical characteristics of a SCOI visualized by diffusion-weighted MRI (DWI) compared with those of a small basal ganglia infarct (SBGI). Methods— Patients with a SCOI (SCOI group; n=38) or SBGI (SBGI group; n=68) ≤15 mm in diameter on conventional MRI and DWI were selected from 582 consecutive patients with acute ischemic stroke. Sex, age, neurological symptoms, vascular risk factors, emboligenic heart disease, arterial occlusive disease in the ipsilateral carotid system, and recurrent stroke within the initial 30 days were compared between the 2 groups. Results— Only 47% of SCOIs but 87% of SBGIs could be identified with the use of conventional MRI, whereas DWI could detect them all. Age, sex, and vascular risk factors were not significantly different between the 2 groups. The SCOI group had more frequently an abrupt onset of symptoms (63% versus 26%;P =0.0002), emboligenic heart diseases (34% versus 12%;P =0.0054), occlusive carotid and/or middle cerebral artery diseases (53% versus 19%;P =0.0004), and recurrent stroke (13% versus 1%;P =0.0216) but less frequently a classic lacunar syndrome (50% versus 81%;P =0.0009) than the SBGI group. On a multivariate analysis, both arterial and heart diseases were independently associated with the SCOI group. Conclusions— Symptomatic SCOIs detected by DWI may be associated with large-vessel and heart diseases and should be distinguished from lacunar infarcts.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"41 1","pages":"1541-1544"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89897554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016463.01398.D0
Tsutomu Sasaki, Manabu Watanabe, Y. Nagai, Taku Hoshi, M. Takasawa, M. Nukata, A. Taguchi, K. Kitagawa, N. Kinoshita, M. Matsumoto
Background and Purpose— Higher plasma total homocysteine (tHcy) levels have been associated with carotid atherosclerosis and cerebral infarction in whites. However, data regarding such associations are limited for Asians. This study examined associations between tHcy levels and severity of carotid atherosclerosis in Japanese subjects. Additionally, because lacunar infarction is the most prevalent type of ischemic stroke in Japan, we also investigated its associations with tHcy levels. Methods— The subjects were 152 Japanese patients (age, 66.2±11.0 years) at our hospital. Using ultrasound, we evaluated severity of carotid atherosclerosis by plaque score, which is defined by the sum of all plaque (intima-media thickness ≥1.1 mm) height in bilateral carotid arteries. In 112 of 152 patients, the existence of lacunar infarction was evaluated on brain MRI scans. Results— A moderate linear association was found between tHcy levels and plaque score (r =0.48, P <0.0001). Moreover, tHcy level was associated with plaque score (&bgr;=0.26, P <0.001) independently of traditional atherosclerotic risk factors. In logistic regression analyses, each 1-&mgr;mol/L-higher tHcy level was associated with a 1.37-fold-higher [95% confidence interval (CI), 1.19 to 1.58] likelihood for lacunar infarction, increasing the likelihood by 1.22-fold (95% CI, 1.04 to 1.43) independently of traditional atherosclerotic risk factors. Conclusions— Higher tHcy levels appear to have associations with increased severity of carotid atherosclerotic plaques and prevalent lacunar infarction in the Japanese. Larger prospective studies are necessary to establish whether higher tHcy levels serve as a harbinger for insidious carotid and cerebrovascular diseases.
背景和目的:较高的血浆总同型半胱氨酸(tHcy)水平与白人颈动脉粥样硬化和脑梗死有关。然而，有关亚洲人这种关联的数据有限。本研究调查了日本受试者中tHcy水平与颈动脉粥样硬化严重程度之间的关系。此外，由于腔隙性梗死是日本最常见的缺血性卒中类型，我们也研究了其与tHcy水平的关系。方法:选取我院收治的日本患者152例(年龄66.2±11.0岁)。通过超声，我们通过斑块评分来评估颈动脉粥样硬化的严重程度，斑块评分由双侧颈动脉中所有斑块(内膜-中膜厚度≥1.1 mm)高度的总和来定义。在152例患者中，112例通过脑MRI扫描评估腔隙性梗死的存在。结果:tHcy水平与斑块评分之间存在中度线性关联(r =0.48, P <0.0001)。此外，tHcy水平与斑块评分相关(&bgr;=0.26, P <0.001)，独立于传统的动脉粥样硬化危险因素。在logistic回归分析中，tHcy水平每升高1 mol/ l，腔隙性梗死的可能性增加1.37倍[95%置信区间(CI)， 1.19至1.58]，独立于传统动脉粥样硬化危险因素的可能性增加1.22倍(95% CI, 1.04至1.43)。结论:在日本，较高的tHcy水平似乎与颈动脉粥样硬化斑块的严重程度增加和普遍的腔隙性梗死有关。需要更大规模的前瞻性研究来确定高tHcy水平是否预示着颈内动脉和脑血管疾病的发生。
{"title":"Association of Plasma Homocysteine Concentration With Atherosclerotic Carotid Plaques and Lacunar Infarction","authors":"Tsutomu Sasaki, Manabu Watanabe, Y. Nagai, Taku Hoshi, M. Takasawa, M. Nukata, A. Taguchi, K. Kitagawa, N. Kinoshita, M. Matsumoto","doi":"10.1161/01.STR.0000016463.01398.D0","DOIUrl":"https://doi.org/10.1161/01.STR.0000016463.01398.D0","url":null,"abstract":"Background and Purpose— Higher plasma total homocysteine (tHcy) levels have been associated with carotid atherosclerosis and cerebral infarction in whites. However, data regarding such associations are limited for Asians. This study examined associations between tHcy levels and severity of carotid atherosclerosis in Japanese subjects. Additionally, because lacunar infarction is the most prevalent type of ischemic stroke in Japan, we also investigated its associations with tHcy levels. Methods— The subjects were 152 Japanese patients (age, 66.2±11.0 years) at our hospital. Using ultrasound, we evaluated severity of carotid atherosclerosis by plaque score, which is defined by the sum of all plaque (intima-media thickness ≥1.1 mm) height in bilateral carotid arteries. In 112 of 152 patients, the existence of lacunar infarction was evaluated on brain MRI scans. Results— A moderate linear association was found between tHcy levels and plaque score (r =0.48, P <0.0001). Moreover, tHcy level was associated with plaque score (&bgr;=0.26, P <0.001) independently of traditional atherosclerotic risk factors. In logistic regression analyses, each 1-&mgr;mol/L-higher tHcy level was associated with a 1.37-fold-higher [95% confidence interval (CI), 1.19 to 1.58] likelihood for lacunar infarction, increasing the likelihood by 1.22-fold (95% CI, 1.04 to 1.43) independently of traditional atherosclerotic risk factors. Conclusions— Higher tHcy levels appear to have associations with increased severity of carotid atherosclerotic plaques and prevalent lacunar infarction in the Japanese. Larger prospective studies are necessary to establish whether higher tHcy levels serve as a harbinger for insidious carotid and cerebrovascular diseases.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"123 1","pages":"1493-1496"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85288577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016332.37292.59
N. Alkayed, T. Goyagi, H. Joh, Judith A. Klaus, D. Harder, R. Traystman, P. Hurn
Background and Purpose— Transient ischemic attack (TIA) is a risk factor for stroke. However, TIA may also serve as a preconditioning stimulus, reducing damage from subsequent stroke. We tested the hypothesis that experimental TIA induces expression of P450 2C11, an arachidonic acid epoxygenase that produces vasodilator epoxyeicosatrienoic acids, leading to increased tissue perfusion and reduced stroke damage. Methods— Wistar rats underwent three 10-minute middle cerebral artery occlusions (TIA) or sham surgery. Three days later, animals were subjected to 2-hour middle cerebral artery occlusion and 24 hours of reperfusion. Brains were stained with 2,3,5-triphenyltetrazolium chloride for infarct size measurement or processed for quantification of P450 2C11 mRNA and protein with the use of RNase protection assay and Western blotting. Regional cerebral blood flow (CBF) at the end of 2-hour ischemia was measured in separate groups of rats with iodoantipyrine autoradiography. Results— Cerebral infarct was reduced by >50% in TIA- versus sham-preconditioned animals. 2C11 mRNA and protein were increased in ipsilateral hemisphere by 3 days after TIA but not sham surgery. Induction of 2C11 by TIA was also evident in ipsilateral hemisphere at 24 hours after 2-hour middle cerebral artery occlusion and 24 hours of reperfusion. End-ischemic regional CBF was not different between TIA- and sham-pretreated groups. Conclusions— We conclude that experimental TIA induces ischemic tolerance by a mechanism temporally linked to upregulation of P450 2C11. Enzyme induction does not attenuate ischemic severity by amplifying end-ischemic CBF.
{"title":"Neuroprotection and P450 2C11 Upregulation After Experimental Transient Ischemic Attack","authors":"N. Alkayed, T. Goyagi, H. Joh, Judith A. Klaus, D. Harder, R. Traystman, P. Hurn","doi":"10.1161/01.STR.0000016332.37292.59","DOIUrl":"https://doi.org/10.1161/01.STR.0000016332.37292.59","url":null,"abstract":"Background and Purpose— Transient ischemic attack (TIA) is a risk factor for stroke. However, TIA may also serve as a preconditioning stimulus, reducing damage from subsequent stroke. We tested the hypothesis that experimental TIA induces expression of P450 2C11, an arachidonic acid epoxygenase that produces vasodilator epoxyeicosatrienoic acids, leading to increased tissue perfusion and reduced stroke damage. Methods— Wistar rats underwent three 10-minute middle cerebral artery occlusions (TIA) or sham surgery. Three days later, animals were subjected to 2-hour middle cerebral artery occlusion and 24 hours of reperfusion. Brains were stained with 2,3,5-triphenyltetrazolium chloride for infarct size measurement or processed for quantification of P450 2C11 mRNA and protein with the use of RNase protection assay and Western blotting. Regional cerebral blood flow (CBF) at the end of 2-hour ischemia was measured in separate groups of rats with iodoantipyrine autoradiography. Results— Cerebral infarct was reduced by >50% in TIA- versus sham-preconditioned animals. 2C11 mRNA and protein were increased in ipsilateral hemisphere by 3 days after TIA but not sham surgery. Induction of 2C11 by TIA was also evident in ipsilateral hemisphere at 24 hours after 2-hour middle cerebral artery occlusion and 24 hours of reperfusion. End-ischemic regional CBF was not different between TIA- and sham-pretreated groups. Conclusions— We conclude that experimental TIA induces ischemic tolerance by a mechanism temporally linked to upregulation of P450 2C11. Enzyme induction does not attenuate ischemic severity by amplifying end-ischemic CBF.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"4 1","pages":"1677-1684"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91252784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016970.51004.D9
D. Georgiadis, S. Schwarz, A. Aschoff, S. Schwab
Background and Purpose— We compared the clinical course of 36 consecutive patients with severe acute ischemic stroke (more than two thirds of the middle cerebral artery territory) treated with hemicraniectomy (CE; n=17) or moderate hypothermia (MH; n=19) in terms of intracranial pressure control, mortality, and specific treatment parameters. Methods— Over a period of 18 months, patients with severe ischemic stroke were treated with CE when the nondominant hemisphere was affected and with MH when the dominant hemisphere was affected. MH (33°C) was induced with either cold blankets and fans (n=11) or endovascular cooling (n=8). Intracranial pressure was monitored invasively in all cases. Results— Age, sex, cranial CT findings, level of consciousness, and time to treatment were similar between the 2 groups; significant differences were noted in National Institute of Health Stroke Scale (NIHSS) score (20 [range, 18 to 22] and 17 [range, 16 to 18] for MH and CE, respectively) but were not present when NIHSS score was corrected for aphasia (17 [range, 15 to 19] and 17 [range, 16 to 18] for MH and CE, respectively). Mortality was 12% for CE and 47% for MH; 1 patient treated with MH died as a result of treatment complications (sepsis) and 3 of intracranial pressure crises that occurred during rewarming. Duration of mechanical ventilation and of neurological intensive care unit stay did not significantly differ, but duration of catecholamine application and maximal catecholamine dosage were significantly higher in the MH group. Conclusions— In patients with severe ischemic stroke, CE results in lower mortality and lower complication rates compared with MH. Both treatment modalities, however, are associated with intensive medical treatment and a prolonged stay in the neurological intensive care unit.
{"title":"Hemicraniectomy and Moderate Hypothermia in Patients With Severe Ischemic Stroke","authors":"D. Georgiadis, S. Schwarz, A. Aschoff, S. Schwab","doi":"10.1161/01.STR.0000016970.51004.D9","DOIUrl":"https://doi.org/10.1161/01.STR.0000016970.51004.D9","url":null,"abstract":"Background and Purpose— We compared the clinical course of 36 consecutive patients with severe acute ischemic stroke (more than two thirds of the middle cerebral artery territory) treated with hemicraniectomy (CE; n=17) or moderate hypothermia (MH; n=19) in terms of intracranial pressure control, mortality, and specific treatment parameters. Methods— Over a period of 18 months, patients with severe ischemic stroke were treated with CE when the nondominant hemisphere was affected and with MH when the dominant hemisphere was affected. MH (33°C) was induced with either cold blankets and fans (n=11) or endovascular cooling (n=8). Intracranial pressure was monitored invasively in all cases. Results— Age, sex, cranial CT findings, level of consciousness, and time to treatment were similar between the 2 groups; significant differences were noted in National Institute of Health Stroke Scale (NIHSS) score (20 [range, 18 to 22] and 17 [range, 16 to 18] for MH and CE, respectively) but were not present when NIHSS score was corrected for aphasia (17 [range, 15 to 19] and 17 [range, 16 to 18] for MH and CE, respectively). Mortality was 12% for CE and 47% for MH; 1 patient treated with MH died as a result of treatment complications (sepsis) and 3 of intracranial pressure crises that occurred during rewarming. Duration of mechanical ventilation and of neurological intensive care unit stay did not significantly differ, but duration of catecholamine application and maximal catecholamine dosage were significantly higher in the MH group. Conclusions— In patients with severe ischemic stroke, CE results in lower mortality and lower complication rates compared with MH. Both treatment modalities, however, are associated with intensive medical treatment and a prolonged stay in the neurological intensive care unit.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"11 1","pages":"1584-1588"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79072738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016344.49819.F7
R. Macwalter, S. Wong, K. Wong, G. Stewart, C. Fraser, H. Fraser, Y. Ersoy, S. Ogston, Rouling Chen
Background and Purpose— The purpose of this study was to investigate renal function as a long-term predictor of mortality in patients hospitalized for acute stroke. Methods— This was a cohort study done in a Scottish tertiary teaching hospital. Participants included 2042 (993 male) unselected consecutive stroke patients (mean age, 73 years) admitted to hospital within 48 hours of stroke between1988 and 1994. Follow-up was up to 7 years. Main outcome measure was all-cause mortality. Results— The total number of deaths at the end of follow-up was 1026. Most subjects (1512) had creatinine <124 &mgr;mol/L. The mean calculated creatinine clearance was 54.8 mL/min (SD, 23 mL/min). Renal function indexes were analyzed by quartiles with Cox proportional-hazards model. Stroke survivors had higher calculated creatinine clearance and lower serum creatinine, urea, and ratios of urea to creatinine. Calculated creatinine clearance ≥51.27 mL/min significantly predicted better long-term survival in these stroke patients even after adjustment for confounders (age, neurological score, ischemic heart disease, hypertension, smoking, and diuretic use). Similarly, creatinine ≥119 &mgr;mol/L “relative risk (RR), 1.59; 95% confidence interval (CI), 1.32 to 1.92”, urea 6.8 to 8.9 mmol/L (RR, 1.34; 95% CI, 1.09 to 1.65) or ≥9 mmol/L (RR, 1.74; 95% CI, 1.42 to 2.13), and ratio of urea to creatinine ≥0.08573 mmol/&mgr;mol (RR, 1.24; 95% CI, 1.03 to 1.50) remained significant predictors of mortality after adjustment for confounders. Conclusions— After acute stroke, patients with reduced admission calculated creatinine clearance, raised serum creatinine and urea concentrations (even within conventional reference intervals), and raised ratio of urea to creatinine had a higher mortality risk. This finding may be used to stratify risk and target interventions, eg, the use of angiotensin-converting enzyme inhibitors.
{"title":"Does Renal Dysfunction Predict Mortality After Acute Stroke?: A 7-Year Follow-Up Study","authors":"R. Macwalter, S. Wong, K. Wong, G. Stewart, C. Fraser, H. Fraser, Y. Ersoy, S. Ogston, Rouling Chen","doi":"10.1161/01.STR.0000016344.49819.F7","DOIUrl":"https://doi.org/10.1161/01.STR.0000016344.49819.F7","url":null,"abstract":"Background and Purpose— The purpose of this study was to investigate renal function as a long-term predictor of mortality in patients hospitalized for acute stroke. Methods— This was a cohort study done in a Scottish tertiary teaching hospital. Participants included 2042 (993 male) unselected consecutive stroke patients (mean age, 73 years) admitted to hospital within 48 hours of stroke between1988 and 1994. Follow-up was up to 7 years. Main outcome measure was all-cause mortality. Results— The total number of deaths at the end of follow-up was 1026. Most subjects (1512) had creatinine <124 &mgr;mol/L. The mean calculated creatinine clearance was 54.8 mL/min (SD, 23 mL/min). Renal function indexes were analyzed by quartiles with Cox proportional-hazards model. Stroke survivors had higher calculated creatinine clearance and lower serum creatinine, urea, and ratios of urea to creatinine. Calculated creatinine clearance ≥51.27 mL/min significantly predicted better long-term survival in these stroke patients even after adjustment for confounders (age, neurological score, ischemic heart disease, hypertension, smoking, and diuretic use). Similarly, creatinine ≥119 &mgr;mol/L “relative risk (RR), 1.59; 95% confidence interval (CI), 1.32 to 1.92”, urea 6.8 to 8.9 mmol/L (RR, 1.34; 95% CI, 1.09 to 1.65) or ≥9 mmol/L (RR, 1.74; 95% CI, 1.42 to 2.13), and ratio of urea to creatinine ≥0.08573 mmol/&mgr;mol (RR, 1.24; 95% CI, 1.03 to 1.50) remained significant predictors of mortality after adjustment for confounders. Conclusions— After acute stroke, patients with reduced admission calculated creatinine clearance, raised serum creatinine and urea concentrations (even within conventional reference intervals), and raised ratio of urea to creatinine had a higher mortality risk. This finding may be used to stratify risk and target interventions, eg, the use of angiotensin-converting enzyme inhibitors.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"2 1","pages":"1630-1635"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86436317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016828.62708.21
S. Mugikura, Shoki Takahashi, S. Higano, R. Shirane, Y. Sakurai, S. Yamada
Background and Purpose— We encountered several patients with childhood onset of moyamoya disease in whom the ipsilateral anterior and posterior circulations were predominantly involved. This study investigated whether this is an angiographic characteristic of this disease. Methods— We evaluated steno-occlusive lesions on angiograms of 85 patients with pediatric onset of moyamoya disease, using two 4-stage angiographic classification scales for the internal carotid artery and posterior cerebral artery systems (ICA and PCA staging, respectively) and determined whether lesions with more advanced ICA and PCA stages were on ipsilateral sides. Results— When positive laterality was defined as the presence of a difference by ≥1 stage between the stages on both sides, lateralities in the ICA stages and in the PCA stages were present in 40 (47%) and 27 patients (32%), respectively. Lesions with more advanced ICA and PCA stages were on the same side, with significant probability (P =0.024, Fisher’s exact test). Lateralities in both ICA and PCA lesions were found in 17 patients. In 14 (82%) of the 17 patients, the more advanced side of ICA lesions was the same as that of PCA lesions, while it was contralateral in 3 patients (18%). Conclusions— In pediatric-onset moyamoya disease, asymmetrical involvement of bilateral ICAs and PCAs was common, and the ipsilateral ICA and PCA tended to be predominantly involved.
{"title":"Predominant Involvement of Ipsilateral Anterior and Posterior Circulations in Moyamoya Disease","authors":"S. Mugikura, Shoki Takahashi, S. Higano, R. Shirane, Y. Sakurai, S. Yamada","doi":"10.1161/01.STR.0000016828.62708.21","DOIUrl":"https://doi.org/10.1161/01.STR.0000016828.62708.21","url":null,"abstract":"Background and Purpose— We encountered several patients with childhood onset of moyamoya disease in whom the ipsilateral anterior and posterior circulations were predominantly involved. This study investigated whether this is an angiographic characteristic of this disease. Methods— We evaluated steno-occlusive lesions on angiograms of 85 patients with pediatric onset of moyamoya disease, using two 4-stage angiographic classification scales for the internal carotid artery and posterior cerebral artery systems (ICA and PCA staging, respectively) and determined whether lesions with more advanced ICA and PCA stages were on ipsilateral sides. Results— When positive laterality was defined as the presence of a difference by ≥1 stage between the stages on both sides, lateralities in the ICA stages and in the PCA stages were present in 40 (47%) and 27 patients (32%), respectively. Lesions with more advanced ICA and PCA stages were on the same side, with significant probability (P =0.024, Fisher’s exact test). Lateralities in both ICA and PCA lesions were found in 17 patients. In 14 (82%) of the 17 patients, the more advanced side of ICA lesions was the same as that of PCA lesions, while it was contralateral in 3 patients (18%). Conclusions— In pediatric-onset moyamoya disease, asymmetrical involvement of bilateral ICAs and PCAs was common, and the ipsilateral ICA and PCA tended to be predominantly involved.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"38 1","pages":"1497-1500"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74036655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.STR.0000016404.14407.77
C. Sommer, A. Fahrner, M. Kiessling
Background and Purpose— Excitotoxic activation of glutamate receptors is currently thought to play a pivotal role in delayed neuronal death (DND) of highly vulnerable CA1 neurons in the gerbil hippocampus after transient global ischemia. Postischemic degeneration of these neurons can be prevented by “preconditioning” with a short sublethal ischemic stimulus. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of ligand binding to excitatory glutamate and/or inhibitory &ggr;-aminobutyric acid (GABA)A receptors compared with ischemia severe enough to induce DND. Methods— With the use of quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801 and [3H]&agr;-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to excitatory N-methyl-d-aspartate (NMDA) and AMPA receptors as well as [3H]muscimol to inhibitory GABAA receptors in hippocampal subfields CA1, CA3, and the dentate gyrus were analyzed in 2 experimental paradigms. Gerbils were subjected to (1) a 5-minute ischemic period resulting in DND of CA1 neurons and (2) a 2.5-minute period of ischemia mediating tolerance induction. Results— [3H]MK-801 and [3H]AMPA binding values to excitatory NMDA and AMPA receptors showed a delayed decrease in relatively ischemia-resistant CA3 and dentate gyrus despite maintained neuronal cell density. [3H]Muscimol binding to GABAA receptors in CA1 neurons was transiently but significantly increased after preconditioning but not after global ischemia with consecutive neuronal death. Conclusions— Downregulation of ligand binding to glutamate receptors in relatively ischemia-resistant CA3 and dentate gyrus neurons destined to survive suggests marked synaptic reorganization processes despite maintained structural integrity. More importantly, upregulation of binding to inhibitory GABAA receptors in the hippocampus indicates a relative shift between inhibitory and excitatory neurotransmission that we suggest may participate in endogenous postischemic neuroprotection.
{"title":"[3H]Muscimol Binding to &ggr;-Aminobutyric AcidA Receptors Is Upregulated in CA1 Neurons of the Gerbil Hippocampus in the Ischemia-Tolerant State","authors":"C. Sommer, A. Fahrner, M. Kiessling","doi":"10.1161/01.STR.0000016404.14407.77","DOIUrl":"https://doi.org/10.1161/01.STR.0000016404.14407.77","url":null,"abstract":"Background and Purpose— Excitotoxic activation of glutamate receptors is currently thought to play a pivotal role in delayed neuronal death (DND) of highly vulnerable CA1 neurons in the gerbil hippocampus after transient global ischemia. Postischemic degeneration of these neurons can be prevented by “preconditioning” with a short sublethal ischemic stimulus. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of ligand binding to excitatory glutamate and/or inhibitory &ggr;-aminobutyric acid (GABA)A receptors compared with ischemia severe enough to induce DND. Methods— With the use of quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801 and [3H]&agr;-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to excitatory N-methyl-d-aspartate (NMDA) and AMPA receptors as well as [3H]muscimol to inhibitory GABAA receptors in hippocampal subfields CA1, CA3, and the dentate gyrus were analyzed in 2 experimental paradigms. Gerbils were subjected to (1) a 5-minute ischemic period resulting in DND of CA1 neurons and (2) a 2.5-minute period of ischemia mediating tolerance induction. Results— [3H]MK-801 and [3H]AMPA binding values to excitatory NMDA and AMPA receptors showed a delayed decrease in relatively ischemia-resistant CA3 and dentate gyrus despite maintained neuronal cell density. [3H]Muscimol binding to GABAA receptors in CA1 neurons was transiently but significantly increased after preconditioning but not after global ischemia with consecutive neuronal death. Conclusions— Downregulation of ligand binding to glutamate receptors in relatively ischemia-resistant CA3 and dentate gyrus neurons destined to survive suggests marked synaptic reorganization processes despite maintained structural integrity. More importantly, upregulation of binding to inhibitory GABAA receptors in the hippocampus indicates a relative shift between inhibitory and excitatory neurotransmission that we suggest may participate in endogenous postischemic neuroprotection.","PeriodicalId":22274,"journal":{"name":"Stroke: Journal of the American Heart Association","volume":"67 1","pages":"1698-1705"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91394782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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