Adhesion of Leukocytes to Cerebral Venules Precedes Neuronal Cell Death and Is Sufficient to Trigger Tissue Damage After Cerebral Ischemia

BackgroundLeukocytes contribute to tissue damage after cerebral ischemia;however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury. MethodsMale wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII-/-)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology. ResultsIn wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%;p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold (p < 0.01);the number of intraparenchymal leukocytes was not affected. ConclusionsOur findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage

Preoperative obliteration of choroidal arteries in the treatment of large hypervascular tumors in the lateral ventricle

BACKGROUND: Removal of large hypervascular tumors in the lateral ventricle still poses a surgical challenge. These tumors are usually fed from choroidal arteries, and vascular control is typically performed late during the removal. We aimed to evaluate the clinical efficacy of our strategy for persistent preoperative obliteration of feeders from the choroidal arteries to manage large hypervascular tumors in the lateral ventricle. METHODS: We retrospectively analyzed six patients with hypervascular tumors in the lateral ventricle. We first attempted to obstruct feeders using endovascular treatment, and, if unavailable, performed initial microsurgical occlusion through the temporal horn for the staged tumor removal. RESULTS: In all patients, feeder obliteration was successfully performed; the anterior choroidal arteries were occluded by the endovascular treatment and microsurgical occlusion in one and five patients, respectively, while the lateral posterior choroidal arteries were occluded via endovascular treatment in four patients. No patients had permanent symptoms due to feeder obliteration, and tumor devascularization was achieved at the mean rate of 69.9%. During the tumor removal, the mean blood loss volume was 253 ml. No postoperative hemorrhage had occurred, and all patients scored ≤ 2 on the modified Rankin Scale at six months post-removal. CONCLUSIONS: Although further studies are warranted, persistent feeder obliteration of choroidal arteries could be an effective treatment strategy against large hypervascular tumors in the lateral ventricle

The bifurcation angle is associated with the progression of saccular aneurysms

The role of the bifurcation angle in progression of saccular intracranial aneurysms (sIAs) has been undetermined. We, therefore, assessed the association of bifurcation angles with aneurysm progression using a bifurcation-type aneurysm model in rats and anterior communicating artery aneurysms in a multicenter case-control study. Aneurysm progression was defined as growth by ≥ 1 mm or rupture during observation, and controls as progression-free for 30 days in rats and ≥ 36 months in humans. In the rat model, baseline bifurcation angles were significantly wider in progressive aneurysms than in stable ones. In the case-control study, 27 and 65 patients were enrolled in the progression and control groups. Inter-observer agreement for the presence or absence of the growth was excellent (κ coefficient, 0.82; 95% CI, 0.61-1.0). Multivariate logistic regression analysis showed that wider baseline bifurcation angles were significantly associated with subsequent progressions. The odds ratio for the progression of the second (145°-179°) or third (180°-274°) tertiles compared to the first tertile (46°-143°) were 5.5 (95% CI, 1.3-35). Besides, the bifurcation angle was positively correlated with the size of aneurysms (Spearman's rho, 0.39; P = 0.00014). The present study suggests the usefulness of the bifurcation angle for predicting the progression of sIAs

Role of Hypoxic OPC in Angiogenesis

Background－Oligodendrocyte precursor cells (OPCs) regulate neuronal, glial, and vascular systems in diverse ways and display phenotypic heterogeneity beyond their established role as a reservoir for mature oligodendrocytes. However, the detailed phenotypic changes of OPCs after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPCs in the ischemic brain. Methods and Results－The behavior of OPCs was evaluated in a mouse model of ischemic stroke produced by transient middle cerebral artery occlusion in vivo. For in vitro experiments, the phenotypic change of OPCs after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPCs was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPCs in the cerebral cortex were increased alongside poststroke angiogenesis in a mouse model of middle cerebral artery occlusion. In vitro RNA‐seq analysis revealed that primary cultured OPCs increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPCs secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPCs. Hypoxic OPC‐derived conditioned media increased the viability and tube formation of endothelial cells. In vivo studies also demonstrated that 5 consecutive daily treatments with hypoxic OPC‐conditioned media, beginning 2 days after middle cerebral artery occlusion, facilitated poststroke angiogenesis, alleviated infarct volume, and improved functional disabilities. Conclusions－Following cerebral ischemia, the phenotype of OPCs in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPCs secretome would provide a novel therapeutic option for stroke

Detrimental effect of anemia after mechanical thrombectomy on functional outcome in patients with ischemic stroke

BackgroundAnemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown.MethodsIn a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11–13 g/dL and 10–12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations &lt;11 g/dL and &lt; 10 g/dL, respectively). A 3-month modified Rankin Scale score of 0–2 indicated a favorable outcome.ResultsOf 470 patients, 166 were classified into the no anemia group, 168 into the mild anemia group, and 136 into the moderate-to-severe anemia group. Patients in the moderate-to-severe anemia group were older and more commonly had congestive heart failure than those in the other groups. Patients in the moderate-to-severe anemia group also had more device passes than those in the other groups (p &lt; 0.001). However, no difference was observed in the rate of final extended thrombolysis in cerebral infarction ≥2b reperfusion or intracranial hemorrhage among the groups. A favorable outcome was less frequently achieved in the moderate-to-severe anemia group than in the no anemia group (adjusted odds ratio, 0.46; 95% confidence interval, 0.26–0.81) independent of the baseline Hb concentration. A restricted cubic spline model with three knots showed that the adjusted odds ratio for a favorable outcome was lower in patients with lower Hb concentrations within 24 h after MT.ConclusionModerate-to-severe anemia within 24 h after MT is independently associated with a reduced likelihood of a favorable outcome.Clinical trial registrationhttps://www.clinicaltrials.gov, NCT02251665

Effects of Comprehensive Stroke Care Capabilities on In-Hospital Mortality of Patients with Ischemic and Hemorrhagic Stroke: J-ASPECT Study

Background: The effectiveness of comprehensive stroke center (CSC) capabilities on stroke mortality remains uncertain. We performed a nationwide study to examine whether CSC capabilities influenced in-hospital mortality of patients with ischemic and hemorrhagic stroke. Methods and Results: Of the 1,369 certified training institutions in Japan, 749 hospitals responded to a questionnaire survey regarding CSC capabilities that queried the availability of personnel, diagnostic techniques, specific expertise, infrastructure, and educational components recommended for CSCs. Among the institutions that responded, data on patients hospitalized for stroke between April 1, 2010 and March 31, 2011 were obtained from the Japanese Diagnosis Procedure Combination database. In-hospital mortality was analyzed using hierarchical logistic regression analysis adjusted for age, sex, level of consciousness on admission, comorbidities, and the number of fulfilled CSC items in each component and in total. Data from 265 institutions and 53,170 emergency-hospitalized patients were analyzed. Mortality rates were 7.8% for patients with ischemic stroke, 16.8% for patients with intracerebral hemorrhage (ICH), and 28.1% for patients with subarachnoid hemorrhage (SAH). Mortality adjusted for age, sex, and level of consciousness was significantly correlated with personnel, infrastructural, educational, and total CSC scores in patients with ischemic stroke. Mortality was significantly correlated with diagnostic, educational, and total CSC scores in patients with ICH and with specific expertise, infrastructural, educational, and total CSC scores in patients with SAH. Conclusions: CSC capabilities were associated with reduced in-hospital mortality rates, and relevant aspects of care were found to be dependent on stroke type

Consciousness Level and Off‐Hour Admission Affect Discharge Outcome of Acute Stroke Patients: A J‐ASPECT Study

Background-Poor outcomes have been reported for stroke patients admitted outside of regular working hours. However, few studies have adjusted for case severity. In this nationwide assessment, we examined relationships between hospital admission time and disabilities at discharge while considering case severity. Methods and Results-We analyzed 35 685 acute stroke patients admitted to 262 hospitals between April 2010 and May 2011 for ischemic stroke (IS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). The proportion of disabilities/death at discharge as measured by the modified Rankin Scale (mRS) was quantified. We constructed 2 hierarchical logistic regression models to estimate the effect of admission time, one adjusted for age, sex, comorbidities, and number of beds; and the second adjusted for the effect of consciousness levels and the above variables at admission. The percentage of severe disabilities/death at discharge increased for patients admitted outside of regular hours (22.8%, 27.2%, and 28.2% for working-hour, off-hour, and nighttime; P<0.001). These tendencies were significant in the bivariate and multivariable models without adjusting for consciousness level. However, the effects of off-hour or nighttime admissions were negated when adjusted for consciousness levels at admission (adjusted OR, 1.00 and 0.99; 95% CI, 1.00 to 1.13 and 0.89 to 1.10; P=0.067 and 0.851 for off-hour and nighttime, respectively, versus working-hour). The same trend was observed when each stroke subtype was stratified. Conclusions-The well-known off-hour effect might be attributed to the severely ill patient population. Thus, sustained stroke care that is sufficient to treat severely ill patients during off-hours is important

ヒト ドウミャク コウカ ビョウヘン ニ オケル レクチン ヨウ サンカ LDL ジュヨウタイ ノ ハツゲン ニ カンスル ケンキュウ

京都大学0048新制・課程博士博士(医学)甲第8824号医博第2327号新制||医||761(附属図書館)UT51-2001-F154京都大学大学院医学研究科脳統御医化学系専攻(主査)教授 中尾 一和, 教授 篠山 重威, 教授 橋本 信夫学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA