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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The progress of a stroke concerns the activation of endothelial cells and platelets. We measured the plasma activities of von Willebrand factor (vWf) and the serum levels of soluble thrombomodulin (sTM) as endothelial markers, and the plasma concentrations of soluble P-selectin (sP-selectin) and soluble E-selectin (sE-selectin) as adhesion molecules during the acute (within 48 h from onset) and subacute (after 1 month from the onset) phases of 52 consecutive patients with acute ischemic stroke and 86 age-matched control subjects. The plasma vWf activities and levels of sP-and sE-selectins in stroke patients were significantly elevated compared with those in controls during both the acute and subacute phases. The serum levels of sTM in stroke patients were significantly higher than those in controls only during the subacute phase. In atherothrombotic infarction, the vWf activities and the levels of sP-selectin, markers for endothelial and platelet activation, remained higher until the subacute phase compared with controls, and the concentrations of sTM, a marker for endothelial injury, were increased during the subacute phase compared with during the acute phase. In lacunar infarction, the levels of sTM and sE-selectin of patients were higher only during the acute phase than controls. These findings suggest that the endothelial cell damage might be maintained until the subacute phase in atherothrombotic infarction, whereas it is remarkable only during the acute phase in lacunar infarction. The evaluation of endothelial markers and adhesion molecules would represent the pathophysiological states of stroke and may provide useful information for the treatment of the ischemic infarction.
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PMID:Endothelial markers and adhesion molecules in acute ischemic stroke--sequential change and differences in stroke subtype. 1188 28

Early intervention after acute ischemic stroke is essential to minimize brain cell injury. Although reperfusion of the ischemic brain is the treatment of choice for acute stroke, reperfusion itself may cause additional injury. The inflammatory cascade, characterized in part by early leukocyte interaction with endothelium, may contribute to this additional injury to blood vessels and surrounding brain tissue, extending the area of infarction. The selectin family of adhesion molecules mediates the initial, rolling and tethering of leukocytes to endothelium. P-selectin is rapidly expressed on ischemic endothelium in the brain vasculature, and L-selectin is expressed on leukocytes. Blocking the selectin-mediated tethering step may limit the inflammatory component of reperfusion injury in the brain. Fucoidin (FCN), a competitive inhibitor of P- and L-selectin, has been reported to decrease leukocyte accumulation during reperfusion of other organs. The effect of both leukocyte and endothelial selectin inhibition after cerebral ischemia and reperfusion has not been previously examined. The purpose of this study was to determine the effects of selectin adhesion molecule blockade on cerebral infarction size and neurological function after middle cerebral artery occlusion and reperfusion (MCAO-R) in the rat. MCAO was induced using the filament method. All animals were subjected to 4 h of MCAO and 24 h of reperfusion. After 24 h, brains were analyzed for size of infarction. Neurological function was assessed during stroke and 24 h after reperfusion. Two groups were studied, an untreated control group (n = 9) and a group treated with the selectin inhibitor, fucoidin (25 mg kg(-1)) (n = 9). We found that selectin blockade significantly reduced cerebral infarction size by 50% (p < 0.05) and improved neurological function (p < 0.05). In addition, a trend toward decreased cerebral edema was demonstrated with selectin inhibition. These results indicate that treatment of the blood and the endothelium with a selectin anti-inflammatory agent is protective after focal stroke and reperfusion in the rat.
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PMID:Protective effects of inhibiting both blood and vascular selectins after stroke and reperfusion. 1195 13

Abnormalities of haemorheology (plasma viscosity, fibrinogen), endothelial function [von Willebrand factor (vWf)], platelet activation (soluble P-selectin) and thrombogenesis [plasminogen activator inhibitor (PAI), and fibrin D-dimer] are common in cardiovascular disease. We investigated changes in these markers in 86 patients (58 males) presenting with acute stroke (all age < 75 years, with ictus < 12 h), and sequential changes at six time points (baseline on admission, 48 h, 1 week, 2 weeks, 3 months and 6 months following the onset of stroke). Baseline plasma viscosity, haematocrit, fibrinogen, vWf, PAI, soluble P-selectin and fibrin D-dimer levels were increased in the acute stroke patients compared with 35 age-matched and sex-matched controls. Following admission, there were significant increases in haematocrit at 2 weeks, vWf at 48 h and 1 week, fibrinogen at 1 week, PAI at 48 h and 1 and 2 weeks, soluble P-selectin at 48 h, and fibrin D-dimer at 48 h and 1 week following admission. Using univariate 'time to event' analysis, high (> median) mean age (log-rank test, P = 0.0262), diastolic blood pressure (P = 0.01), haematocrit (P = 0.0234), PAI-1 (P = 0.0066) and fibrin D-dimer levels (P = 0.0356) were associated with a shortened event-free survival. Using a multivariate Cox survival analysis, only PAI-1 levels remained an independent predictor of survival (P = 0.0349). We conclude that acute stroke patients have marked baseline abnormalities of haemorheology, endothelial disturbance, thrombogenesis, platelet activation and abnormal fibrinolysis, with further changes over the subsequent follow-up period. Abnormal thrombogenesis and fibrinolysis may significantly influence survival in patients with acute stroke. These changes may have potential implications for the pathogenesis of stroke and its complications, although the possibility remains that we are documenting an acute phase response that previous studies, which included stroke patients with a wide time range since ictus onset, have neglected to consider.
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PMID:Sequential alterations in haemorheology, endothelial dysfunction, platelet activation and thrombogenesis in relation to prognosis following acute stroke: The West Birmingham Stroke Project. 1203

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90

The selectins are a family of cell-adhesion proteins that mediate the rolling of leukocytes on activated endothelial cells through the recognition of the carbohydrate epitope sialyl Lewis(x) (sLe(x)). Control of the leukocyte-endothelial cell adhesion process may prove useful in cases where excess recruitment of leukocytes can contribute to acute diseases such as stroke and reperfusion injury and chronic diseases such as psoriasis and rheumatoid arthritis. The development of molecules that block the interactions between sLe(x) and the selectins has become an active area of research. In this review, we will highlight the various approaches taken toward the development of sLe(x) mimetics as antagonists of E- and P-selectin, including the use of structural information about the selectins and their interactions with sLe(x) that have been revealed through the use of NMR, protein crystallography and molecular modeling.
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PMID:Design and synthesis of sialyl Lewis(x) mimics as E- and P-selectin inhibitors. 1236 89

Although inhibiting interaction of beta(2) integrins with cognate immunoglobulin class adhesion receptor ligands is an effective neuroprotective strategy in small mammal models of stroke, the strategy has failed in human trials. A completely different antiadhesion receptor strategy was therefore rigorously tested in a model that may more closely approximate human reperfused stroke. Early leukoadhesive events in postischemic cerebral microvessels are mediated by upregulated selectin-class adhesion receptors on endothelial cells. Therefore, a blocking antibody prepared against common P- and E-selectin epitopes was humanized to suppress complement activation and tested in a reperfused hemispheric stroke model in Papio anubis (baboon). Histological examination of postischemic cerebral microvessels revealed a strong upregulation of E-and P-selectin expression. Placebo-blinded administration of the humanized anti-human E- and P-selectin monoclonal antibody (HuEP5C7, 20 mg/kg IV, n=9; placebo, n=9) immediately after the onset of 1 hour of temporary ischemia resulted in trends showing reduced polymorphonuclear leukocyte (PMN) infiltration into ischemic cortex, reduced infarct volumes (by 41%), improved neurological score (by 35%), and improved ability to self-care (by 39%). Importantly, there was no evidence of systemic complement activation, immune suppression, or pathological coagulopathy associated with this therapy. These data suggest that a humanized anti-E/P-selectin antibody approach is safe and may be effective as a clinical treatment for human stroke.
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PMID:HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. 1243 35

Platelet activation has a critical role in arterial disorders. In this study, we showed that the upregulation of P-selectin expression on platelets was related with clinical worsening in acute ischemic stroke. We serially (within 24 hr, at 72 hr, and 7 days) measured the expression of P-selectin on platelets in patients with acute ischemic stroke (n=45) and investigated the correlation between their extents and clinical severity of ischemic stroke. A significant relationship between the P-selectin expressions and National Institute of Health Stroke Scale (NIHSS) was observed at 72 hr and 7 days after ischemic stroke onset. Patients with clinical deterioration showed significantly increased expression of P-selectin on platelets as compared to those without deterioration. These results suggest that the P-selectin expression on platelets may contribute to the aggravation of clinical course in acute ischemic stroke. Thus, adequate manipulation of activated platelets is an important therapeutic strategy in acute ischemic stroke.
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PMID:Surface expression of P-selectin on platelets is related with clinical worsening in acute ischemic stroke. 1248 7

Cytokine-mediated inflammatory cell recruitment into the brain is a critical step in the response to diverse insults, including infection, trauma, and stroke. Hence, continous intra-cerebroventricular infusion of interleukin (IL)-1beta leads to an impressive cell invasion into the cerebrospinal fluid, as well as the brain parenchyma. Neither tumor necrosis factor-alpha nor IL-6 induced any significant cell invasion at all. However, the diverse immune cells (granulocytes, monocytes/macrophages) showed a different time course of invasion. Moreover, there was an association between the number of infiltrating immune cells and the infused IL-1 concentration. By analyzing intra-brain immune events, we demonstrated a time- and dose-dependent induction of intercellular adhesion molecule (ICAM)-1, whereas there were no differences for P-selectin, vascular cell adhesion molecule (VCAM)-1, and monocyte-chemotractant protein (MCP)-1, comparing vehicle and IL-1-infused animals. In conclusion, we assume IL-1beta to be a key cytokine for the granulocyte and monocyte recruitment into the central nervous system after various insults. However, granulocytes anticipate monocyte invasion.
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PMID:Differences in immune cell invasion into the cerebrospinal fluid and brain parenchyma during cerebral infusion of interleukin-1beta. 1252 76

Inflammation has been implicated as a secondary injury mechanism following ischemia and stroke. A variety of experimental models, including thromboembolic stroke, focal and global ischemia, have been used to evaluate the importance of inflammation. The vasculature endothelium promotes inflammation through the upregulation of adhesion molecules such as ICAM, E-selectin, and P-selectin that bind to circulating leukocytes and facilitate their migration into the CNS. Once in the CNS, the production of cytotoxic molecules may facilitate cell death. The macrophage and microglial response to injury may either be beneficial by scavenging necrotic debris or detrimental by facilitating cell death in neurons that would otherwise recover. While many studies have tested these hypotheses, the importance of inflammation in these models is inconclusive. This review summarizes data regarding the role of the vasculature, leukocytes, blood-brain barrier, macrophages, and microglia after experimental and clinical stroke.
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PMID:Inflammatory mechanisms after ischemia and stroke. 1257 22

The aim of this study was to investigate whether soluble adhesion molecule levels differ by ethnic group. Soluble plasma adhesion molecules [soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1)] were measured in 261 white (120 females), 188 African origin (99 females) and 215 South Asian (99 females) individuals living in England. All were free from coronary heart disease, stroke and other cardiovascular disease, diabetes, drug therapy for hypertension or high lipids, hormone-replacement therapy or oral contraceptive pill. The results of the study indicated that there were important differences in the levels of adhesion molecules by sex and smoking. However, when adjusting for these and other potential confounders, there were no differences in levels between white subjects and individuals of South Asian origin. In contrast, people of African origin had significantly lower levels of sICAM-1 [Caribbean -30% (-36 to -23%); West African -22% (-29 to -15%), values are means (95% confidence intervals)], sVCAM-1 [Caribbean -14% (-19 to -8%); West African -10% (-17 to -3%)] and sP-selectin [Caribbean -10% (-17 to -2%); West African -24% (-31 to -16%)] than white individuals. In conclusion, circulating levels of some soluble adhesion molecules are lower in individuals of Caribbean or West African origin compared with white or South Asian individuals. These relationships may contribute to the low risk of coronary heart disease seen in people of African origin living in England.
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PMID:Ethnic differences in circulating soluble adhesion molecules: the Wandsworth Heart and Stroke Study. 1267 19


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