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1.
J Stroke Cerebrovasc Dis ; 29(7): 104805, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32334917

RESUMEN

INTRODUCTION: The prognostic value of leptomeningeal collateral circulation in thrombectomy-treated patients remains unclear. We evaluated the construct validity of assessing leptomeningeal collateral circulation using a new regional perfusion CT source image-based approach, the Perfusion Acquisition for THrombectomy Scale (PATHS). We also compared the prognostic value of PATHS with a further 6 scales based on various techniques: CT-angiography, perfusion CT, and digital subtraction angiography. Additionally, we studied the relationship between the scores for the different scales. PATIENTS AND METHODS: We performed a retrospective study of consecutive patients with stroke and M1/terminal carotid occlusion treated with thrombectomy in our center. Leptomeningeal collateral circulation was prospectively evaluated using 7 scales: Tan and Miteff (CT Angiography); Calleja, Cao, American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology, and PATHS (perfusion); and Christoforidis (Digital Subtraction Angiography). Correlations were studied using the Spearman method. RESULTS: The study population comprised 108 patients. All scales predicted the modified Rankin Scale at 3 months (P ≤ .02) and all but 1 (Christoforidis) correlated with 24-hour brain infarct volume (P ≤ .02). These correlations were higher with PATHS (rho = -0.47, P < .001 for 3-month modified Rankin Scale; rho = -0.35, P < .001 for follow-up infarct volume). The multivariate analysis showed PATHS to be an independent predictor of modified Rankin Scale at 3 months less than equal to 2. A crosscorrelation analysis revealed a better correlation between scales that used the same techniques. CONCLUSIONS: PATHS can be used to assess leptomeningeal collateral circulation. PATHS had better prognostic value than other scales; therefore, it might be considered for assessment of leptomeningeal collateral circulation in candidates for thrombectomy. The moderate correlation between scales suggests that scores are not interchangeable.


Asunto(s)
Circulación Cerebrovascular , Circulación Colateral , Infarto de la Arteria Cerebral Media/terapia , Arteria Cerebral Media/diagnóstico por imagen , Tomografía Computarizada Multidetector , Imagen de Perfusión/métodos , Trombectomía , Anciano , Angiografía Cerebral , Angiografía por Tomografía Computarizada , Evaluación de la Discapacidad , Femenino , Humanos , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/mortalidad , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Persona de Mediana Edad , Arteria Cerebral Media/fisiopatología , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Trombectomía/efectos adversos , Trombectomía/mortalidad , Factores de Tiempo , Resultado del Tratamiento
2.
J Stroke Cerebrovasc Dis ; 24(11): 2484-90, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26375795

RESUMEN

BACKGROUND: Perimesencephalic subarachnoid hemorrhage (p-SAH) is linked to a benign prognosis compared with aneurysmal SAH. However, the outcome in nonperimesencephalic angiographically negative SAH (np-SAH) is not well established. We reviewed our experience and evaluated the clinical and prognostic differences between patients with p-SAH and np-SAH. METHODS: Retrospective observational study based on data collected prospectively from all patients admitted to our hospital with SAH during the past 11 years. After selecting patients with normal angiography, we categorized them as either p-SAH or np-SAH according to the Rinkel criteria. Demographic, clinical, radiologic, and prognostic features were recorded. RESULTS: We collected a total of 41 (12.53%) angiographically negative SAH: 17 p-SAH (41.46%) and 24 np-SAH (58%-53%). The np-SAH group included the 6 patients with Glasgow Coma Scale (GCS) less than 15 (P = .083), and all 5 patients with Hunt & Hess (H&H) scores more than II (P = .045), being the GCS = 15 and H&H less than II in the rest of np-SAH and in all of the p-SAH patients. The average hospital stay in days was longer in the np-SAH group (24 ± 7.08) than in the p-SAH group (17 ± 5.11; P = .55). Hydrocephalus requiring external ventricular drainage (EVD) was only recorded in the np-SAH group (29.16%, P = .029). On discharge, all patients had H&H grade less than II and modified Rankin Scale measured 3 months later was less than 2 in both groups. CONCLUSIONS: Our results agree with other studies showing a low complication rate for SAH patients with a normal angiography, especially in the p-SAH group. The prognosis appears to be less favorable in terms of a more frequent need for EVD, so a more cautious approach is recommended in this subgroup.


Asunto(s)
Angiografía por Resonancia Magnética , Accidente Cerebrovascular/complicaciones , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/etiología , Adulto , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X
3.
Stroke ; 44(12): 3498-508, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24135932

RESUMEN

BACKGROUND AND PURPOSE: Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome. METHODS: Brain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed. RESULTS: Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset. CONCLUSIONS: We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.


Asunto(s)
Encéfalo/efectos de los fármacos , Encefalitis/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Neutrófilos/efectos de los fármacos , PPAR gamma/agonistas , Accidente Cerebrovascular/metabolismo , Tiazolidinedionas/farmacología , Encéfalo/metabolismo , Encefalitis/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neutrófilos/metabolismo , Rosiglitazona , Accidente Cerebrovascular/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico
4.
Radiology ; 268(2): 515-20, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23525205

RESUMEN

PURPOSE: To investigate if glutamate levels also increase in carotid angioplasty and stent placement (CAS) procedures, since high plasma glutamate levels are associated with ischemic infarction and transient ischemic attacks, but the length of ischemia needed to elicit such elevation has not been assessed. MATERIALS AND METHODS: All patients or their relatives signed informed consent. By using high-performance liquid chromatography, plasma glutamate concentrations were determined in 74 patients treated with CAS. Blood samples were obtained with arterial and peripheral venous catheterization before and after the procedure, and venous blood samples were obtained 24, 48, and 72 hours after CAS. Glutamate concentrations were also analyzed in two different control groups: 16 patients without carotid stenosis before and after diagnostic cerebral angiography and 20 patients treated with coronary angioplasty and stent placement. The χ(2) test, t test, and analysis of variance were used to compare glutamate concentrations among the groups. RESULTS: Baseline glutamate concentrations were similar between patients who underwent CAS and both control groups. In CAS patients, glutamate concentrations in venous blood increased immediately after the procedure (354.1 µmol/L ± 132.8) and returned to baseline levels at 24 hours (129.5 µmol/L ± 56.8) (P < .0001). Glutamate concentrations remained unchanged over time in both control groups. CONCLUSION: A rapid increase in plasma glutamate levels occurs after CAS procedures, unrelated to stroke.


Asunto(s)
Angioplastia , Isquemia Encefálica/sangre , Estenosis Carotídea/cirugía , Ácido Glutámico/sangre , Stents , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biomarcadores/sangre , Isquemia Encefálica/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Estudios de Casos y Controles , Angiografía Cerebral , Distribución de Chi-Cuadrado , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estadísticas no Paramétricas , Ultrasonografía Doppler Transcraneal
5.
Stroke ; 43(1): 211-9, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22020035

RESUMEN

BACKGROUND AND PURPOSE: Ischemic stroke continues to be one of the main causes of death worldwide. Inflammation accounts for a large part of damage in this pathology. The cannabinoid type 2 receptor (CB2R) has been proposed to have neuroprotective properties in neurological diseases. Therefore, our aim was to determine the effects of the activation of CB2R on infarct outcome and on ischemia-induced brain expression of classic and alternative markers of macrophage/microglial activation. METHODS: Swiss wild-type and CB2R knockout male mice were subjected to a permanent middle cerebral artery occlusion. Mice were treated with either a CB2R agonist (JWH-133), with or without a CB2R antagonist (SR144528) or vehicle. Infarct outcome was determined by measuring infarct volume and neurological outcome. An additional group of animals was used to assess mRNA and protein expression of CB2R, interleukin (IL)-1ß, IL-6, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide (MIP) -1α, RANTES, inducible nitric oxide synthase (iNOS), cyclooxygenase-2, IL-4, IL-10, transforming growth factor ß (TGF-ß), arginase I, and Ym1. RESULTS: Administration of JWH-133 significantly improved infarct outcome, as shown by a reduction in brain infarction and neurological impairment. This effect was reversed by the CB2R antagonist and was absent in CB2R knockout mice. Concomitantly, administration of JWH-133 led to a lower intensity of Iba1+ microglia/macrophages and a decrease in middle cerebral artery occlusion-induced gene expression of both classic (IL-6, TNF-α, MCP-1, MIP-1α, RANTES, and iNOS) and alternative mediators/markers (IL-10, TGF-ß, and Ym1) of microglial/macrophage activation after permanent middle cerebral artery occlusion. CONCLUSIONS: The inhibitory effect of CB2R on the activation of different subpopulations of microglia/macrophages may account for the protective effect of the selective CB2R agonist JWH-133 after stroke.


Asunto(s)
Encéfalo/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Receptor Cannabinoide CB2/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Canfanos/farmacología , Cannabinoides/farmacología , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Infarto de la Arteria Cerebral Media/patología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pirazoles/farmacología , Receptor Cannabinoide CB2/genética
6.
Antioxidants (Basel) ; 10(8)2021 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-34439518

RESUMEN

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40-60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40-60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50-58% of the 40-60 mg/Kg/day DFO-treated patients.

7.
J Neurosci ; 29(12): 3875-84, 2009 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-19321784

RESUMEN

Peroxisome proliferator-activated receptors gamma (PPARgamma) are nuclear receptors with essential roles as transcriptional regulators of glucose and lipid homeostasis. PPARgamma are also potent anti-inflammatory receptors, a property that contributes to the neuroprotective effects of PPARgamma agonists in experimental stroke. The mechanism of these beneficial actions, however, is not fully elucidated. Therefore, we have explored further the actions of the PPARgamma agonist rosiglitazone in experimental stroke induced by permanent middle cerebral artery occlusion (MCAO) in rodents. Rosiglitazone induced brain 5-lipoxygenase (5-LO) expression in ischemic rat brain, concomitantly with neuroprotection. Rosiglitazone also increased cerebral lipoxin A(4) (LXA(4)) levels and inhibited MCAO-induced production of leukotriene B4 (LTB(4)). Furthermore, pharmacological inhibition and/or genetic deletion of 5-LO inhibited rosiglitazone-induced neuroprotection and downregulation of inflammatory gene expression, LXA(4) synthesis and PPARgamma transcriptional activity in rodents. Finally, LXA(4) caused neuroprotection, which was partly inhibited by the PPARgamma antagonist T0070907, and increased PPARgamma transcriptional activity in isolated nuclei, showing for the first time that LXA(4) has PPARgamma agonistic actions. Altogether, our data illustrate that some effects of rosiglitazone are attributable to de novo synthesis of 5-LO, able to induce a switch from the synthesis of proinflammatory LTB(4) to the synthesis of the proresolving LXA(4). Our study suggests novel lines of study such as the interest of lipoxin-like anti-inflammatory drugs or the use of these molecules as prognostic and/or diagnostic markers for pathologies in which inflammation is involved, such as stroke.


Asunto(s)
Araquidonato 5-Lipooxigenasa/fisiología , Lipoxinas/biosíntesis , Fármacos Neuroprotectores/farmacología , PPAR gamma/agonistas , Accidente Cerebrovascular/metabolismo , Tiazolidinedionas/farmacología , Animales , Araquidonato 5-Lipooxigenasa/biosíntesis , Araquidonato 5-Lipooxigenasa/genética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Infarto Encefálico/etiología , Infarto Encefálico/metabolismo , Infarto Encefálico/patología , Infarto de la Arteria Cerebral Media/complicaciones , Leucotrieno B4/biosíntesis , Ratones , PPAR gamma/fisiología , Ratas , Rosiglitazona , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/patología
8.
Circulation ; 118(14): 1450-9, 2008 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-18794391

RESUMEN

BACKGROUND: The liver X receptors (LXRs) belong to the nuclear receptor superfamily and act as transcriptional regulators of cholesterol metabolism in several tissues. Recent work also has identified LXRs as potent antiinflammatory molecules in macrophages and other immune cells. Combined changes in lipid and inflammatory profiles are likely mediating the protective role of LXRs in models of chronic injury like atherosclerosis. These beneficial actions, however, have not been illustrated in other models of acute injury such as stroke in which inflammation is an important pathophysiological feature. METHODS AND RESULTS: We have studied LXR expression and function in the course of experimental stroke caused by permanent middle cerebral artery occlusion in rats and mice. Here, we show that administration of the synthetic LXR agonists GW3965 or TO901317 after the ischemic occlusion improves stroke outcome as shown by decreased infarct volume area and better neurological scores in rats. Neuroprotection observed with LXR agonists correlated with decreased expression of proinflammatory genes in the brain and with reduced nuclear factor-kappaB transcriptional activity. Loss of function studies using LXRalpha,beta(-/-) mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXRalpha,beta(-/-) mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting. CONCLUSIONS: This work highlights the transcriptional action of LXR as a protective pathway in brain injury and the potential use of LXR agonists as therapeutic agents in stroke.


Asunto(s)
Isquemia Encefálica/patología , Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Receptores Citoplasmáticos y Nucleares/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/prevención & control , Animales , Benzoatos/farmacología , Benzoatos/uso terapéutico , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Proteínas de Unión al ADN/agonistas , Inflamación/patología , Inflamación/prevención & control , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Fármacos Neuroprotectores/farmacología , Receptores Nucleares Huérfanos , Ratas , Ratas Endogámicas F344 , Receptores Citoplasmáticos y Nucleares/agonistas , Accidente Cerebrovascular/metabolismo
9.
Dis Markers ; 25(3): 181-8, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-19096131

RESUMEN

BACKGROUND AND PURPOSE: Increased body iron stores have been related to greater oxidative stress and brain injury in clinical and experimental cerebral ischemia and reperfusion. We aimed to investigate the biological signatures of excitotoxicity, inflammation and blood brain barrier disruption potentially associated with high serum ferritin levels-related damage in acute stroke patients treated with i.v. t-PA. METHODS: Serum levels of ferritin (as index of increased cellular iron stores), glutamate, interleukin-6, matrix metalloproteinase-9 and cellular fibronectin were determined in 134 patients treated with i.v. t-PA within 3 hours from stroke onset in blood samples obtained before t-PA treatment, at 24 and 72 hours. RESULTS: Serum ferritin levels before t-PA infusion correlated to glutamate (r = 0.59, p < 0.001) and interleukin-6 (r = 0.55, p < 0.001) levels at baseline, and with glutamate (r = 0.57, p < 0.001), interleukin-6 (r = 0.49, p < 0.001), metalloproteinase-9 (r = 0.23, p = 0.007) and cellular fibronectin (r = 0.27, p = 0.002) levels measured at 24 hours and glutamate (r = 0.415, p < 0.001), interleukin-6 (r = 0.359, p < 0.001) and metalloproteinase-9 (r = 0.261, p = 0.004) at 72 hours. The association between ferritin and glutamate levels remained after adjustment for confounding factors in generalized linear models. CONCLUSIONS: Brain damage associated with increased iron stores in acute ischemic stroke patients treated with iv. tPA may be mediated by mechanisms linked to excitotoxic damage. The role of inflammation, blood brain barrier disruption and oxidative stress in this condition needs further research.


Asunto(s)
Lesiones Encefálicas/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/tratamiento farmacológico , Ferritinas/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Lesiones Encefálicas/etiología , Isquemia Encefálica/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/complicaciones , Activador de Tejido Plasminógeno/uso terapéutico
10.
Stroke ; 38(1): 90-5, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17138950

RESUMEN

BACKGROUND AND PURPOSE: Iron overload has been associated with greater oxidative stress and brain injury in experimental cerebral ischemia and reperfusion. This study investigates whether high serum ferritin levels, as an index of increased cellular iron stores, are associated with poor outcome, hemorrhagic transformation, and brain edema after treatment with tissue plasminogen activator in patients with acute ischemic stroke. METHODS: A total of 134 consecutive patients treated with intravenous tissue plasminogen activator were prospectively studied in four centers. Serum ferritin levels were determined at baseline, 24 and 72 hours after treatment. Cranial computed tomography was performed on admission and at 24 to 36 hours after tissue plasminogen activator infusion. Stroke severity and outcome were evaluated by using the National Institute of Health Stroke Scale and the modified Rankin Scale. RESULTS: Computed tomography showed hemorrhagic transformation in 27 patients (hemorrhagic infarction in 15 and parenchymal hematoma in 12; symptomatic in four) and brain swelling with midline shift in 15. Poor outcome (modified Rankin Scale >2) at 90 days was observed in 54.5% of patients. Ferritin levels at baseline were higher in patients with poor outcome at 90 days (median [quartiles], 165 [98,307] versus 17 [12,37] ng/mL; P<0.001) and in those who developed parenchymal hematoma (P=0.006), symptomatic hemorrhagic transformation (P=0.008), and severe brain edema (P<0.001). Serum ferritin levels higher than 79 ng/mL before tissue plasminogen activator treatment were independently associated with poor outcome (OR, 117 [95% CI, 25 to 557]). CONCLUSIONS: Increased body iron stores are associated with poor outcome, symptomatic hemorrhagic transformation, and severe edema in patients treated with tissue plasminogen activator after ischemic stroke. These findings suggest that iron overload may offset the beneficial effect of thrombolytic therapies.


Asunto(s)
Hemorragia Cerebral/sangre , Hemorragia Cerebral/inducido químicamente , Hierro/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/tratamiento farmacológico , Activador de Tejido Plasminógeno/efectos adversos , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Edema Encefálico/sangre , Edema Encefálico/inducido químicamente , Edema Encefálico/fisiopatología , Causalidad , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/metabolismo , Arterias Cerebrales/patología , Hemorragia Cerebral/fisiopatología , Femenino , Ferritinas/sangre , Fibrinolíticos/efectos adversos , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Medición de Riesgo , Accidente Cerebrovascular/fisiopatología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
11.
Stroke ; 38(6): 1855-9, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17478737

RESUMEN

BACKGROUND AND PURPOSE: Plasma levels of cellular fibronectin (c-Fn) > or =3.6 microg/mL and of matrix metalloproteinase-9 (MMP-9) > or =140 ng/mL have been associated with parenchymal hematoma (PH) after treatment with tissue-type plasminogen activator (t-PA) in patients with acute ischemic stroke. In this prospective study, we sought to validate the predictive capacity of the preestablished cutoff values of these biomarkers for PH in a larger series of patients. METHODS: We studied 134 patients treated with t-PA within 3 hours from symptom onset according to the SITS-MOST criteria (median time to infusion, 152 minutes; median National Institutes of Health Stroke Scale score, 14) in 4 university hospitals. Hemorrhagic transformation was classified according to the European-Australasian Acute Stroke Study II definitions on computed tomography scans performed 24 to 36 hours after treatment. Relevant hemorrhagic transformation was defined as hemorrhagic infarction type 2 or any PH. Serum c-Fn and MMP-9 levels were determined by an ELISA om blood samples obtained before treatment. RESULTS: Cranial computed tomography showed hemorrhagic transformation in 27 patients (20%), hemorrhagic infarction in 15 (type 2 in 8 patients), and PH in 12 patients (symptomatic in 4). Serum c-Fn and MMP-9 concentrations at baseline were significantly higher in patients with relevant hemorrhagic transformation and PH than in those without (all P<0.001). The sensitivity, specificity, and positive and negative predictive values for PH by c-Fn levels > or =3.6 microg/mL were 100%, 60%, 20%, and 100%, respectively, whereas corresponding values were 92%, 74%, 26%, and 99% for MMP-9 levels > or =140 ng/mL. When both biomarkers were at levels above the cutoff points, specificity increased to 87% and the positive predictive value increased to 41%. CONCLUSIONS: This prospective study confirmed the high sensitivity and negative predictive value, with retained good specificity, of c-Fn and MMP-9 for the prediction of PH in patients treated with t-PA. Development of faster analytic methods will prove the applicability of these biomarkers in routine clinical practice.


Asunto(s)
Isquemia Encefálica/sangre , Fibronectinas/sangre , Hematoma Epidural Craneal/sangre , Metaloproteinasa 9 de la Matriz/sangre , Accidente Cerebrovascular/sangre , Terapia Trombolítica , Anciano , Biomarcadores/sangre , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/epidemiología , Femenino , Hematoma Epidural Craneal/tratamiento farmacológico , Hematoma Epidural Craneal/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Terapia Trombolítica/efectos adversos
12.
J Cereb Blood Flow Metab ; 27(7): 1327-38, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17213861

RESUMEN

Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P<0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARgamma transcriptional activity in neurons and astrocytes (122.1%+/-8.1% and 158.6%+/-22.6% of control PPARgamma transcriptional activity, n=6, P<0.05). Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.


Asunto(s)
Encéfalo/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Transportador 2 de Aminoácidos Excitadores/metabolismo , Precondicionamiento Isquémico , PPAR gamma/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Benzamidas/farmacología , Western Blotting , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Células Cultivadas , Cromatografía Líquida de Alta Presión , Técnicas de Cocultivo , Expresión Génica , Ácido Glutámico/análisis , Ácido Glutámico/metabolismo , Hipoglucemiantes/farmacología , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Regiones Promotoras Genéticas , Piridinas/farmacología , ARN Mensajero/análisis , ARN Mensajero/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Ratas Wistar , Elementos de Respuesta , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rosiglitazona , Tiazolidinedionas/farmacología
14.
J Neuropathol Exp Neurol ; 64(9): 797-805, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16141790

RESUMEN

Some agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) belonging to the thiazolidinedione (TZD) family, as well as the cyclopentenone prostaglandin 15-dPGJ2, have been shown to cause neuroprotection in animal models of stroke. We have tested whether the TZD-unrelated PPARgamma agonist L-796,449 is neuroprotective after permanent middle cerebral artery occlusion (MCAO) in the rat brain. Our results show that L-796,449 decreases MCAO-induced infarct size and improves neurologic scores. This protection is concomitant to inhibition of MCAO-induced brain expression of inducible NO synthase (iNOS) and the matrix metalloproteinase MMP-9 and to upregulation of the cytoprotective stress protein heme oxygenase-1 (HO-1). Analysis of the NF-kappaB p65 monomer and the NF-kappaB inhibitor IkappaBalpha protein levels as well as gel mobility shift assays indicate that L-796,449 inhibits NF-kappaB signaling, and that it may be recruiting both PPARgamma-dependent and independent pathways. In summary, our results provide new insights for stroke treatment.


Asunto(s)
Benzofuranos/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Inflamación/prevención & control , Fármacos Neuroprotectores/uso terapéutico , PPAR gamma/agonistas , Fenilacetatos/uso terapéutico , Animales , Western Blotting , Caspasa 3 , Caspasas/metabolismo , Ciclooxigenasa 2 , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Hemo Oxigenasa (Desciclizante)/biosíntesis , Hemo Oxigenasa (Desciclizante)/efectos de los fármacos , Hemo-Oxigenasa 1 , Proteínas I-kappa B/efectos de los fármacos , Proteínas I-kappa B/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II , PPAR gamma/metabolismo , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Ratas
15.
J Leukoc Biol ; 95(4): 587-98, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24338629

RESUMEN

PPARγ-achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5-LO, Alox5, is involved. In addition, PPARγ is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARγ-induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5-LO might also be involved. Homogenates, sections, and cellular suspensions were prepared from brains of WT and Alox5(-/-) mice exposed to distal pMCAO. BMMs were obtained from Lys-M Cre(+) PPARγ(f/f) and Lys-M Cre(-) PPARγ(f/f) mice. Stereological counting of double-immunofluorescence-labeled brain sections and FACS analysis of cell suspensions was performed. In vivo and in vitro phagocytosis of neutrophils by microglia/macrophages was analyzed. PPARγ activation with RSG induced CD36 expression in resident microglia. This process was mediated by the 5-LO gene, which is induced in neurons by PPARγ activation and at least by one of its products--LXA4--which induced CD36 independently of PPARγ. Moreover, CD36 expression helped resolution of inflammation through phagocytosis, concomitantly to neuroprotection. Based on these findings, in addition to a direct modulation by PPARγ, we propose in brain a paracrine model by which products generated by neuronal 5-LO, such as LXA4, increase the microglial expression of CD36 and promote tissue repair in pathologies with an inflammatory component, such as stroke.


Asunto(s)
Araquidonato 5-Lipooxigenasa/fisiología , Antígenos CD36/fisiología , Hipoglucemiantes/farmacología , Inflamación/inmunología , Neutrófilos/inmunología , PPAR gamma/fisiología , Tiazolidinedionas/farmacología , Animales , Isquemia Encefálica/inmunología , Antígenos CD36/análisis , Células Cultivadas , Lipoxinas/biosíntesis , Ratones , Ratones Endogámicos C57BL , PPAR gamma/agonistas , Fagocitosis , Ratas , Rosiglitazona , Regulación hacia Arriba
16.
Ann Thorac Surg ; 96(3): 1068-70, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23992702

RESUMEN

Primary cardiac tumors constitute an infrequent heart pathology with a generally good prognosis. We present the case of a 45-year-old woman without a relevant medical history and with recurrent transient ischemic attacks of unknown origin. After follow-up with neurologic examination and repeated echocardiograms, an elongated mobile mass image was seen in the left atrial appendage. Surgical treatment consisted of resecting the mass by left atrial appendage excision through left atriotomy, closing with running suture. Anatomopathologic examination revealed findings compatible with a hamartomatous-like malformation. Discharged 5 days after surgery, the patient has no symptoms and does not require any drugs 1 year later.


Asunto(s)
Apéndice Atrial/patología , Hamartoma/cirugía , Cardiopatías/cirugía , Ataque Isquémico Transitorio/etiología , Apéndice Atrial/cirugía , Procedimientos Quirúrgicos Cardíacos/métodos , Ecocardiografía Doppler , Femenino , Estudios de Seguimiento , Hamartoma/complicaciones , Hamartoma/diagnóstico por imagen , Atrios Cardíacos , Cardiopatías/complicaciones , Cardiopatías/diagnóstico por imagen , Humanos , Ataque Isquémico Transitorio/fisiopatología , Persona de Mediana Edad , Medición de Riesgo , Resultado del Tratamiento
18.
Neurología (Barc., Ed. impr.) ; 29(3): 168-183, abr. 2014. tab
Artículo en Español | IBECS (España) | ID: ibc-188069

RESUMEN

FUNDAMENTO Y OBJETIVO: Actualizar las guías terapéuticas del Comité ad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la SEN en el tratamiento preventivo de ictus isquémico (II) y ataque isquémico transitorio (AIT). MÉTODOS: Revisión de evidencias disponibles sobre la prevención del ictus isquémico y AIT en función del subtipo etiológico. Los niveles de evidencia y grados de recomendación se han basado en la clasificación del Centro de Medicina Basada en la Evidencia. RESULTADOS: En el II de origen aterotrombótico reducen el riesgo de recurrencias el tratamiento antiagregante y los procedimientos revascularizadores en casos seleccionados de estenosis carotidea ipsilateral (70-99%). La prevención de II de origen cardioembólico (fibrilación auricular, valvulopatías, prótesis valvulares y en infarto de miocardio con trombo mural) se basa en el uso de anticoagulantes orales. En el II de origen inhabitual, las terapias preventivas dependerán de la etiología; en la trombosis venosa cerebral la anticoagulación oral es eficaz. CONCLUSIONES: Se concluye con recomendaciones de práctica clínica en prevención de ictus isquémico y AIT adaptadas al subtipo etiológico de II que ha presentado el paciente


BACKGROUND AND OBJECTIVE: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and Transient Ischaemic Attack (TIA). METHODS: We reviewed the available evidence on ischaemic stroke and TIA prevention according to aetiological subtype. Levels of evidence and recommendation levels are based on the classification of the Centre for Evidence-Based Medicine. RESULTS: In atherothrombotic IS, antiplatelet therapy and revascularization procedures in selected cases of ipsilateral carotid stenosis (70%-90%) reduce the risk of recurrences. In cardioembolic IS (atrial fibrillation, valvular diseases, prosthetic valves and myocardial infarction with mural thrombus) prevention is based on the use of oral anticoagulants. Preventive therapies for uncommon causes of IS will depend on the aetiology. In the case of cerebral venous thrombosis oral anticoagulation is effective. CONCLUSIONS: We conclude with recommendations for clinical practice in prevention of IS according to the aetiological subtype presented by the patient


Asunto(s)
Humanos , Isquemia Encefálica/prevención & control , Ataque Isquémico Transitorio/prevención & control , Accidente Cerebrovascular/prevención & control , Isquemia Encefálica/etiología , Medicina Basada en la Evidencia , Ataque Isquémico Transitorio/clasificación , Ataque Isquémico Transitorio/etiología , Accidente Cerebrovascular/clasificación , Accidente Cerebrovascular/etiología
19.
Neurología (Barc., Ed. impr.) ; 29(6): 353-370, jul.-ago. 2014. tab, graf
Artículo en Español | IBECS (España) | ID: ibc-188070

RESUMEN

OBJETIVO: Actualización de la guía para el diagnóstico y tratamiento de la hemorragia subaracnoidea de la Sociedad Española de Neurología. MATERIAL Y MÉTODOS: Revisión y análisis de la bibliografía existente. Se establecen recomendaciones en función del nivel de evidencia que ofrecen los estudios revisados. RESULTADOS: La causa más frecuente de hemorragia subaracnoidea espontánea (HSA) es la rotura de un aneurisma cerebral. Su incidencia se sitúa en torno 9 casos por 100.000 habitantes/año y supone un 5% de todos los ictus. La hipertensión arterial y el tabaquismo son sus principales factores de riesgo. Se ha de realizar el tratamiento en centros especializados. Se debe considerar el ingreso en unidades de ictus de aquellos pacientes con HSA y buena situación clínica inicial (grados I y II en la escala de Hunt y Hess). Se recomienda la exclusión precoz de la circulación del aneurisma. El estudio diagnóstico de elección es la tomografía computarizada (TC) craneal sin contraste. Si esta es negativa y persiste la sospecha clínica se aconseja realizar una punción lumbar. Los estudios de elección para identificar la fuente de sangrado son la resonancia magnética (RM) y la angiografía. Los estudios ultrasonográficos son útiles para el diagnóstico y seguimiento del vasoespasmo. Se recomienda el nimodipino para la prevención de la isquemia cerebral diferida. La terapia hipertensiva y el intervencionismo neurovascular pueden plantearse para tratar el vasoespasmo establecido. CONCLUSIONES: La HSA es una enfermedad grave y compleja que debe ser atendida en centros especializados, con suficiente experiencia para abordar el proceso diagnóstico y terapéutico


OBJECTIVE: To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment. MATERIAL AND METHODS: A review and analysis of the existing literature. Recommendations are given based on the level of evidence for each study reviewed. RESULTS: The most common cause of spontaneous subarachnoid haemorrhage (SAH) is cerebral aneurysm rupture. Its estimated incidence in Spain is 9/100 000 inhabitants/year with a relative frequency of approximately 5% of all strokes. Hypertension and smoking are the main risk factors. Stroke patients require treatment in a specialised centre. Admission to a stroke unit should be considered for SAH patients whose initial clinical condition is good (Grades I or II on the Hunt and Hess scale). We recommend early exclusion of aneurysms from the circulation. The diagnostic study of choice for SAH is brain CT (computed tomography) without contrast. If the test is negative and SAH is still suspected, a lumbar puncture should then be performed. The diagnostic tests recommended in order to determine the source of the haemorrhage are MRI (magnetic resonance imaging) and angiography. Doppler ultrasonography studies are very useful for diagnosing and monitoring vasospasm. Nimodipine is recommended for preventing delayed cerebral ischaemia. Blood pressure treatment and neurovascular intervention may be considered in treating refractory vasospasm. CONCLUSIONS: SAH is a severe and complex disease which must be managed in specialised centres by professionals with ample experience in relevant diagnostic and therapeutic processes


Asunto(s)
Humanos , Guías de Práctica Clínica como Asunto , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/terapia , Isquemia Encefálica/complicaciones , Angiografía Cerebral , Aneurisma Intracraneal/complicaciones , Imagen por Resonancia Magnética , Nimodipina/uso terapéutico , Factores de Riesgo , Hemorragia Subaracnoidea/etiología , Tomografía Computarizada por Rayos X
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