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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.

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.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.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.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.

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.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.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 HuntHess (HH) scores more than II (P = .045), being the GCS = 15 and HH 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 HH grade less than II and modified Rankin Scale measured 3 months later was less than 2 in both groups.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.

Objective: To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment. Materials 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. 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. Keywords: Subarachnoid haemorrhage, Cerebral aneurysm, Diagnosis, Vasospasm, Delayed cerebral ischaemia, Rebleeding, Medical treatment, Palabras clave: Hemorragia subaracnoidea, Aneurisma cerebral, Diagnóstico, Vasoespasmo, Isquemia cerebral diferida, Resangrado, Tratamiento médico

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. Abstract: 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. Palabras clave: Guía de práctica clínica, Ictus isquémico, Ataque isquémico transitorio, Prevención, Keywords: Guidelines, Ischaemic stroke, Transient ischemic attack, Prevention

Introduction: Update of Acute Ischaemic Stroke Treatment Guidelines of the Spanish Neurological Society based on a critical review of the literature. Recommendations are made based on levels of evidence from published data and studies. Development: Organised systems of care should be implemented to ensure access to the optimal management of all acute stroke patients in stroke units. Standard of care should include treatment of blood pressure (should only be treated if values are over 185/105 mmHg), treatment of hyperglycaemia over 155 mg/dl, and treatment of body temperature with antipyretic drugs if it rises above 37.5 °C. Neurological and systemic complications must be prevented and promptly treated. Decompressive hemicraniectomy should be considered in cases of malignant cerebral oedema. Intravenous thrombolysis with rtPA should be administered within 4.5 hours from symptom onset, except when there are contraindications. Intra-arterial pharmacological thrombolysis can be considered within 6 hours, and mechanical thrombectomy within 8 hours from onset, for anterior circulation strokes, while a wider window of opportunity up to 12–24 hours is feasible for posterior strokes. There is not enough evidence to recommend routine use of the so-called neuroprotective drugs. Anticoagulation should be administered to patients with cerebral vein thrombosis. Rehabilitation should be started as early as possible. Conclusion: Treatment of acute ischaemic stroke includes management of patients in stroke units. Systemic thrombolysis should be considered within 4.5 hours from symptom onset. Intra-arterial approaches with a wider window of opportunity can be an option in certain cases. Protective and restorative therapies are being investigated. Resumen: Introducción: Actualización de la guía para el tratamiento del infarto cerebral agudo de la Sociedad Española de Neurología basada en la revisión y análisis de la bibliografía existente sobre el tema. Se establecen recomendaciones en base al nivel de evidencia que ofrecen los estudios revisados. Desarrollo: Los sistemas de asistencia urgente extrahospitalaria se organizarán para asegurar la atención especializada de los pacientes y el ingreso en unidades de ictus (UI). Deben aplicarse cuidados generales para mantener la homeostasis (tratar la tensión arterial sistólica > 185 mmHg o diastólica > 105 mmHg, evitar hiperglucemia > 155 mg/dl y controlar la temperatura, tratando con antitérmicos cifras > 37,5 °C), y prevenir y tratar las complicaciones. La craniectomía descompresiva debe ser considerada en casos seleccionados de oedema cerebral maligno. La trombólisis intravenosa con rtPA se administrará en las primeras 4,5 horas en pacientes sin contraindicación. La trombólisis intraarterial farmacológica puede indicarse en las primeras 6 horas de evolución y la trombectomía mecánica hasta las 8 horas. En el territorio posterior la ventana puede ampliarse hasta 12–24 horas. No hay evidencias para recomendar el uso rutinario de los fármacos denominados neuroprotectores. Se recomienda la anticoagulación en pacientes con trombosis de senos venosos. Se aconseja el inicio precoz de rehabilitación. Conclusiones: El tratamiento del infarto cerebral se basa en la atención especializada en UI, la aplicación urgente de cuidados generales y el tratamiento trombolítico intravenoso en las primeras 4,5 horas. La recanalización intraarterial farmacológica o mecánica pueden ser útiles en casos seleccionados. Terapias de protección y reparación cerebral están en desarrollo. Keywords: Cerebral infarct, Ischaemic stroke, Thrombolysis, Brain protection, Stroke units, Cerebral venous thrombosis, Palabras clave: Infarto cerebral, Ictus isquémico, Trombólisis, Cerebroprotección, Unidades de ictus, Trombosis venosa cerebral

Resumen: Introducción: Actualización de la guía para el tratamiento del infarto cerebral agudo de la Sociedad Española de Neurología basada en la revisión y análisis de la bibliografía existente sobre el tema. Se establecen recomendaciones en base al nivel de evidencia que ofrecen los estudios revisados. Desarrollo: Los sistemas de asistencia urgente extrahospitalaria se organizarán para asegurar la atención especializada de los pacientes y el ingreso en unidades de ictus (UI). Deben aplicarse cuidados generales para mantener la homeostasis (tratar la tensión arterial sistólica > 185 mmHg o diastólica > 105 mmHg, evitar hiperglucemia > 155 mg/dl y controlar la temperatura, tratando con antitérmicos cifras > 37,5 °C), y prevenir y tratar las complicaciones. La craniectomía descompresiva debe ser considerada en casos seleccionados de edema cerebral maligno. La trombólisis intravenosa con rtPA se administrará en las primeras 4,5 horas en pacientes sin contraindicación. La trombólisis intraarterial farmacológica puede indicarse en las primeras 6 horas de evolución y la trombectomía mecánica hasta las 8 horas. En el territorio posterior la ventana puede ampliarse hasta 12-24 horas. No hay evidencias para recomendar el uso rutinario de los fármacos denominados neuroprotectores. Se recomienda la anticoagulación en pacientes con trombosis de senos venosos. Se aconseja el inicio precoz de rehabilitación. Conclusiones: El tratamiento del infarto cerebral se basa en la atención especializada en UI, la aplicación urgente de cuidados generales y el tratamiento trombolítico intravenoso en las primeras 4,5 horas. La recanalización intraarterial farmacológica o mecánica pueden ser útiles en casos seleccionados. Terapias de protección y reparación cerebral están en desarrollo. Abstract: Introduction: Update of Acute Ischaemic Stroke Treatment Guidelines of the Spanish Neurological Society based on a critical review of the literature. Recommendations are made based on levels of evidence from published data and studies. Development: Organized systems of care should be implemented to ensure access to the optimal management of all acute stroke patients in stroke units. Standard of care should include treatment of blood pressure (should only be treated if values are over 185/105 mmHg), treatment of hyperglycaemia over 155 mg/dl, and treatment of body temperature with antipyretic drugs if it rises above 37.5 °C. Neurological and systemic complications must be prevented and promptly treated. Decompressive hemicraniectomy should be considered in cases of malignant cerebral oedema. Intravenous thrombolysis with rtPA should be administered within 4.5 hours from symptom onset, except when there are contraindications. Intra-arterial pharmacological thrombolysis can be considered within 6 hours, and mechanical thrombectomy within 8 hours from onset, for anterior circulation strokes, while a wider window of opportunity up to 12-24 hours is feasible for posterior strokes. There is not enough evidence to recommend routine use of the so called neuroprotective drugs. Anticoagulation should be administered to patients with cerebral vein thrombosis. Rehabilitation should be started as early as possible. Conclusion: Treatment of acute ischaemic stroke includes management of patients in stroke units. Systemic thrombolysis should be considered within 4.5 hours from symptom onset. Intra-arterial approaches with a wider window of opportunity can be an option in certain cases. Protective and restorative therapies are being investigated Palabras clave: Infarto cerebral, Ictus isquémico, Trombólisis, Cerebroprotección, Unidades de ictus, Trombosis venosa cerebral, Keywords: Cerebral infarct, Ischaemic stroke, Thrombolysis, Brain protection, Stroke units, Cerebral venous thrombosis

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. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness CSD2010-00045 (to M.A.M.) SAF2009-08145 and SAF2012-33216 (to M.A.M.), SAF2011-23354 (toI.L.), SAF2009-07466 and SAF2012-31483 (to M.R.), from Fondo Europeo de Desarrollo Regional (FEDER) “Instituto de Salud Carlos III” RETICS RD12/0014/0003 (to I.L. and from the local govern-ment of Madrid S2010/BMD-2336 (to M.A.M.) and S2010/BMD-2349 (to I.L.). I.B. and M.I.C. are fellows of the Spanish Ministry ofEconomy and Competitiveness. The authors thank Tamara Atanesand Roberto Cañadas for their technical assistance. Sí

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.

Resumen: La hemorragia intracerebral sólo representa entre el 10 y el 15% de todos los ictus, sin embargo condiciona un peor pronóstico, con unas tasas más elevadas de morbilidad y mortalidad. Es frecuente que durante las primeras horas tras el inicio de los síntomas se produzca un empeoramiento clínico, lo cual condiciona un peor pronóstico, por lo que la hemorragia intracerebral constituye una emergencia neurológica en la que debe realizarse un diagnóstico y tratamiento adecuado de manera precoz. En esta guía realizamos una revisión de los procedimientos diagnósticos y los factores que influyen en el pronóstico de los pacientes con hemorragia intracerebral y establecemos unas recomendaciones para la estrategia asistencial, sistemática diagnóstica, tratamiento en fase aguda y prevención secundaria en la hemorragia intracerebral. Abstract: Intracerebral haemorrhage accounts for 10%-15% of all strokes; however it has a poor prognisis with higher rates of morbidity and mortality. Neurological deterioration is often observed during the first hours after onset and determines poor prognosis. Intracerebral haemorrhage, therefore, is a neurological emergency which must be diagnosed and treated properly as soon as possible. In this guide we review the diagnostic procedures and factors that influence the prognosis of patients with intracerebral haemorrhage and we establish recommendations for the therapeutic strategy, systematic diagnosis, acute treatment and secondary prevention for this condition. Palabras clave: Hemorragia intracerebral, Guías, Ictus, Keywords: Intracerebral haemorrhage, Guidelines, Stroke

Resumen: 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 los factores de riesgo y la oportunidad de su modificación para prevenir el ictus isquémico y AIT. Los niveles de evidencia y grados de recomendación se han basado en la clasificación del Centro de Medicina Basada en la Evidencia. Resultados: En esta primera parte se resumen las recomendaciones sobre la actuación sobre los siguientes factores: presión arterial, DM, lípidos plasmáticos, consumo de tabaco y alcohol, dieta y actividad física, cardiopatías embolígenas, estenosis carotídea asintomática, terapia hormonal sustitutiva y anticonceptivos, hiperhomocisteinemía, estados protrombóticos y síndrome de apnea del sueño. Conclusiones: La modificación de los estilos de vida y el tratamiento farmacológico de la hipertensión arterial, diabetes méllitus y dislipemia según criterios de prevención primaria y secundaria se recomiendan en la prevención de ictus isquémico. Abstract: 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 available evidence on risk factors and means of modifying them to prevent ischaemic stroke and TIA. Levels of evidence and recommendation grades are based on the classification of the Centre for Evidence-Based Medicine. Results: This first section summarises the recommendations for action on the following factors: blood pressure, diabetes, lipids, tobacco and alcohol consumption, diet and physical activity, cardio-embolic diseases, asymptomatic carotid stenosis, hormone replacement therapy and contraceptives, hyperhomocysteinemia, prothrombotic states and sleep apnea syndrome. Conclusions: Changes in lifestyle and pharmacological treatment for hypertension, diabetes mellitus and dyslipidemia, according to criteria of primary and secondary prevention, are recommended for preventing ischemic stroke. Palabras clave: Guías de práctica clínica, Prevención de ictus, Ictus, Ataque isquémico transitorio, Keywords: Guidelines, Ischaemic stroke, Transient ischemic attack, Prevention

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 available evidence on risk factors and means of modifying them to prevent IS and TIA. Levels of evidence and recommendation grades are based on the classification of the Centre for Evidence-Based Medicine. Results: This first section summarises the recommendations for action on the following factors: blood pressure, diabetes, lipids, tobacco and alcohol consumption, diet and physical activity, cardio-embolic diseases, asymptomatic carotid stenosis, hormone replacement therapy (HRT) and contraceptives, hyperhomocysteinemia, prothrombotic states and sleep apnea syndrome. Conclusions: Changes in lifestyle and pharmacological treatment for hypertension, diabetes mellitus and dyslipidemia, according to criteria of primary and secondary prevention, are recommended for preventing IS. Resumen: 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 los factores de riesgo y la oportunidad de su modificación para prevenir el ictus isquémico y AIT. Los niveles de evidencia y grados de recomendación se han basado en la clasificación del Centro de Medicina Basada en la Evidencia. Resultados: En esta primera parte se resumen las recomendaciones sobre la actuación sobre los siguientes factores: presión arterial, DM, lípidos plasmáticos, consumo de tabaco y alcohol, dieta y actividad física, cardiopatías embolígenas, estenosis carotídea asintomática, terapia hormonal sustitutiva y anticonceptivos, hiperhomocisteinemía, estados protrombóticos y síndrome de apnea del sueño. Conclusiones: La modificación de los estilos de vida y el tratamiento farmacológico de la hipertensión arterial, diabetes méllitus y dislipemia según criterios de prevención primaria y secundaria se recomiendan en la prevención de ictus isquémico. Keywords: Guidelines, Ischaemic stroke, Transient ischaemic attack, Prevention, Palabras clave: Guías de práctica clínica, Prevención de ictus, Ictus, Ataque isquémico transitorio

Peroxisome proliferator-activated receptors gamma (PPARγ) are nuclear receptors with essential roles as transcriptional regulators of glucose and lipid homeostasis. PPARγ are also potent anti-inflammatory receptors, a property that contributes to the neuroprotective effects of PPARγ agonists in experimental stroke. The mechanism of these beneficial actions, however, is not fully elucidated. Therefore, we have explored further the actions of the PPARγ 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 A4(LXA4) levels and inhibited MCAO-induced production of leukotriene B4 (LTB4). Furthermore, pharmacological inhibition and/or genetic deletion of 5-LO inhibited rosiglitazone-induced neuroprotection and downregulation of inflammatory gene expression, LXA4synthesis and PPARγ transcriptional activity in rodents. Finally, LXA4caused neuroprotection, which was partly inhibited by the PPARγ antagonist T0070907, and increased PPARγ transcriptional activity in isolated nuclei, showing for the first time that LXA4has PPARγ agonistic actions. Altogether, our data illustrate that some effects of rosiglitazone are attributable tode novosynthesis of 5-LO, able to induce a switch from the synthesis of proinflammatory LTB4to the synthesis of the proresolving LXA4. 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.

Objective: To determine the relationship between body temperature (BT), arterial recanalization, functional outcome, and hemorrhagic transformation (HT) of cerebral infarction in patients treated with i.v. tissue plasminogen activator (tPA). Methods: We studied 254 patients treated with tPA within 3 h from stroke onset. National Institute of Health Stroke Scale score, BT, and transcranial Doppler ultrasound (n = 99) on admission and at 24 h were recorded. Hypodensity volume and HT were evaluated on CT at 24–36 h. Poor outcome (Rankin Scale > 2) was evaluated at 3 months. Results: Arterial recanalization at 24 h was found in 70.7% of patients, HT in 24.8% (symptomatic in 4.7%) and poor outcome in 44.1%. Baseline BT was not associated with greater stroke severity at admission or at 24 h, HT or poor outcome. However, BT at 24 h correlated to stroke severity (P

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,pr= 0.57,pr= 0.49,pr= 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.

Pretreatment with statins has been shown to reduce brain injury in cerebral ischemia. In this controlled randomized study, we investigated the influence of statin pretreatment and its withdrawal on the outcome of acute ischemic stroke patients.From 215 patients admitted within 24 hours of a hemispheric ischemic stroke, 89 patients on chronic statin treatment were randomly assigned either to statin withdrawal for the first 3 days after admission (n = 46) or to immediately receive atorvastatin 20 mg/day (n = 43). The primary outcome event was death or dependency (modified Rankin Scale [mRS] score2) at 3 months. Early neurologic deterioration (END) and infarct volume at days 4 to 7 were secondary outcome variables. In a secondary analysis, outcome variables were compared with the nonrandomized patients without previous statin therapy (n = 126).Patients with statin withdrawal showed a higher frequency of mRS score2 at the end of follow-up (60.0% vs 39.0%; p = 0.043), END (65.2% vs 20.9%; p0.0001), and greater infarct volume (74 [45, 126] vs 26 [12, 70] mL; p = 0.002) compared with the non-statin-withdrawal group. Statin withdrawal was associated with a 4.66 (1.46 to 14.91)-fold increase in the risk of death or dependency, a 8.67 (3.05 to 24.63)-fold increase in the risk of END, and an increase in mean infarct volume of 37.63 mL (SE 10.01; p0.001) after adjusting for age and baseline stroke severity. Compared with patients without previous treatment with statins, statin withdrawal was associated with a 19.01 (1.96 to 184.09)-fold increase in the risk of END and an increase in mean infarct volume of 43.51 mL (SE 21.91; p = 0.048).Statin withdrawal is associated with increased risk of death or dependency at 90 days. Hence, this treatment should be continued in the acute phase of ischemic stroke.

Background and Purpose— Plasma levels of cellular fibronectin (c-Fn) ≥3.6 μg/mL and of matrix metalloproteinase-9 (MMP-9) ≥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 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.

Background: Hemorrhagic transformation (HT) after cerebral ischemia seems to be related to the endothelial disruption secondary to the ischemic process. Albuminuria has recently been found to be a marker of chronic endothelial damage. Objective: To investigate the relationship between albuminuria and HT in patients with acute ischemic stroke. Methods: We studied 200 patients (51.5% men, age 72.5 ± 8.5 years) with ischemic stroke within the first 24 hours of evolution. HT development was assessed on CT performed between days 4 and 7 of evolution and classified according to the ECASS II criteria. Urinary samples were collected within the first 3 hours after admission and the presence of albuminuria, which was considered to be present when the ratio albumin-to-creatinine was ≥30 mg/g creatinine, was determined by nephelometry within the first 24 hours of evolution. Results: Forty-nine patients (24.5%) had albuminuria and 36 (18%) had HT on the second CT scan. After adjusting for potential confounders including a previous history of diabetes mellitus, hypertension and atrial fibrillation, stroke severity, the presence of early signs of ischemia and leukoaraiosis on the baseline CT scan, and IV anticoagulant treatment, logistic regression analysis showed that albuminuria was independently associated with HT (OR, 7.45; 95% CI 2.30 to 24.16). Moreover, albuminuria was also a significant and independent predictor of parenchymal hemorrhage type 1 and 2 (OR, 8.30; 95% CI 1.77 to 38.89). Conclusion: Albuminuria is an independent predictor of hemorrhagic transformation, and particularly of the most severe bleedings, in patients with acute ischemic stroke. Due to the small number of events, the predictive capacity of albuminuria should be confirmed in larger studies.

The influence of temperature on the outcome observed in experimental models of ischaemic stroke has not been definitively proved in patients with stroke. Interleukin-6 (IL-6) acts as important endogenous pyrogen, and it is an important regulator of spontaneous body temperature during cerebral ischaemia. The objective of this study was to determine, during the acute phase of cerebral ischaemia, the potential relationship between proinflammatory cytokines and hyperthermia as a cause of larger cerebral infarcts.We studied 229 patients with a first-ever acute hemispheric infarction admitted within the first 24 h from onset of symptoms. On admission, axillary temperature was recorded and blood chemistry studies and cranial computed tomography were performed. We classified body temperature into two groups: hyperthermia (or=37.5 degrees C) and normothermia (37.5 degrees C). We determined proinflammatory markers [IL-6, tumour necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule (ICAM-1) and vascular cellular adhesion molecule] on admission. Two outcome variables were evaluated: (i) infarct volume; (ii) Canadian Stroke Scale (CSS) at 3 months (CSSor= 7 was considered poor outcome and CSS7 good outcome).Patients with hyperthermia had higher infarct volume [46.5 (9.8-78.5) cm(3) vs. 19.1 (5.0-23.5) cm(3); P0.0001], as well as poor outcome at 3 months. Plasma levels of IL-6, TNF-alpha and ICAM-1 were significantly higher in the group of patients with hyperthermia than in the normothermic group. There was a significant correlation between body temperature on admission and infarct volume (r = 0.302; P0.0001), and between proinflammatory markers (IL-6 and TNF-alpha) and infarct volume. A significant association was also found between proinflammatory markers (IL-6, TNF-alpha, and ICAM-1) and poor outcome. However, after adjustment for potential confounders, hyperthermia was not independently associated with either larger infarct volume or with poor outcome at 3 months.Inflammatory mediators play a role in acute ischaemic brain damage independently of hyperthermia.

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.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.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.A rapid increase in plasma glutamate levels occurs after CAS procedures, unrelated to stroke.

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.

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)-1β, 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 β (TGF-β), 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-β, 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. © 2011 American Heart Association. All rights reserved., This work was supported by grants from Spanish Ministry of Science and Innovation (MICINN) SAF2009-08145 (M.A.M.), SAF2011-23354 (I.L.), SAF 2008-01106 (J.M.), and from both MICINN and Fondo Europeo de Desarrollo Regional (FEDER) grants Consolider CSD2010-00045 (M.A.M.) and Red Neurovascular (RENEVAS) RD06/0026/0005 (I.L.), RD06/0026/0001 (M.T.) and RD06/0026/0006 (M.C.B.). J.G.Z. was supported by the Programme Alban, scholarship No. E07D400805CO. M.S.G.-G. is a predoctoral fellow of the Ministry of Science and Innovation. M.C.B. was supported by a postdoctoral grant from the Spanish Ministry of Health CD07/00236.

Background and objective: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischemic 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 (70–99%) 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. 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, valulopatías, 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 dela 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. Keywords: Guidelines, Ischaemic stroke, Transient ischemic attack, Prevention, Palabras clave: Guía de práctica clínica, Ictus isquémico, Ataque isquémico transitorio, Prevención

Intracerebral haemorrhage accounts for 10% to 15% of all strokes, however it has a poor prognosis with higher rates of morbidity and mortality. Neurological deterioration is often observed during the first hours from onset, and determines the poor prognosis. Intracerebral haemorrhage, therefore, is a neurological emergency which must be diagnosed and treated properly as soon as possible. In this guide we review the diagnostic procedures and factors that influence the prognosis of patients with intracerebral haemorrhage and we establish recommendations for the therapeutic strategy, systematic diagnosis, acute treatment and secondary prevention for this condition. Resumen: La hemorragia intracerebral sólo representa entre el 10 y el 15% de todos los ictus, sin embargo condiciona un peor pronóstico, con unas tasas más elevadas de morbilidad y mortalidad. Es frecuente que durante las primeras horas tras el inicio de los síntomas se produzca un empeoramiento clínico, lo cual condiciona un peor pronóstico, por lo que la hemorragia intracerebral constituye una emergencia neurológica en la que debe realizarse un diagnóstico y tratamiento adecuado de manera precoz. En esta guía realizamos una revisión de los procedimientos diagnósticos y los factores que influyen en el pronóstico de los pacientes con hemorragia intracerebral y establecemos unas recomendaciones para la estrategia asistencial, sistemática diagnóstica, tratamiento en fase aguda y prevención secundaria en la hemorragia intracerebral. Keywords: Intracerebral haemorrhage, Guidelines, Stroke, Palabras clave: Hemorragia intracerebral, Guías, Ictus

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-κB transcriptional activity. Loss of function studies using LXRα,β −/− mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXRα,β −/− mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting. Conclusion— 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.

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)γ, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARγ 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 μmol/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 PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P < 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]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 μmol/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 PPARγ leading to neuroprotection by increasing glutamate uptake.

To study the association of previously unknown high blood pressure (HBP) during the acute phase of stroke (new-onset hypertension) with the inflammatory response and clinical outcome.We classified 844 patients with hemispheric ischemic stroke into three groups according to history of hypertension and presence of HBP within the first 24 hours after symptom onset: Group I (n = 412), normotensive patients; Group II (n = 265), chronic hypertensive patients; and Group III (n = 167), new-onset hypertensive patients. Interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and metalloproteinase 9 (MMP-9) were measured in blood samples obtained on admission. The influence of new-onset HBP and markers of inflammation on poor neurologic outcome at 3 months was evaluated by logistic regression analysis.New-onset HBP was found in 19.9% of patients. Patients in this group had higher plasma concentrations of IL-6, TNF-alpha, ICAM-1, VCAM-1, and MMP-9 than the other two groups. New-onset HBP was associated with poor outcome at 3 months (odds ratio [OR] 2.10; 95% CI 1.54 to 3.52; p0.0001) after adjustment for other prognostic factors. However, when markers of inflammation were included in the model, IL-6 (OR 1.01; 95% CI 1.00 to 1.03; p = 0.020) and MMP-9 (OR 1.01; 95% CI 1.00 to 1.01; p0.0001), but not new-onset HBP, were independently associated with poor neurologic outcome.New-onset high blood pressure in acute ischemic stroke, but not chronic hypertension, is associated with an inflammatory response and poor neurologic outcome.

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 P =0.006), symptomatic hemorrhagic transformation ( P =0.008), and severe brain edema ( P 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.

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.