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Hospital de Órbigo, Spain

Ludewig P.,University of Hamburg | Gallizioli M.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Urra X.,Functional Unit of Cerebrovascular Diseases | Urra X.,August Pi i Sunyer Biomedical Research Institute IDIBAPS | And 6 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016

Dendritic cells (DCs) are professional antigen presenting cells that constantly survey the environment acting as sentinels of the immune system, including in the CNS. DCs are strategically located near the cerebrospinal fluid, but they can potentiallymigrate to draining cervical lymph nodes either triggering immunogenic T cell responses or displaying tolerogenic functions. Under physiological conditions, the presence of DCs in the brain parenchyma is minimal but their numbers increase in neuroinflammation. Although DCs belong to a distinct immune cell lineage, they show various phenotypes and share certain common markers with monocytes, macrophages, and microglia. All these cells can expressmajor histocompatibility complex class II, and acquire similar morphologies hampering their precise identification. Neuroinflammation is increasingly recognized in many brain disorders; here we review the literature reporting DCs in the inflamed brain in disease conditions and corresponding animal models of multiple sclerosis, stroke, brain tumors, Alzheimer's disease, Parkinson's disease, and epilepsy. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. © 2015 Elsevier B.V.

Paciaroni M.,University of Perugia | Inzitari D.,University of Florence | Agnelli G.,University of Perugia | Caso V.,University of Perugia | And 72 more authors.
Journal of Neurology | Year: 2014

The aim of the ICARO-3 study was to evaluate whether intra-arterial treatment, compared to intravenous thrombolysis, increases the rate of favourable functional outcome at 3 months in acute ischemic stroke and extracranial ICA occlusion. ICARO-3 was a non-randomized therapeutic trial that performed a non-blind assessment of outcomes using retrospective data collected prospectively from 37 centres in 7 countries. Patients treated with endovascular treatment within 6 h from stroke onset (cases) were matched with patients treated with intravenous thrombolysis within 4.5 h from symptom onset (controls). Patients receiving either intravenous or endovascular therapy were included among the cases. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale (mRS), dichotomized as favourable (score of 0–2) or unfavourable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Included in the analysis were 324 cases and 324 controls: 105 cases (32.4 %) had a favourable outcome as compared with 89 controls (27.4 %) [adjusted odds ratio (OR) 1.25, 95 % confidence interval (CI) 0.88–1.79, p = 0.1]. In the adjusted analysis, treatment with intra-arterial procedures was significantly associated with a reduction of mortality (OR 0.61, 95 % CI 0.40–0.93, p = 0.022). The rates of patients with severe disability or death (mRS 5–6) were similar in cases and controls (30.5 versus 32.4 %, p = 0.67). For the ordinal analysis, adjusted for age, sex, NIHSS, presence of diabetes mellitus and atrial fibrillation, the common odds ratio was 1.15 (95 % IC 0.86–1.54), p = 0.33. There were more cases of intracranial bleeding (37.0 versus 17.3 %, p = 0.0001) in the intra-arterial procedure group than in the intravenous group. After the exclusion of the 135 cases treated with the combination of I.V. thrombolysis and I.A. procedures, 67/189 of those treated with I.A. procedures (35.3 %) had a favourable outcome, compared to 89/324 of those treated with I.V. thrombolysis (27.4 %) (adjusted OR 1.75, 95 % CI 1.00–3.03, p = 0.05). Endovascular treatment of patients with acute ICA occlusion did not result in a better functional outcome than treatment with intravenous thrombolysis, but was associated with a higher rate of intracranial bleeding. Overall mortality was significantly reduced in patients treated with endovascular treatment but the rates of patients with severe disability or death were similar. When excluding all patients treated with the combination of I.V. thrombolysis and I.A. procedures, a potential benefit of I.A. treatment alone compared to I.V. thrombolysis was observed. © 2014, Springer-Verlag Berlin Heidelberg.

Perez-de-Puig I.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Miro-Mur F.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Ferrer-Ferrer M.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Ferrer-Ferrer M.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | And 11 more authors.
Acta Neuropathologica | Year: 2015

Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow–Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion. © 2014, Springer-Verlag Berlin Heidelberg.

Urra X.,Functional Unit of Cerebrovascular Diseases | Urra X.,Institute dInvestigacions Biomediques August Pi i Sunyer | Chamorro A.,Functional Unit of Cerebrovascular Diseases | Chamorro A.,Institute dInvestigacions Biomediques August Pi i Sunyer
Journal of Neurology | Year: 2013

In this update we review studies on a wide range of topics, from diagnostic aspects of acute stroke to the clinical implications of the complex interaction between the brain and the immune system. Recent randomized trials and observational studies have reinforced the effectiveness of intravenous thrombolysis with t-PA in patients that qualify for this treatment, including patients presenting with mild symptoms or on subtherapeutic oral anticoagulation. Despite all the negative studies on the endovascular treatment of acute stroke, the utility of newer mechanical thrombectomy devices in patients with stroke and large vessel occlusion is being assessed in ongoing clinical trials. In addition to the various revascularization therapies that have a limited time window, treatments aimed at protecting the neurovascular unit may be used in more patients if their efficacy is confirmed in humans, and experimental studies suggest that the modulation of specific aspects of the immune system may increase the likelihood of successful recovery after cerebral ischemia. © 2013 Springer-Verlag Berlin Heidelberg.

Abilleira S.,Agency for Health Quality and Assessment of Catalonia | Ribera A.,Agency for Health Quality and Assessment of Catalonia | Davalos A.,Hospital Germans Trias i Pujol | Ribo M.,Neurovascular Unit | And 24 more authors.
Cerebrovascular Diseases | Year: 2014

Background: Among the acute ischemic stroke patients with large vessel occlusions and contraindications for the use of IV thrombolysis, mainly on oral anticoagulation or presenting too late, primary endovascular therapy is often performed as an alternative to the standard therapy even though evidence supporting the use of endovascular reperfusion therapies is not yet established. Using different statistical approaches, we compared the functional independence rates at 3 months among patients undergoing primary endovascular therapy and patients treated only with IV thrombolysis. Methods: We used data from a prospective, government-mandated and externally audited registry of reperfusion therapies for ischemic stroke (January 2011 to November 2012). Patients were selected if treated with either IV thrombolysis alone (n = 1,582) or primary endovascular thrombectomy (n = 250). A series of exclusions were made to homogenize the clinical characteristics among the two groups. We then carried out multivariate logistic regression and propensity score matching analyses on the final study sample (n = 1,179) to compare functional independence at 3 months, as measured by the modified Rankin scale scores 0-2, between the two groups. Results: The unadjusted likelihood of good outcome was poorer among the endovascular group (OR: 0.69; 95% CI: 0.47-1.0). After adjustment, no differences by treatment modality were seen (OR: 1.51; 95% CI: 0.93-2.43 for primary endovascular therapy). Patients undergoing endovascular thrombectomy within 180-270 min (OR: 2.89; 95% CI: 1.17-7.15) and patients with severe strokes (OR: 1.84; 95% CI: 1.02-3.35) did better than their intravenous thrombolysis counterparts. The propensity score-matched analyses with and without adjustment by additional covariates showed that endovascular thrombectomy was as effective as intravenous thrombolysis alone in achieving functional independence (OR for unadjusted propensity score matched: 1.35; 95% CI: 0.9-2.02, OR for adjusted propensity score matched: 1.45; 95% CI: 0.91-2.32). Conclusion: This comparative effectiveness study shows that in ischemic stroke patients with contraindications for IV thrombolysis, primary endovascular treatment might be an alternative therapy at least as effective as IV thrombolysis alone. Randomized controlled trials are urgently needed. © 2014 S. Karger AG, Basel.

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