Reperfusion therapy in acute ischaemic stroke due to cervical and cerebral artery dissection: Results from a Spanish multicentre study.

INTRODUCTION: Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. METHODS: We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. RESULTS: The study included 21,037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanical thrombectomy, and less frequently received intravenous fibrinolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. CONCLUSIONS: Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologies.

Reperfusion treatment in acute ischaemic stroke due to cervical and cerebral artery dissection: results of a Spanish national multicentre study. / Tratamiento de reperfusión en el ictus isquémico agudo por disección arterial cervicocerebral: descripción de los resultados de un estudio nacional multicéntrico.

INTRODUCTION: Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. METHOD: We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. RESULTS: The study included 21,037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanical thrombectomy, and less frequently received intravenous fibrinolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. CONCLUSIONS: Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologies.

Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment.

BACKGROUND: Cognitive manifestations associated with the severity of a novel coronavirus (COVID-19) infection are unknown. An early detection of neuropsychological manifestations could modify the risk of subsequent irreversible impairment and further neurocognitive decline. METHODS: In our single-center cohort study, we included all consecutive adult patients, aged between 20 and 60 years old with confirmed COVID-19 infection. Neuropsychological assessment was performed by the same trained neuropsychologist from April, 22nd through June 16th, 2020. Patients with previous known cognitive impairment, any central nervous system or psychiatric disease were excluded. Demographic, clinical, pharmacological and laboratory data were extracted from medical records. RESULTS: Thirty-five patients met inclusion criteria and were included in the study. Patients presenting headache, anosmia, dysgeusia, diarrhea and those who required oxygen therapy had lower scores in memory, attention and executive function subtests as compared to asymptomatic patients. Patients with headache and clinical hypoxia scored lower in the global Cognitive Index (P â€‹= â€‹0.002, P â€‹= â€‹0.010). A T score lower than 30 was observed in memory domains, attention and semantic fluency (2 [5.7%]) in working memory and mental flexibility (3 [8.6%]) and in phonetic fluency (4 [11.4%]). Higher scores in anxiety and depression (P â€‹= â€‹0.047, P â€‹= â€‹0.008) were found in patients with cognitive complaints. CONCLUSIONS: In our cohort of COVID-19 patients neurologic manifestations were frequent, including cognitive impairment. Neurological symptoms during infection, diarrhea and oxygen therapy were risk factors for neurocognitive impairment. Cognitive complaints were associated with anxiety and depression.

Aplicabilidad del índice SPAN-100 en una cohorte prospectiva y contemporánea de pacientes tratados con rtPA por vía intravenosa en Cataluña / Applicability of the SPAN-100 index in a prospective and contemporary cohort of patients treated with intravenous rtPA in Catalonia

Introducción: Las escalas pronósticas pueden ayudar a seleccionar pacientes para tratamientos de reperfusión. Objetivo: aplicar el índice SPAN-100 en una cohorte de pacientes tratados con rtPA por vía intravenosa y evaluar su capacidad pronóstica. Métodos: Se utilizaron datos del registro prospectivo de reperfusión de Cataluña y se seleccionaron casos consecutivos que recibieron rtPA por vía intravenosa aislado en 2011-2012. A partir del sumatorio de edad y NIHSS se categorizó la cohorte en SPAN-100 positivos [≥ 100] y SPAN-100 negativos [< 100 puntos]. Se determinaron las tasas crudas y ajustadas de hemorragia sintomática (HICS), muerte e independencia funcional (ERm 0-2) a partir del índice SPAN-100 y se calculó la curva ROC para la predicción de las principales medidas de resultado. Resultados: De los 1.685 casos incluidos, 1.405 (83%) eran SPAN-100 negativos. La tasa de HICS ajustada por sexo, ERm preictus, hipertensión, diabetes, dislipemia, cardiopatía isquémica, insuficiencia cardíaca, fibrilación auricular, ictus/AIT previos y tiempo hasta la trombólisis no fue diferente según las dos categorías pero la probabilidad de tener una ERm 0-2 al 3.er mes fue hasta casi 8 veces mayor entre los SPAN-100 negativos. El riesgo de muerte al 3.er mes fue 5 veces superior en los SPAN-100 positivos. El análisis ROC mostró especificidades altas tanto en la predicción de independencia funcional como mortalidad al 3.er mes cuando el punto de corte era de 100. Conclusiones: El índice SPAN-100 es un índice sencillo y de fácil aplicación que puede guiar la selección de pacientes para trombólisis cuando existen dudas razonables y asesorar al paciente/familia acerca de los resultados esperables

Background: Prognostic scales can be helpful for selecting patients for reperfusion treatment. This study aims to assess the prognostic ability of the recently published SPAN-100 index in a large cohort of stroke patients treated with intravenous thrombolysis (IV rtPA). Methods: Using data from the prospective registery of all reperfusion treatments administered in Catalonia, we selected patients treated with IV rtPA alone between 2011 and 2012. The SPAN-100 index was calculated as the sum of age (years) and NIHSS score, and patients in the cohort were classified as SPAN-100 positive [≥ 100] or SPAN-100 negative [< 100]. We measured raw and adjusted rates of symptomatic intracerebral haemorrhage (SICH), mortality, and 3-month functional outcome (mRS 0-2) for each SPAN-100 category. Area under the ROC curve was calculated to predict the main outcome measures. Results: We studied 1685 rtPA-treated patients, of whom 1405 (83%) were SPAN-100 negative. The SICH rates adjusted for sex, pre-stroke mRS, hypertension, diabetes, dyslipidaemia, ischaemic heart disease, heart failure, atrial fibrillation, prior TIA/stroke and time to thrombolysis did not differ between groups, but likelihood of functional independence (mRS 0-2) at 3 months was nearly 8 times higher in the SPAN-100 negative group than in the positive group. Furthermore, the 3-month mortality rate was 5 times higher in the SPAN-100 positive group. ROC curve analysis showed high specificities for predicting both functional independence and 3-month mortality for a cut-off point of 100. Conclusion: The SPAN-100 index is a simple and straightforward method that may be useful for selecting candidates for rtPA treatment in doubtful cases, and for informing patients and their relatives about likely outcomes

Applicability of the SPAN-100 index in a prospective and contemporary cohort of patients treated with intravenous rtPA in Catalonia. / Aplicabilidad del índice SPAN-100 en una cohorte prospectiva y contemporánea de pacientes tratados con rtPA por vía intravenosa en Cataluña.

BACKGROUND: Prognostic scales can be helpful for selecting patients for reperfusion treatment. This study aims to assess the prognostic ability of the recently published SPAN-100 index in a large cohort of stroke patients treated with intravenous thrombolysis (IV rtPA). METHODS: Using data from the prospective registery of all reperfusion treatments administered in Catalonia, we selected patients treated with IV rtPA alone between 2011 and 2012. The SPAN-100 index was calculated as the sum of age (years) and NIHSS score, and patients in the cohort were classified as SPAN-100 positive [≥ 100] or SPAN-100 negative [< 100]. We measured raw and adjusted rates of symptomatic intracerebral haemorrhage (SICH), mortality, and 3-month functional outcome (mRS 0-2) for each SPAN-100 category. Area under the ROC curve was calculated to predict the main outcome measures. RESULTS: We studied 1685 rtPA-treated patients, of whom 1405 (83%) were SPAN-100 negative. The SICH rates adjusted for sex, pre-stroke mRS, hypertension, diabetes, dyslipidaemia, ischaemic heart disease, heart failure, atrial fibrillation, prior TIA/stroke and time to thrombolysis did not differ between groups, but likelihood of functional independence (mRS 0-2) at 3 months was nearly 8 times higher in the SPAN-100 negative group than in the positive group. Furthermore, the 3-month mortality rate was 5 times higher in the SPAN-100 positive group. ROC curve analysis showed high specificities for predicting both functional independence and 3-month mortality for a cut-off point of 100. CONCLUSION: The SPAN-100 index is a simple and straightforward method that may be useful for selecting candidates for rtPA treatment in doubtful cases, and for informing patients and their relatives about likely outcomes.

La resistencia en el tratamiento secundario del ictus isquémico, el componente genético en la respuesta a ácido acetilsalicílico y clopidogrel / Drug resistance and secondary treatment of ischaemic stroke: The genetic component of the response to acetylsalicylic acid and clopidogrel

Introducción: Las enfermedades cerebrovasculares están entre las principales causas de mortalidad y discapacidad en los países desarrollados. El ácido acetilsalicílico (AAS) y el clopidogrel son los tratamientos antiagregantes plaquetarios más utilizados para la profilaxis de nuevos eventos tromboembólicos. Sin embargo, se han observado casos en los que el tratamiento antiagregante no inhibe la actividad plaquetaria, un fenómeno llamado resistencia y que posiblemente puede estar modulado a nivel genético. Desarrollo: Tras una búsqueda bibliográfica se realizó una revisión sobre el estado actual del tratamiento antiagregante plaquetario. Se tratan los diferentes tipos de resistencia a la terapia antiagregante, de qué manera se mide, la problemática y limitaciones actuales, así como los factores genéticos que se han asociado a esta resistencia. Principalmente se analizan los estudios genéticos realizados en el campo de la resistencia a AAS y clopidogrel mediante Genome Wide Association. Conclusiones: Parece existir una asociación entre diferentes factores genéticos y la resistencia a los fármacos antiagregantes medida mediante la actividad plaquetaria; no obstante, no hay una asociación evidente entre estos factores genéticos y el riesgo de nuevos eventos tromboembólicos

Introduction: Cerebrovascular diseases are among the leading causes of death and disability in developed countries. Acetylsalicylic acid (ASA) and clopidogrel are the most widely-used antiplatelet drugs for secondary prevention of recurrent thromboembolic events. However, there have been cases in which antiplatelet drugs did not inhibit platelet activity; this phenomenon is called resistance, and it may be modulated at the genetic level. Development: Following a literature search, we reviewed the current state of antiplatelet therapy and covered the different types of resistance to antiplatelet therapy, how it is measured, current problems and limitations, and any genetic factors that have been associated with resistance. We mainly used the Genome Wide Association Studies in the field of ASA and clopidogrel resistance. Conclusions: We observed an association between different genetic factors and antiplatelet drug resistance as measured by platelet activity. However, there is no evident association between these genetic factors and risk of new thromboembolic events

Monomeric C-reactive protein--a key molecule driving development of Alzheimer's disease associated with brain ischaemia?

Alzheimer's disease (AD) increases dramatically in patients with ischaemic stroke. Monomeric C-reactive protein (mCRP) appears in the ECM of ischaemic tissue after stroke, associating with microvasculature, neurons and AD-plaques, Aß, also, being able to dissociate native-CRP into inflammatory, mCRP in vivo. Here, mCRP injected into the hippocampal region of mice was retained within the retrosplenial tract of the dorsal 3rd ventrical and surrounding major vessels. Mice developed behavioural/cognitive deficits within 1 month, concomitant with mCRP staining within abnormal looking neurons expressing p-tau and in beta-amyloid 1-42-plaque positive regions. mCRP co-localised with CD105 in microvessels suggesting angiogenesis. Phospho-arrays/Western blotting identified signalling activation in endothelial cells and neurons through p-IRS-1, p-Tau and p-ERK1/2-which was blocked following pre-incubation with mCRP-antibody. mCRP increased vascular monolayer permeability and gap junctions, increased NCAM expression and produced haemorrhagic angiogenesis in mouse matrigel implants. mCRP induced tau244-372 aggregation and assembly in vitro. IHC study of human AD/stroke patients revealed co-localization of mCRP with Aß plaques, tau-like fibrils and IRS-1/P-Tau positive neurons and high mCRP-levels spreading from infarcted core regions matched reduced expression of Aß/Tau. mCRP may be responsible for promoting dementia after ischaemia and mCRP clearance could inform therapeutic avenues to reduce the risk of future dementia.

Drug resistance and secondary treatment of ischaemic stroke: The genetic component of the response to acetylsalicylic acid and clopidogrel.

INTRODUCTION: Cerebrovascular diseases are among the leading causes of death and disability in developed countries. Acetylsalicylic acid (ASA) and clopidogrel are the most widely-used antiplatelet drugs for secondary prevention of recurrent thromboembolic events. However, there have been cases in which antiplatelet drugs did not inhibit platelet activity; this phenomenon is called resistance, and it may be modulated at the genetic level. DEVELOPMENT: Following a literature search, we reviewed the current state of antiplatelet therapy and covered the different types of resistance to antiplatelet therapy, how it is measured, current problems and limitations, and any genetic factors that have been associated with resistance. We mainly used the Genome Wide Association Studies in the field of ASA and clopidogrel resistance. CONCLUSIONS: We observed an association between different genetic factors and antiplatelet drug resistance as measured by platelet activity. However, there is no evident association between these genetic factors and risk of new thromboembolic events.

Expression of the vitamin K-dependent proteins GAS6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques.

The GAS6/ProS-TAM system is composed of two vitamin K-dependent ligands (GAS6 and protein S) and their three protein tyrosine kinase receptors TYRO3, AXL and MERTK, known as the TAM receptors. The system plays a prominent role in conditions of injury, inflammation and repair. In murine models of atherosclerotic plaque formation, mutations in its components affect atherosclerosis severity. Here we used Taqman low-density arrays and immunoblotting to study mRNA and protein expression of GAS6, ProS and the TAM receptors in human carotid arteries with different degrees of atherosclerosis. The results show a clear down-regulation of the expression of AXL in atheroma plaques with respect to normal carotids that is matched by decreased abundance of AXL in protein extracts detected by immunoblotting. A similar decrease was observed in PROS1 mRNA expression in atherosclerotic carotids compared to the normal ones, but in this case protein S (ProS) was clearly increased in protein extracts of carotid arteries with increasing grade of atherosclerosis, suggesting that ProS is carried into the plaque. MERTK was also increased in atherosclerotic carotid arteries with respect to the normal ones, suggesting that the ProS-MERTK axis is functional in advanced human atherosclerotic plaques. MERTK was expressed in macrophages, frequently in association with ProS, while ProS was abundant also in the necrotic core. Our data suggest that the ProS-MERTK ligand-receptor pair was active in advanced stages of atherosclerosis, while AXL signalling is probably down-regulated.

Combining nanotechnology with current biomedical knowledge for the vascular imaging and treatment of atherosclerosis.

Activation of vasa vasorum (the microvessels supplying the major arteries) at specific sites in the adventitia initiates their proliferation or 'angiogenesis' concomitant with development of atherosclerotic plaques. Haemorrhagic, leaky blood vessels from unstable plaques proliferate abnormally, are of relatively large calibre but are immature neovessels poorly invested with smooth muscle cells and possess structural weaknesses which may contribute to instability of the plaque by facilitation of inflammatory cell infiltration and haemorrhagic complications. Weak neovascular beds in plaque intima as well as activated adventitial blood vessels are potential targets for molecular imaging and targeted drug therapy, however, the majority of tested, currently available imaging and therapeutic agents have been unsuccessful because of their limited capacity to reach and remain stably within the target tissue or cells in vivo. Nanoparticle technology together with magnetic resonance imaging has allowed the possibility of imaging of neovessels in coronary or carotid plaques, and infusion of nanoparticle suspensions using infusion catheters or implant-based drug delivery represents a novel and potentially much more efficient option for treatment. This review will describe the importance of angiogenesis in mediation of plaque growth and development of plaque instability and go on to investigate the possibility of future design of superparamagnetic/perfluorocarbon-derived nanoparticles for imaging of the vasculature in this disease or which could be directed to the adventitial vasa vasorum or indeed intimal microvessels and which can release active payloads directed against primary key external mitogens and intracellular signalling molecules in endothelial cells responsible for their activation with a view to inhibition of angiogenesis.

Identification of a 'snapshot' of co-expressed angiogenic markers in laser-dissected vessels from unstable carotid plaques with targeted arrays.

BACKGROUND/AIMS: Angiogenesis is a feature of the atherogenic process, with intimal neovascularisation arising from vessels in the adventitia, adjacent to a plaque. Immature, leaky blood vessels from unstable plaques proliferate abnormally and, being poorly invested with smooth muscle cells, may contribute to instability of the plaque by facilitation of inflammatory cell infiltration and haemorrhagic complications. METHODS: We used laser-capture microdissection to isolate angiogenic areas of the extracellular matrix (containing CD105/flt-1-positive, fragile thin-walled vessels) and non-angiogenic vascular areas (CD105-negative, with smooth muscle cell covering) of complicated endarterectomy plaques, and specifically designed angiogenesis-TaqMan real-time PCR microarrays to identify gene expression. RESULTS: Important pro-angiogenic components, including Notch-3, delta-like-4 (DLL4), Tie-2, angiopoietin-1 (Angio-1) and receptor for advanced glycation end products (RAGE), and one anti-angiogenic factor, endostatin, were up-regulated in these regions. Immunohistochemistry demonstrated localisation within intimal, active (CD105-positive) microvessels and co-localisation of Notch-3 and DLL4/Tie-2 and Angio-1 in the same vessels indicating multiple/synergistic signalling mechanisms associated with vessel development. CONCLUSION: These data, although providing only a snapshot of information, demonstrate that plaque vascularisation occurs in the presence of multiple angiogenically active factors. Knowledge of their combined effects could help in the formulation of novel therapeutics designed to stabilise or prevent their formation in the treatment of atherosclerosis.

A role for monomeric C-reactive protein in regulation of angiogenesis, endothelial cell inflammation and thrombus formation in cardiovascular/cerebrovascular disease?

Native CRP (nCRP) is a pentameric oligoprotein composed of identical 23 KDa subunits which can be irreversibly dissociated to form free subunits or monomeric CRP (mCRP). mCRP has a reduced aqueous solubility and a tendency to aggregate into matrix-like lattices in various tissues, in particular, blood vessel walls. A dramatic increase in expression of mCRP occurs in angiogenic blood vessels derived from stroked brain regions, atherosclerotic arteries and active vessels from other angiogenic diseases such as Alzheimer's. Furthermore, mCRP unlike the native molecule is highly angiogenic to vascular endothelial cells in vitro and therefore might impact on the processes of vascularization and re-modelling thus affecting tissue survival and development. In this mini-review, we will discuss the differences in the biological properties between nCRP and mCRP. We will provide a brief historical background to the importance of nCRP as a biomarker for cardiovascular disease. We will explain the mechanisms of conversion of nCRP to its monomeric form and describe evidence for the role of mCRP in modulation of endothelial cell activation, promotion of inflammatory status and thrombus formation in cardio/cerebrovascular disease. Finally, we will provide evidence for the accumulation of mCRP in angiogenic microvessels from diseased tissue, and demonstrate its highly pro-angiogenic capabilities. The discovery of the existence of this tissue-associated, highly angiogenic monomeric form of CRP capable of cellular binding and intra-cellular signal transduction activation may help in our understanding of the processes responsible for modulation of angiogenesis and inflammation in disease.

B-cell translocation gene 2 is over-expressed in peri-infarct neurons after ischaemic stroke.

OBJECTIVES: Recovery from stroke is dependent on the survival of neurons in the dynamic peri-infarcted region. Although several markers of neuronal injury and apoptotic cell death have been described, administration of neuroprotective drugs directed at specific molecules has had limited success. A complete understanding of deregulated genes associated with neuronal death would be beneficial. Our previous microarray studies identified increased expression of a novel protein, the B-cell translocation gene 2 (BTG2), in infarcted regions. METHODS: We have used immunohistochemistry and Western blotting to examine the expression and localization of BTG2 in stroked brain tissue and immunofluorescent staining of human fetal brain neurons to determine if oxygen-glucose deprivation affected its expression. RESULTS: We show that BTG2 is strongly expressed in peri-infarcted and infarcted regions of brain tissue, localizing in neuronal nuclei and cytoplasm, whilst being absent or very weakly expressed in normal looking contralateral tissue. Exposure of human fetal brain neurons to oxygen-glucose deprivation also induced BTG2 expression in the cytoplasm and perinuclear regions of cells staining positive for propidium iodide (a marker of nuclear damage). CONCLUSIONS: BTG2 may be a modulator of cell survival and differentiation and could help to protect against cell death by inhibition of necrosis and/or apoptotic signalling pathways.

New VEGF antagonists as possible therapeutic agents in vascular disease.

BACKGROUND: In this review we provide the reader with an analysis of the importance of VEGF in modulating the angiogenic process in vascular diseases. OBJECTIVES: We have described the key role of VEGF in the development of the major angiogenic diseases including ocular retinopathies, solid tumour growth and atherosclerotic plaque development. METHODS: Following a brief description of the disease, a detailed literature review of the mechanisms through which VEGF induces promotion of neovascularisation and current anti-VEGF therapies is provided for the reader. RESULTS/CONCLUSIONS: Current and future potential clinical therapies are discussed in particular concerning our thoughts on future directives involving adenoviral-mediated gene targeting, nanotechnology and combinational therapies.

Atherothrombosis and plaque heterology: different location or a unique disease?

Formation of unstable plaques frequently results in atherothrombosis, the major cause for ischaemic stroke, myocardial infarction and peripheral arterial disease. Patients who have symptomatic thrombosis in one vascular bed are at increased risk of disease in other beds. However, the development of the disease in carotid, coronary and peripheral arteries may have different pathophysiology suggesting that more complex treatment protocols may have to be designed to reduce plaque development at different locations. In this review we describe the known risk factors, compare the developmental features of coronary and carotid plaque development and determine their association with end-point ischaemic events. Differences are also seen in the genetic contribution to plaque development as well as in the deregulation of gene and protein expression and cellular signal transduction activity of active cells in regions susceptible to thrombosis. Differences between carotid and coronary artery plaque development might help to explain the differences in anatomopathological appearance and risk of rupture.

Leukaemia inhibitory factor is over-expressed by ischaemic brain tissue concomitant with reduced plasma expression following acute stroke.

Leukaemia inhibitory factor (LIF) is a glycoprotein of the interleukin-6 family, which has potent pro-inflammatory properties and is involved in regulation of neuronal differentiation. We have previously identified its upregulation in gene microarrays following acute ischaemic stroke in man. LIF expression and localization was measured in human ischaemic stroke autopsy specimens, in a rat model of middle cerebral artery occlusion (MCAO) and in human foetal neural cell cultures following oxygen-glucose deprivation (OGD) by Western blotting and immunohistochemistry. Circulating LIF was determined in the plasma of patients in the hyper-acute stroke phase using a multiplex enzyme-linked-immunosorbent serologic assay system. Patients demonstrated an increase in LIF expression in peri-infarcted regions with localization in neurons and endothelial cells of microvessels surrounding the infarcted core. The rat MCAO model showed similar upregulation in neurons with a peak increase at 90 min. Circulating serum LIF expression was significantly decreased in the hyper-acute phase of stroke. Brain-derived neurons and glia cultured in vitro demonstrated an increase in gene/protein and protein expression respectively following exposure to OGD. Increased LIF expression in peri-infarcted regions and sequestration from the peripheral circulation in acute stroke patients are characteristic of the pathobiological response to ischaemia and tissue damage.

Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial.

Although statins are being used for secondary prevention of ischemic stroke, recent experimental data have shown new pleiotropic effects of these drugs responsible for their role in neuroprotection. We conducted a pilot, double-blind, randomized, multicenter clinical trial to study for the first time safety and efficacy of simvastatin in the acute phase of ischemic stroke. Simvastatin/placebo was given at 3-12 h from symptom onset to 60 patients with cortical strokes. Efficacy on the evolution of several inflammation markers [interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, C-reactive protein, sApo/Fas, tumor necrosis factor-alpha, E-selectin, L-selectin and nitrites+nitrates] and neurological outcome was evaluated at baseline, day 1, 3, 5, 7 and 90. No differences were found amongst the biomarkers studied regarding treatment allocation. Although simvastatin patients improved significantly by the third day (46.4% vs. 17.9%, P = 0.022), a non-significant increase in mortality and greater proportion of infections (odds ratio 2.4, confidence interval 1.06-5.4) in the simvastatin group were the main safety concerns. Therefore, a larger clinical trial is needed to confirm the net benefit of this therapeutic approach.

Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets.

Stroke continues to be a major cause of death and disability. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signalling proteins which could be exploited to design novel therapeutic modalities. The pathophysiology of stroke is a complex process. Delaying interventions from the first hours to days or even weeks following blood vessel occlusion may lead to worsening or impairment of recovery in later stages. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, especially the role of cell signalling in excitotoxicity, inflammation, apoptosis, neuroprotection and angiogenesis, and highlight potential novel targets for drug discovery.

Citicoline inhibits MAP kinase signalling pathways after focal cerebral ischaemia.

The link between membrane phospholipids and different intracellular signal transduction pathways affected by cerebral ischaemia is unclear. CDP-choline, a major neuronal membrane lipid precursor and its intracellular target proteins and transcription factors were studied to further understand its role in ischaemic stroke. Cerebral ischaemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Animals receiving 500 mg/kg of CDP-choline in 0.5 ml of 0.9% saline, intraperitoneally, 24 h and 1 h before MCAO and 23 h after MCAO demonstrated a notable reduction in the phosphorylation of MAP-kinase family members, ERK1/2 and MEK1/2, as well as Elk-1 transcription factor, compared with control animals treated with 0.5 ml of 0.9% saline. Immunohistochemistry showed a particular reduction in immunoreactivity in glia. The effects of CDP-choline on intracellular mechanisms of signal transduction, suggests that this molecule may play a key role in recovery after ischaemic stroke.

Gene activation and protein expression following ischaemic stroke: strategies towards neuroprotection.

Current understanding of the patho-physiological events that follow acute ischaemic stroke suggests that treatment regimens could be improved by manipulation of gene transcription and protein activation, especially in the penumbra region adjacent to the infarct. An immediate reduction in excitotoxicity in response to hypoxia, as well as the subsequent inflammatory response, and beneficial control of reperfusion via collateral revascularization near the ischaemic border, together with greater control over apoptotic cell death, could improve neuronal survival and ultimately patient recovery. Highly significant differences in gene activation between animal models for stroke by middle cerebral artery occlusion, and stroke in patients, may explain why current treatment strategies based on animal models of stroke often fail. We have highlighted the complexities of cellular regulation and demonstrated a requirement for detailed studies examining cell specific protective mechanisms after stroke in humans.