Molecular Mechanism of Electroacupuncture Regulating Cerebral Arterial Contractile Protein in Rats with Cerebral Infarction Based on MLCK Pathway / 中国结合医学杂志

OBJECTIVE@#To explore the effect of electroacupuncture (EA) intervention on the vasoconstriction of cerebral artery smooth muscle cells after cerebral infarction.@*METHODS@#Male Wistar rats were randomly divided into 3 groups by a random number table: the model group (n=24), the EA group (n=24), and the normal group (n=6). The model and the EA groups were divided into different time subgroups at 0.5, 1, 3, and 6 h after middle cerebral artery occlusion (MCAO), with 6 rats in each subgroup. MCAO model was established using intraluminal suture occlusion method. The EA group was given EA treatment at acupoint Shuigou (GV 26) instantly after MCAO for 20 min. The contents of cerebrovascular smooth muscle MLCK, the 3 subunits of myosin light chain phosphatase (MLCP) MYPT1, PP1c-δ and M20, as well as myosin-ATPase activity were detected using immunohistochemistry and Western blotting.@*RESULTS@#The overall expression level of the MYPT1 and PP1c-δ in the model group was significantly higher (P<0.01). After EA intervention, the 0.5 h group expression level was close to that of the normal group (P>0.05), and the other subgroups were still significantly higher than the normal group (P<0.01). After EA intervention, the expression level of each subgroup was significantly lower than the corresponding model group. There was a significant difference between the 0.5 and 1 h subgroups (P<0.01), while a difference was also observed between the 3 and 6 h subgroups (P<0.05). The dynamic change rule gradually increased with the prolongation of infarction time within 6 h after infarction.@*CONCLUSION@#EA intervention can inhibit contraction of cerebral vascular smooth muscle cells and regulate smooth muscle relaxation by regulating MLCK pathway.

Epidemiological analysis of stroke patients with emphasis on access to acute-phase therapies / Análise epidemiológica de pacientes com AVC com ênfase no acesso às terapias de fase aguda

ABSTRACT Background: Stroke is a public health problem. For patients with ischemic stroke, venous thrombolysis and mechanical thrombectomy are effective therapeutic options. However, even after the National Stroke Treatment Guidelines were published in 2012, the number of cases treated is still lower than expected. Objective: To identify the determining factors for obtaining access to acute-phase therapies in the state of Espírito Santo (ES) and investigate the profile of stroke patients treated at the Central State Hospital (HEC). Methods: Retrospective data from the medical records of 1078 patients from May 2018 to December 2019 were analyzed. Results: Among the 1,078 patients, 54.9% were men and the most prevalent age group was 60 to 79 years. Systemic arterial hypertension was the main single risk factor. Regarding treatment modality among the patients who arrived at the HEC within the therapeutic window, 47% received some type of acute-phase therapy. Waking up with the deficit was the main contraindication for venous thrombolysis in these cases. Conclusions: Application of the flowchart established by SESA-ES seemed to be effective for enabling responsiveness of care for stroke victims. Public emergency transport services had a fundamental role in this process. In addition, the care provided by the tertiary stroke center provided excellent access to acute-phase therapies. However, despite the efficiency of the service provided at the HEC, it only reached a maximum of 50% of the ES population. This service model therefore needs to be expanded throughout the state.

RESUMO Antecedentes: O acidente vascular cerebral (AVC) é um problema de saúde pública. Nos casos de AVC isquêmico, a trombólise venosa e a trombectomia mecânica são efetivas opções terapêuticas de fase aguda. Entretanto, mesmo com a Diretriz Nacional de AVC publicada desde 2012, o número de casos tratados ainda é baixo. Objetivo: Apurar os fatores determinantes para o acesso às terapias de fase aguda na realidade espírito-santense e investigar o perfil dos pacientes de AVC atendidos no Hospital Estadual Central de Vitória (HEC). Métodos: O presente estudo analisou dados retrospectivos de prontuários de 1.078 pacientes no período de maio de 2018 a dezembro de 2019. Resultados: Dos 1.078 pacientes, 54,9% eram homens e a faixa etária mais prevalente foi a de 60 a 79 anos. A hipertensão arterial sistêmica foi o principal fator de risco isolado. Quanto ao tratamento, identificou-se que entre os pacientes que chegaram ao HEC na janela terapêutica 47% receberam terapia de fase aguda e que acordar com o déficit foi a principal contraindicação para trombólise venosa nesses casos. Conclusões: As análises demonstraram que a aplicação do fluxograma estabelecido pela Secretaria de Estado da Saúde do Espírito Santo parece ser eficaz na agilidade de atendimento das vítimas de AVC e que o Serviço de Atendimento Móvel de Urgência tem um papel fundamental nesse processo. Além disso, a assistência de um centro terciário de AVC permite acesso às terapias de fase aguda com excelência. Todavia, mesmo que o modelo de serviço prestado no HEC seja eficiente, ele atinge no máximo 50% da população do ES, sendo necessária a sua ampliação.

Analysis of status quo of outcome indicators of randomized controlled trials in treatment of acute ischemic stroke with acupuncture in recent three years / 中国中药杂志

To analyze the use of outcome indicators of randomized controlled trial(RCT) of acupuncture in the treatment of acute ischemic stroke in recent three years, so as to provide a basis for building a study on the core outcome indicators for the treatment of acute ischemic stroke with acupuncture. The RCTs of acupuncture treatment for acute ischemic stroke in recent three years were collec-ted through computer retrieval of eight Chinese and English databases and two clinical trial registries at home and abroad. Literature was screened out, and data was extracted. Risk of assessment bias tool Cochrane 6.1 was used for bias risk assessment, outcome indicators were summarized and analyzed. A total of 47 RCTs were included, and 3 studies were trials registration scheme. Outcome indicators were divided into 6 categories according to functional attributes, namely physical symptoms/signs, physical and chemical examination, quality of life, traditional Chinese medicine symptoms/syndromes, safety events and long-term prognosis. The study found that in addition to the common problems in previous studies covered by the status quo of outcome indicators selection of RCT of acupuncture in the treatment of acute ischemic stroke, there were also the other problems as follows: emphasis on macroscopic efficacy indicators but neglect of acupuncture specific indicators, lack of characteristic indicators and economic indicators of traditional Chinese medicine therapy, and unification of indicators measurement tool and measurement time point. In the future, the outcome indicators set for the treatment of acute ischemic stroke with acupuncture shall be established, and the core outcome indicators set shall be in line with the characteristics of traditional Chinese medicine treatment.

Effect of Yes-associated protein in regulation of electroacupuncture pretreatment on cerebral ischemia reperfusion injury rats / 中国针灸

OBJECTIVE@#To observe the effect of electroacupuncture (EA) pretreatment on inflammatory reaction, apoptosis and expression of Yes-associated protein (YAP) of ischemic penumbra of cerebral cortex in cerebral ischemia reperfusion injury rats, and to explore the possible mechanism of its neuroprotection effect.@*METHODS@#A total of 84 SD rats were randomized into a sham operation group (12 rats), a model group (18 rats), an EA group (18 rats), an EA+YAP virus transfection group (18 rats) and an EA+virus control group (18 rats). Except for the sham operation group, thread embolization method was adopted to establish the middle cerebral artery occlusion (MCAO) model in rats of the other groups. EA was applied at "Baihui" (GV 20) and "Dazhui" (GV 14) for 30 min in the 3 EA intervention groups 2 h before model establishment, disperse-dense wave, 2 Hz/15 Hz in frequency and 1 mA in intensity. Adenovirus transfection technique was used to induce gene silencing of YAP in the EA+YAP virus transfection group, and adenovirus vectors was injected as negative control in the EA+virus control group 4 d before model establishment. Twenty-four hours after model establishment, neurological function score was evaluated, the relative cerebral infarction area was observed by TTC staining, the apoptosis in the ischemic penumbra of cerebral cortex was detected by TUNEL staining, the levels of inflammatory factors IL-1β, IL-6 and TNF-α in the ischemic penumbra of cerebral cortex was detected by ELISA method, the expression of YAP was detected by Western blot and immunofluorescence.@*RESULTS@#Compared with the sham operation group, the expression of YAP was increased in the model group (@*CONCLUSION@#Electroacupuncture pretreatment can effectively improve the ischemia reperfusion injury, its mechanism may be related to up-regulating the expression of YAP in the ischemic penumbra of cerebral cortex and relieving the apoptosis and inflammatory reaction.

The use of e-ASPECTS in acute stroke care: validation of method performance compared to the performance of specialists / O uso do e-ASPECTS no AVC agudo: validação da performance do método comparada com a performance dos especialistas

ABSTRACT Background: The rapid evaluation of non-contrast-enhanced computed tomography (NCCT) brain scans in patients with anterior stroke symptoms saves time and favors optimal and prompt treatment. e-ASPECTS is a tool that automatically calculates the Alberta Stroke Program Early CT Score (ASPECTS) values, leading to a more accurate and timely image evaluation. Objective: To determine the ability of e-ASPECTS in differentiating images with and without injury. Methods: One-hundred sixteen patients admitted to a stroke unit in a Brazilian tertiary hospital underwent a CT scan at admission and at least one control brain imaging (NCCT or magnetic resonance imaging - MRI) 24 hours after admission. ASPECTS evaluation was performed by three neuroradiologists, three neurologists, and three neurology residents, all blinded to the symptoms and the injury side. The scores were compared to the ground truth, and an ASPECTS score was provided by two independent non blinded evaluators. Sensitivity and specificity were analyzed, and receiver operating characteristic curves, Bland-Altman plots with mean error score, and Matthews correlation coefficients (MCCs) were obtained for ASPECTS scores, assuming values equal to 10 for images without injury and values other than 10 for images with ischemic injury. Results: e-ASPECTS demonstrated similar performance to that of neuroradiologists and neurologists, with an area under the curve of 0.78 and an MCC value of 0.48 in the dichotomous analysis. The sensitivity and specificity of e-ASPECTS were 75% and 73%, respectively. Conclusion: e-ASPECTS is a validated and reliable tool for determining early signs of ischemia in NCCT.

RESUMO Introdução: A avaliação rápida da tomografia de crânio sem contraste (TCSC) em pacientes com AVC de circulação anterior economiza tempo e permite um tratamento rápido e otimizado. O e-ASPECTS é um software que calcula automaticamente os valores do ASPECTS e permite uma avaliação da imagem mais precisa e ágil. Objetivo: Determinar a habilidade do e-ASPECTS em diferenciar imagens com e sem lesão. Métodos: Cento e dezesseis pacientes admitidos em uma unidade de AVC de um hospital terciário brasileiro foram submetidos a uma TCSC na admissão e pelo menos uma imagem de controle (TC ou Ressonância de Crânio) 24 horas após a admissão. A avaliação do ASPECTS foi realizada por três neurorradiologistas, três neurologistas e três residentes em neurologia, todos cegados para os sintomas e para o lado da lesão. Os valores foram comparados ao ground truth (GT) e uma pontuação ASPECTS foi obtida por dois avaliadores independentes não cegos. Análise da sensibilidade e especificidade, características das curvas ROC, gráficos de Bland-Altman com média de escore de erro e coeficientes de correlação de Matthews (CCM) foram realizados para os valores de ASPECTS, assumindo valores iguais a 10 como imagens sem lesões e valores diferentes de 10 como imagens com alguma lesão isquêmica. Resultados: o e-ASPECTS demonstrou uma performance similar aos neurorradiologistas e neurologistas, com uma área sob a curva de 0,78 e um valor de CCM de 0,48 na análise dicotômica. Sensibilidade e especificidade do e-ASPECTS foram, respectivamente, 75 e 73%. Conclusão: O e-ASPECTS é uma ferramenta confiável e validada para determinar sinais precoces de isquemia nas TCSC.

Morphometric analysis and pattern of protein and gene expression of apoptosis in focal cerebral ischemia in rats and the neuroprotetive action of hypothermia and ketoprofen / Análisis morfométrico y modelo de expresión de proteína y genes de apoptosis en isquemia cerebral focal en ratas y la acción neuroprotectora de hipotermia y ketoprofeno

This study aimed to investigate the morphometric and the pattern of protein and gene expression related to the extrinsic apoptotic pathway in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. For this analysis, 120 rats were randomly divided into 3 groups (20 animals each): control - no surgery (20 animals); sham - simulation of surgery (20 animals); ischemic - focal ischemia for 1 hour, without reperfusion (80 animals) and divided into four subgroups with 20 animals each: ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the apoptosis genes (Fas, c-Flip, caspase-8 and caspase-3) and the apoptosis protein caspase-3 were evaluated by quantitative real-time PCR and immunohistochemistry, respectively. Hypo expression of genes of extrinsic pathway of apoptosis was observed: Fas receptor, c-Flip and caspase-8 in the ischemics areas. Increases in the gene and protein caspase-3 in the ischemic areas were also observed, and these increases were reduced by hypothermia and ketoprofen, also noted in the morphometric study. The caspases-3 increase suggests that this gene plays an important role in apoptosis, probably culminating in cell death and that the neuroprotective effect of hypothermia and ketoprofen is involved.

Este estudio tuvo como objetivo investigar la morfometría y el patrón de expresión de proteínas y genes relacionados con la vía apoptótica extrínseca en la isquemia cerebral focal experimental y el agujero de neuroprotección con hipotermia y ketoprofeno. Se dividieron aleatoriamente 120 ratas en 3 grupos (20 animales cada uno): control - sin cirugía (20 animales); simulación - simulación de cirugía (20 animales); isquemia isquemia focal durante 1 hora, sin reperfusión (80 animales) y dividida en cuatro subgrupos con 20 animales cada uno: isquemia + hipotermia intraisquémica; isquemia + ketoprofeno intravenoso previo, e isquemia + hipotermia y ketoprofeno. El volumen del infarto se midió utilizando un análisis morfométrico de áreas de infarto definidas por cloruro de trifenil tetrazolio y los patrones de expresión de los genes de apoptosis (Fas, c-Flip, caspase-8 y caspase-3) y la proteína de apoptosis caspase-3 fueron evaluados por PCR cuantitativa en tiempo real e inmunohistoquímica, respectivamente. Se observó hipoexpresión de genes de la vía extrínseca de la apoptosis: receptor Fas, c-Flip y caspasa-8 en las áreas isquémicas. También se observaron aumentos en el gen y la proteína caspasa-3 en las áreas isquémicas y estos aumentos se redujeron por hipotermia y ketoprofeno, también observado por estudio morfométrico. El aumento de caspasas-3 sugiere que este gen tiene un papel importante en la apoptosis, y probable causa de muerte celular, involucrando el efecto neuroprotector de la hipotermia y el ketoprofeno.

Combinación de bardoxolona y DMF Mejora la isquemia cerebral/reperfusión Lesión en ratas macho / Combination of Bardoxolone and DMF Ameliorates Cerebral Ischemia / Reperfusion Injury in Male Rats

Background: Ischemic stroke has been ranked as the second cause of death in patients worldwide. Inflammation which is activated during cerebral ischemia/reperfusion (I/R) is an important mechanism leading to brain injury. The present study aimed to investigate the effect of Berberine on cerebral I/R injury and the role of inflammation in this process. Material and Methods: The study was carried out on 36 Wistar-albino rats, divided into four groups including: Sham group, I/R group, I/R+ (control-vehicle DMSO) and I/R+ Berberine 5 mg/kg injected intraperitoneally 1 hour before induction of ischemia. Measurement of brain tissue IL-1ß, ICAM1, caspase-3, Notch 1 and Jagged 1 was done after one hour of reperfusion in addition to assessment of the brain infracted area and histopathological analysis. Results: Berberine attenuates cerebral I/R injury induced increase in inflammatory cytokine (IL-1ß), adhesion molecule (ICAM-1) and proapoptotic enzyme (caspase-3). Additionally, it reduces the size of infracted area and histopathological damage; such protective effect could be mediated by Notch 1 signaling pathway since Berberine further unregulated the increased levels of Notch 1 and Jagged 1 seen in brain with I/R injury. Conclusions: Berberine has a neurocytoprotective outcome against cerebral I/R injury which is manifested as anti-inflammatory anti-apoptotic effect that preserved cell structure and viability, in the meantime this effect could be mediated by Notch 1 signaling pathway.

Mechanical thrombectomy for reperfusion of acute ischemic stroke in a Stroke Unit in Argentina / Trombectomía mecánica para la reperfusión en el accidente cerebrovascular agudo en una Unidad Cerebrovascular de Argentina

Abstract Stroke is an important cause of morbidity and mortality worldwide. Reperfusion therapy with intravenous tissue plasminogen activator (IV-tPA) was first implemented in 1996. More recently, endovascular reperfusion with mechanical thrombectomy (MT) demonstrated a robust beneficial effect, extending the 4.5 h time window. In our country, there are difficulties to achieve the implementation of both procedures. Objective: Our purpose is to report the early experience of a Comprehensive Stroke Center in the use of MT for acute stroke. Methods: Analysis of consecutive patients from January 2015 to September 2018, who received reperfusion treatment with MT. Demographic data, treatment times, previous use of IV-tPA, site of obstruction, recanalization, outcomes and disability after stroke were assessed. Results: We admitted 891 patients with acute ischemic stroke during this period. Ninety-seven received IV-tPA (11%) and 27 were treated with MT (3%). In the MT group, mean age was 66.0±14.5 years. Median NIHSS before MT was 20 (range:14‒24). The most prevalent etiology was cardioembolic stroke (52%). Prior to MT, 16 of 27 patients (59%) received IV-tPA. Previous tPA treatment did not affect onset to recanalization time or door-to-puncture time. For MT, door-to-puncture time was 104±50 minutes and onset to recanalization was 289±153 minutes. Successful recanalization (mTICI grade 2b/3) was achieved in 21 patients (78%). At three-month follow-up, the median NIHSS was 5 (range:4‒15) and mRS was 0‒2 in 37%, and ≥3 in 63%. Conclusions: With adequate logistics and strict selection criteria, MT can be implemented in our population with results like those reported in large clinical trials.

Resumen El accidente cerebrovascular isquémico (ACVi) es una importante causa de morbi-mortalidad a nivel mundial. La reperfusión con trombólisis endovenosa es utilizada desde 1996. Más recientemente, la reperfusión con trombectomía mecánica (TM) ha demostrado un beneficio consistente extendiendo la ventana terapéutica. En nuestro país existen dificultades para que su implementación sea una práctica habitual. Objetivo: Reportamos la experiencia de un Centro Integral de Neurología Vascular en el uso de TM como tratamiento del ACVi agudo. Métodos: Análisis retrospectivo de pacientes consecutivos desde enero 2015 a septiembre 2018, que recibieron reperfusión con TM. Se registraron datos demográficos, tiempos de tratamiento, uso de rtPA, sitio de obstrucción, recanalización, severidad del evento y discapacidad. Resultados: Se evaluaron 891 pacientes con ACVi en este periodo. 97 recibieron rtPA (11%) y 27 recibieron TM (3%). En el grupo TM, la edad promedio fue 66 años (±14.5). Mediana de NIHSS previo a TM: 20 (RIC 14‒24). La etiología más frecuente fue cardioembolia (52%). Previo a TM, 16 pacientes (59%) recibieron rtPA endovenoso. No hallamos efecto del rtPA en tiempo de recanalización por TM o tiempo puerta-punción. Para la TM, el tiempo puerta-punción fue 104±50 minutos y el tiempo entre inicio de síntomas-recanalización fue 289±153 minutos. En 21 pacientes (78%) se logró recanalización exitosa (TICI 2B/3). En el seguimiento a tres meses, el mRS fue 0‒2 en el 37% y ≥3 en el 63%. Conclusión: Una logística adecuada y un estricto criterio de selección ha posibilitado el uso de TM en nuestra población, obteniendo resultados similares a aquellos reportados en los estudios clínicos publicados.

Accidente cerebrovascular pediátrico isquémico en niños: reporte de un caso / Ischemic Childhood Stroke: a case report

A stroke is a rare entity in pediatrics patients; that implies a very important clinical challenge. It is produced by the interruption of flow at the vascular level, producing neurological focus. Causes of childhood stroke are varied and different from adults; constituting one of the 10 leading causes of childhood mortality. We present of previously healthy 6 years old male patient who was admitted for hemiparesis, who was studied with neuroimaging and laboratory; diagnosed of ischemic stroke

Aneurysmal subarachnoid hemorrhage: current concepts and updates / Hemorragia subaracnoidea aneurismática: conceitos atuais

ABSTRACT Aneurysmal subarachnoid hemorrhage is a condition with a considerable incidence variation worldwide. In Brazil, the exact epidemiology of aneurysmal SAH is unknown. The most common presenting symptom is headache, usually described as the worst headache ever felt. Head computed tomography, when performed within six hours of the ictus, has a sensitivity of nearly 100%. It is important to classify the hemorrhage based on clinical and imaging features as a way to standardize communication. Classification also has prognostic value. In order to prevent rebleeding, there still is controversy regarding the ideal blood pressure levels and the use of antifibrinolytic therapy. The importance of definitely securing the aneurysm by endovascular coiling or surgical clipping cannot be overemphasized. Hydrocephalus, seizures, and intracranial pressure should also be managed. Delayed cerebral ischemia is a severe complication that should be prevented and treated aggressively. Systemic complications including cardiac and pulmonary issues, sodium abnormalities, fever, and thromboembolism frequently happen and may have na impact upon prognosis, requiring proper management.

RESUMO Hemorragia subaracnoidea aneurismática (aHSA) é uma condição com grande variação de incidência mundialmente. No Brasil, não dispomos de números epidemiológicos exatos. A apresentação clínica mais comum da HSA é a cefaleia, usualmente descrita como a pior da vida. A tomografia de crânio, quando feita nas primeiras 6 horas do ictus, tem uma sensibilidade próxima a 100%. É importante classificar a hemorragia utilizando escalas clínicas e radiológicas, como forma de padronizar a comunicação, e também predizer prognóstico. Para prevenção de ressangramento, ainda há controvérsias quanto aos níveis pressóricos ideais e uso de antifibrinolíticos. O tratamento definitivo do aneurisma, por sua vez, é fundamental, seja por meio endovascular ou cirúrgico. Hidrocefalia, crises epilépticas e a pressão intracraniana devem ser manejadas de forma apropriada. Isquemia cerebral tardia é uma complicação grave que deve ser prevenida e tratada agressivamente. Complicações sistêmicas, incluindo cardíacas, pulmonares, anormalidades de sódio, febre e tromboembolismo ocorrem frequentemente e podem ter impacto no prognóstico, necessitando de manejo adequado.

Angiographic Findings in Refractory Delayed Cerebral Ischemia

Background Delayed cerebral ischemia (DCI) follows a refractory course in a subgroup of patients with aneurysmal subarachnoid hemorrhage (SAH), leading to diffuse ischemic injury. The role of angiographic vasospasm (AV) is unknown. Our goal is to study the angiographic alterations and the clinical profile of refractory DCI patients. Methods Retrospective study of patients with SAH who presented with DCI treated with medical and endovascular therapy, with a refractory evolution, defined asmultiple ischemic infarction and brain death. Results Out of a cohort of 336 patients, 7 (2%) developed refractory DCI. The median age of the patients was 48 (38­60) years old. Five patients had ruptured anterior communicating artery (ACoA) aneurysms. Four patients were treated with coil embolization, and three with microsurgical clipping. Angiographic vasospasm was classified as severe in 5 cases. Compromise of bilateral circulation was detected in six patients. Distal circulation vasospasm occurred in five cases. Slow circulatory transit times were observed in three patients. Conclusion Angiographic findings such as bilateral circulatory compromise and distal vasospasm were frequent alterations. Further studies are required to establish the association of these findings with the clinical outcomes.

Consenso sobre accidente cerebrovascular isquémico agudo / Consensus on acute ischemic stroke

El accidente cerebrovascular es la tercera causa de muerte y la primera de discapacidad en la Argentina. Los eventos isquémicos constituyen el 80% de los casos. Los accidentes vasculares cerebrales requieren la implementación de protocolos sistematizados que permitan reducir los tiempos en la atención, la morbilidad y mortalidad. En el consenso participaron especialistas de nueve sociedades médicas relacionadas con la atención de pacientes con enfermedad cerebrovascular. Se consensuó un temario separado en capítulos y para la redacción de los mismos se conformaron grupos de trabajo con miembros de diferentes especialidades médicas. Se discutió y acordó para cada tema el nivel de recomendación en base a la mejor evidencia clínica disponible para cada tópico. Se realizó una adaptación al ámbito local de las recomendaciones cuando se consideró necesario. El sistema de la American Heart Association se utilizó para redactar las recomendaciones y su grado de evidencia. La corrección y edición fue realizada por cinco revisores externos, que no participaron en la redacción y con amplia experiencia en enfermedad vascular. Finalizado el documento preliminar, se organizó una reunión general con todos los integrantes de los grupos de trabajo y los revisores para redactar las recomendaciones definitivas. El consenso abarca la atención del paciente con accidente cerebrovascular isquémico en la fase pre-hospitalaria, evaluación inicial en la central de emergencias, terapias de recanalización (trombolisis y/o trombectomía mecánica), craniectomía descompresiva, neuroimágenes y cuidados clínicos en la internación.

Stroke is the third cause of death and the first cause of disability in Argentina. Ischemic events constitute 80% of cases. It requires the implementation of systematized protocols that allow reducing the time of care, morbidity and mortality. Specialists from nine medical societies related to the care of patients with cerebrovascular disease participated in the consensus. A separate agenda was agreed upon in chapters and for the writing of them, work groups were formed with members of different medical specialties. The level of recommendation was discussed and agreed upon for each topic based on the best clinical evidence available for each of them. An adaptation to the local scope of the recommendations was made when it was considered necessary.The American Heart Association system was used to draft the recommendations and their level of evidence. The correction and editing were done by five external reviewers, who did not participate in the writing and with extensive experience in vascular pathology. Once the preliminary document was finalized, a general meeting was held with all the members of the working groups and the reviewers to reach final recommendations. The consensus covers the management of ischemic stroke in the pre-hospital phase, initial evaluation in the emergency center, recanalization therapies (thrombolysis and/ or mechanical thrombectomy), decompressive craniectomy, neuroimaging and clinical care in the hospital.

Hypothermia treatment ameliorated cyclin-dependent kinase 5-mediated inflammation in ischemic stroke and improved outcomes in ischemic stroke patients

OBJECTIVES: The inflammatory response is a key mechanism of neuronal damage and loss during acute ischemic stroke. Hypothermia has shown promise as a treatment for ischemic stroke. In this study, we investigated the molecular signaling pathways in ischemic stroke after hypothermia treatment. METHODS: Cyclin-dependent kinase 5 (CDK5) was overexpressed or silenced in cultured cells. Nuclear transcription factor-κB (NF-κB) activity was assessed by measurement of the luciferase reporter gene. An ischemic stroke model was established in Sprague-Dawley (SD) rats using the suture-occluded method. Animals were assigned to three groups: sham operation control, ischemic stroke, and ischemic stroke + hypothermia treatment groups. Interleukin 1β (IL-1β) levels in the culture supernatant and blood samples were assessed by ELISA. Protein expression was measured by Western blotting. RESULTS: In HEK293 cells and primary cortical neuronal cultures exposed to hypothermia, CDK5 overexpression was associated with increased IL-1β, caspase 1, and NF-κB levels. In both a murine model of stroke and in patients, increased IL-1β levels were observed after stroke, and hypothermia treatment was associated with lower IL-1β levels. Furthermore, hypothermia-treated patients showed significant improvement in neurophysiological functional outcome. CONCLUSIONS: Overall, hypothermia offers clinical benefit, most likely through its effects on the inflammatory response.

Neurogenesis and gliogenesis modulation in cerebral ischemia by CDK5 RNAi-based therapy / Modulación de la neurogénesis y la gliogénesis en la isquemia cerebral mediante una terapia basada en la interferencia de CDK5

Abstract Introduction: Cerebral ischemia is the third cause of death risk in Colombia and the first cause of physical disability worldwide. Different studies on the silencing of the cyclin-dependent kinase 5 (CDK5) have shown that reducing its activity is beneficial in ischemic contexts. However, its effect on neural cell production after cerebral ischemia has not been well studied yet. Objective: To evaluate CDK5 silencing on the production of neurons and astrocytes after a focal cerebral ischemia in rats. Materials and methods: We used 40 eight-week-old male Wistar rats. Both sham and ischemia groups were transduced at CA1 hippocampal region with an adeno-associated viral vector using a noninterfering (shSCRmiR) and an interfering sequence for CDK5 (shCDK5miR). We injected 50 mg/kg of bromodeoxyuridine intraperitoneally from hour 24 to day 7 post-ischemia. We assessed the neurological abilities during the next 15 days and we measured the immunoreactivity of bromodeoxyuridine (BrdU), doublecortin (DCX), NeuN, and glial fibrillary acid protein (GFAP) from day 15 to day 30 post-ischemia. Results: Our findings showed that CDK5miR-treated ischemic animals improved their neurological score and presented increased BrdU+ cells 15 days after ischemia, which correlated with higher DCX and lower GFAP fluorescence intensities, and, although mature neurons populations did not change, GFAP immunoreactivity was still significantly reduced at 30 days post-ischemia in comparison with untreated ischemic groups. Conclusion: CDK5miR therapy generated the neurological recovery of ischemic rats associated with the induction of immature neurons proliferation and the reduction of GFAP reactivity at short and longterm post-ischemia.

Resumen Introducción. La isquemia cerebral es la tercera causa de riesgo de muerte en Colombia y la primera causa de discapacidad física en el mundo. En diversos estudios en los que se silenció la cinasa 5 dependiente de la ciclina (CDK5) se ha demostrado que la reducción de su actividad es beneficiosa frente a la isquemia. Sin embargo, su efecto sobre la neurogénesis después de la isquemia no se ha dilucidado suficientemente. Objetivo. Evaluar el silenciamiento de la CDK5 en la neurogénesis y la gliogénesis después de la isquemia cerebral focal en ratas. Materiales y métodos. Se usaron 40 machos de rata Wistar de ocho semanas de edad. Los grupos de control y los isquémicos sometidos a transducción en la región del hipocampo CA1, se inyectaron intraperitonealmente por estereotaxia con 50 mg/kg de bromodesoxiuridina (BrdU) a partir de las 24 horas y hasta el día 7 después de la isquemia, con un vector viral asociado a adenovirus usando una secuencia no interferente (SCRmiR) y una interferente (CDK5miR). Se evaluó la capacidad neurológica durante los quince días siguientes y se detectó la capacidad de inmunorreacción para la BrdU, la proteína doblecortina (DCX), los núcleos neuronales (NeuN), y la proteína fibrilar acídica de la glía (Glial Fibrillary Acidic Protein, GFAP) a los 15 y 30 días de la isquemia. Resultados. Los animales isquémicos tratados con CDK5miR mejoraron su puntuación neurológica y presentaron un incremento de la BrdU+ a los 15 días de la isquemia, lo cual se correlacionó con una mayor intensidad de la DCX+ y una menor de la GFAP+. No hubo modificación de los NeuN+, pero sí una reducción significativa de la GFAP+ a los 30 días de la isquemia en los animales tratados comparados con los animales isquémicos no tratados. Conclusión. La terapia con CDK5miR generó la recuperación neurológica de ratas isquémicas asociada con la inducción de la neurogénesis y el control de la capacidad de reacción de la proteína GFAP a corto y largo plazo después de la isquemia.

Experiencia en el tratamiento endovascular del accidente cerebrovascular isquémico agudo en un centro chileno / Emergency endovascular management of ischemic stroke: experience in 104 patients

Background: Recently, five randomized controlled trials confirmed the efficacy and safety of endovascular treatment with or without intravenous thrombolysis in acute ischemic stroke with large-vessel occlusion. Aim: To report patients with ischemic stroke treated with endovascular methods. Material and Methods: Retrospective analysis of 104 patients aged 61 ± 15 years (54% males) with ischemic stroke who received endovascular treatment at a single medical center between 2009 and 2017. Results: Sixty one percent were treated with intravenous thrombolysis plus endovascular procedures and 39% with endovascular procedures alone. The median door-to needle time was 61 minutes and door-to femoral puncture was 135 minutes. The median National Institute of Health Stroke Scale (NIHSS) scores on admission, 24 hours later and at discharge were 12,4 and 1 points, respectively. Middle cerebral artery was occluded in 60% of cases. Other frequent localizations where distal carotid artery in 17% and vertebro-basilar artery in 14%. Thrombolysis in cerebral infarction (TICI) scale flow score after the procedure was 3 or 2b in 58% of cases and significantly correlated with NIHSS scores at 24 hours and discharge. Fifty percent of patients had a mRankin score < = 1 and ten patients died (9.6%). Eight percent had a symptomatic intracerebral hemorrhage. Conclusions: The clinical improvement of these patients 24 hours after the procedure and at discharge demonstrate the effectiveness of endovascular treatment in ischemic stroke. The presence neurologists able to interpret multimodal images at the emergency room, the use of local guidelines, the availability of an experienced neuro-interventional team engaged with the workflow and the use of stent retrievers are strongly associated with good outcomes.

Physicians are not well informed about the new guidelines for the treatment of acute stroke / Os médicos não estão bem informados sobre as novas diretrizes para o tratamento de AVC agudo

ABSTRACT Treatment of cerebrovascular disease has advanced rapidly in the last two decades. Recent data has added challenges to the treatment of ischemic stroke in the acute phase. Objective: To evaluate the knowledge of physicians about the treatment of ischemic stroke in the acute phase. Methods: An online questionnaire was submitted to all physicians enrolled in the Regional Council of Medicine in Brazil. Results: 456 physicians from different specialties answered the questions. Most of them did not know that mechanical endovascular thrombectomy is often considered as the gold standard treatment in cases of ischemic stroke in the acute phase; and 85% of them did not realize that thrombectomy together with intravenous thrombolysis was possible. The maximum time to act in an acute event also presented many divergences, even with regard to the infusion of rtPA. The lack of structure, medication and absence of a neurologist were considered the main barriers to treatment. Conclusion: Physicians are not well informed about the new guidelines for the treatment of acute stroke. Most physicians incorrectly answered most of the questions on the questionnaire.

RESUMO O tratamento da doença cerebrovascular tem avançado rapidamente nas últimas duas décadas. Dados recentes acrescentaram desafios ao tratamento do AVC isquêmico na fase aguda (AIFA). Objetivo: Avaliar o conhecimento médico sobre o tratamento do AIFA. Métodos: Um questionário on-line foi submetido a todos os médicos inscritos no Conselho Regional de Medicina. Resultados: 456 médicos de diferentes especialidades responderam às perguntas. A maioria deles não sabia que a trombectomia endovascular mecânica é freqüentemente considerada como tratamento padrão-ouro nos casos de AIFA. 85% não realizariam trombectomia junto com a trombólise intravenosa. O tempo máximo para atuar no evento agudo também apresentou muitas divergências, mesmo em relação à infusão de rtPA. A falta de estrutura, medicação e neurologista foram consideradas as principais barreiras ao tratamento. Conclusão: Os médicos não estão bem informados sobre as novas diretrizes para o tratamento do AIFA. A maioria dos médicos errou a maioria das perguntas desse questionário.

The direct first pass aspiration technique in the treatment of acute ischemic stroke resulting from large vessel occlusions / Técnica de aspiração primária no tratamento do acidente vascular cerebral isquêmico por oclusões de grandes vasos

ABSTRACT Mechanical thrombectomy using stent retrievers is the standard treatment for acute ischemic stroke that results from large vessel occlusions. The direct aspiration first pass technique (ADAPT) has been proposed as an efficient, fast, and cost-effective thrombectomy strategy. The aim of this study was to assess the safety and efficacy of ADAPT. Methods Recanalization was assessed using the modified thrombolysis in cerebral infarction (mTICI) score. Neurological outcomes were assessed using the National Institutes of Health Stroke Scale and modified Rankin Scale. Results Fifteen patients were evaluated. The mTICI score was 2b-3 in 80%, and it was 3 in 60% of patients. No intracranial hemorrhage was seen. At three months, modified Rankin Scale scores ≤ 2 were observed in 60% of patients and the mortality rate was 13.3%. Conclusions The ADAPT appears to be a safe, effective, and fast recanalization strategy for treatment of acute ischemic stroke resulting from large vessel occlusions.

RESUMO A trombectomia mecânica com stent retrievers é o tratamento padrão ouro do acidente vascular cerebral isquêmico agudo (AVCi) por oclusão de grandes artérias. A técnica de aspiração primária (ADAPT) tem sido proposta como uma estratégia de trombectomia rápida e com boa custo-efetividade. O objetivo deste estudo foi avaliar a segurança e eficácia da técnica ADAPT. Métodos A recanalização foi avaliada utilizando a escala mTICI. Os desfechos neurológicos foram avaliados utilizando as escalas do NIHSS e mRS. Resultados Quinze pacientes foram avaliados. Foram obtidas taxas de mTICI = 2b-3 em 80% e TICI = 3 em 60% dos pacientes. Não ocorreram hemorragias intracranianas. Em 3 meses as taxas de mRS≤2 e mortalidade foram respectivamente 60% e 13.3%. Conclusão A técnica ADAPT parece ser uma estratégia de recanalização rápida, segura e efetiva para o tratamento do AVC por oclusão de grandes artérias.

Brazilian guidelines for endovascular treatment of patients with acute ischemic stroke / Diretrizes brasileiras para o tratamento endovascular de pacientes com acidente vascular cerebral isquêmico agudo

ABSTRACT These guidelines are the result of a joint effort from writing groups of the Brazilian Stroke Society, the Scientific Department of Cerebrovascular Diseases of the Brazilian Academy of Neurology, the Brazilian Stroke Network and the Brazilian Society of Diagnostic and Therapeutic Neuroradiology. Members from these groups participated in web-based discussion forums with predefined themes, followed by videoconference meetings in which controversies and position statements were discussed, leading to a consensus. This guidelines focuses on the implications of the recent clinical trials on endovascular therapy for acute ischemic stroke due to proximal arterial occlusions, and the final text aims to guide health care providers, health care managers and public health authorities in managing patients with this condition in Brazil.

RESUMO Estas diretrizes são o resultado de um esforço conjunto de membros da Sociedade Brasileira de Doenças Cerebrovasculares (SBDCV), Departamento científico de Doenças Cerebrovasculares da Academia Brasileira de Neurologia (ABN), Rede Brasil AVC (RBAVC) e da Sociedade Brasileira de Neurorradiologia Diagnóstica e Terapêutica (SBNR). Membros destas 4 entidades participaram de fórum de discussões por internet de temas pré-definidos, seguidos de encontros de videoconferência para discussão de pontos controversos e das recomendações, em busca de um consenso final. Estas diretrizes tem seu foco sobre as implicações dos recentes ensaios clínicos de tratamento endovascular do acidente vascular cerebral (AVC) isquêmico agudo relacionado a oclusão de artérias proximais. O texto final foi elaborado para servir de orientação no manejo destes pacientes AVC isquêmico pelos diferentes profissionais de saúde, gestores de saúde pública e de saúde complementar no Brasil.

Hospitalização por acidente vascular encefálico isquêmico no Brasil: estudo ecológico sobre possível impacto do Hiperdia / Hospitalization for ischemic stroke in Brazil: an ecological study on the possible impact of Hiperdia

RESUMO: Objetivo: O estudo avaliou a tendência de hospitalização por acidente vascular encefálico isquêmico (HAVEI) e a sua mortalidade hospitalar no Brasil nos últimos 15 anos, assim como o impacto do programa Hiperdia nesse cenário. Métodos: Delineou-se um estudo ecológico com abordagem analítica e dados coletados no Sistema de Internação Hospitalar sobre episódios de AVEI, referentes aos anos de 1998 a 2012. Todos os dados foram estratificados por sexo e faixa etária, criando-se um indicador para HAVEI e proporção de mortalidade hospitalar. A fim de estimar a tendência dos dados criou-se uma curva polinomial de melhor aderência e para a averiguar o impacto do Hiperdia aplicou-se o Modelo Linear Generalizado tomados como desfecho a HAVEI e a mortalidade hospitalar. Adotou-se um nível de significância de 5% para minimizar um erro tipo I. Resultados: Foi evidenciada redução das HAVEI de 37,57/105 habitantes em 1998 a 2001 para 10,33/105 habitantes em 2002 a 2005, declinando 73,64%. A redução aconteceu em ambos os sexos, assim como para todas as faixas etárias. A mortalidade hospitalar por AVEI também declinou no Brasil a partir de 2002, tanto em homens como em mulheres, porém em menos de 3% e apenas nas faixas entre 0 e 14 anos e acima de 80 anos não detectamos tendência. Conclusão: Portanto, o declínio das HAVEI coincidiu temporalmente com a implementação do Hiperdia no ano de 2002 e essa tendência se mantém até hoje.

ABSTRACT: Objective: The study evaluated the trend of hospitalization for ischemic stroke (HIS) and its hospital mortality in Brazil over the last 15 years as well as the impact of the Hiperdia program in this scenario. Methods: An ecological study was designed with analytical approach and data collected in the Hospital Admission System on episodes of stroke, over the years 1998 to 2012. All data were stratified by sex and age, creating an indicator for HIS and proportion of hospital mortality. To estimate the trend of the data a polynomial curve fitting was created; and the Generalized Linear Model was applied to investigate the impact of Hiperdia on the endpoint HIS and hospital mortality. We adopted a 5% significance level to minimize an error type I. Results: We observed a reduction of HIS from 37.57/105 inhabitants in 1998 to 2001 to 10.33/105 inhabitants in 2002 to 2005, declining 73.64%. The reduction occurred in both sexes and for all age groups. The mortality rate of ischemic stroke also declined in Brazil since 2002, in both men and women, therefore in less than 3%; and only in the groups aged between 0 and 14 and above 80 years, we did not detect trend. Conclusion: Therefore, the decline of HIS temporally coincided with the implementation of Hiperdia in 2002 and this trend continues today.