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1.
Medicine (Baltimore) ; 99(2): e18719, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914086

RESUMO

BACKGROUND: Hematoma expansion (HE) is related to clinical deterioration and unfavorable prognosis in intracerebral hemorrhage (ICH). Some studies have revealed that low serum magnesium level is associated with larger hematoma volume at admission, HE, and unfavorable outcomes. However, the conclusions remain unsettled. The purpose of this study is to evaluate the association between low serum magnesium level and HE by meta-analysis. METHODS: We will search the following electronic bibliographic databases: PubMed, Medline, Embase, Web of Science, and The Cochrane Library. Studies will be included if they reported a relationship of low serum magnesium level and HE, mortality or poor outcome. RESULTS: The results of this study will be submitted to a peer-reviewed journal for publication. CONCLUSION: This will be the first systematic review and meta-analysis to evaluate the association of HE following ICH with Hypomagnesemia. We look forward to the results will offer scientific proof to predict HE for ICH patients with low serum magnesium level. PROSPERO REGISTRATION NUMBER: This protocol has been registered in the PROSPERO network with number: CRD42019135995.


Assuntos
Hemorragia Cerebral/patologia , Hematoma/patologia , Magnésio/sangue , Biomarcadores , Deterioração Clínica , Humanos , Prognóstico
2.
Hu Li Za Zhi ; 67(1): 106-112, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31960402

RESUMO

Preterm infants face increased rates of mortality and developmental complications, which are a burden on children's parents (and caregivers), who suffer from exhaustion and situational uncertainty. This case focused on an extremely-low-birth-weight (908 gm) premature infant with initial unstable vital signs complicated by a grade 4 intraventricular hemorrhage (IVH) that led to partial brain atrophy and enlarged brain ventricles. A poor neurological outcome was expected due to the high risk of cerebral palsy and impaired cognitive abilities. Long-term healthcare for this critical infant was causing tremendous physical, emotional, and financial strains on the family. The parents suffered from worries over the poor prognosis, resulting in stress, sleep disorders, and relationship difficulties with the healthcare professionals. Considering the poor prognosis of the infant, the parents faced a medical dilemma between choosing aggressive treatment and withdrawal of treatment, which led to stress and sleep disorders. Differences between the parents and health professionals regarding disease severity perception and treatment opinions further strained their mutual relationship. To ameliorate this issue, the author implemented family-centered care (the FOCUS family intervention) to help the patient and his family. This intervention is designed to increase family involvement, foster an optimistic attitude and effective stress coping techniques, and reduce uncertainty and negative emotions. For the patient, we provided symptom-relief management to improve abnormal muscle tone and development delay. Our intervention ameliorated the negative emotions, insomnia symptoms, and imbalanced family relationships and improved the life quality of the caregivers. Furthermore, the intervention enhanced the patient's autoregulatory ability, and both physical and neurological development. This case study is expected to provide experience in critical care for premature infants with a poor prognosis and their family using a FOCUS family intervention as well as to improve the quality of healthcare delivery in intensive clinical settings.


Assuntos
Hemorragia Cerebral/terapia , Família/psicologia , Doenças do Prematuro/terapia , Relações Profissional-Família , Hemorragia Cerebral/patologia , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/patologia
3.
J Stroke Cerebrovasc Dis ; 29(1): 104483, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31727597

RESUMO

OBJECTIVE: Gastrodin, a glucoside of gastrodigenin, inhibits cerebral oxidant stress and apoptosis in multiple central nervous system injury, but its effect in intracerebral hemorrhage (ICH) remains unclear. This study investigated the effect of gastrodin on neuronal apoptosis and neurological deficits in rat ICH model. METHODS: In vitro experiments were performed using hematoma lysate-induced cell damage model in primary cortical neurons. Rat ICH model was produced by a caudatum injection of collagenase. Gastrodin was intraperitoneal injected after 2 hours following ICH. Cell viability, brain water content, neurological score, western blot, and immunofluorescence experiments were performed. RESULTS: Gastrodin significantly decreased hematoma lysate-induced reduction of cell viability and cell apoptosis in primary cortical neurons. Gastrodin significantly improved brain edema and neurological deficits post-ICH. Moreover, gastrodin administration significantly reduced levels of ROS, 8-OHDG, 3-Nitrotyrosine and MDA, while increased GSH-Px and SOD activity, and stimulated the upregulation of Keap1, Nrf2, and HO-1 signaling at 72 hours post-ICH. Furthermore, gastrodin significantly increased Bcl-2 expression, while reduced level of Bax, active caspase-3 and active caspase-9, also reduced the number of active caspase-3 or TUNEL positive neurons at 72 hours post-ICH. CONCLUSION: These results suggest that gastrodin is neuroprotective after ICH and the mechanism may be associated with the inhibition of oxidative stress and neuronal apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Álcoois Benzílicos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Glucosídeos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais
4.
J Stroke Cerebrovasc Dis ; 29(1): 104468, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31694784

RESUMO

OBJECTIVES: Intracerebral hemorrhage (ICH) is one of the leading causes of disability and mortality in adult, which lacks effective therapies. Edaravone has showed its neuroprotective effects after ischemia stroke, but its effects and possible mechanisms after ICH are poorly understood. Here, we investigated whether edaravone confers neuroprotection after ICH in rats and explored the potential mechanisms involved. METHODS: ICH was induced in the right basal ganglia of Sprague-Dawley rats by stereotacticly injection of 200 µl autologous blood. Edaravone (3 mg/kg) or vehicle (saline) was administered intravenously and NLRP3 selective antagonist (MCC950, 10 mg/kg) was intraperitoneally injected to study the potential mechanism. Water Morris Maze Test and Rotarod test were used to elucidate neurological function and Fluoro-Jade C was used to study neurodegeneration after ICH. Western blot assay, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to check the expression of molecules involved. RESULTS: As a result, we found that edaravone significantly alleviated brain edema and conferred the neurological deficits of rats after ICH. Hematoma increased NLRP3 expression in microglia, which was decreased by edaravone. Moreover, we demonstrated that edaravone shared a similar effect with MCC950 on alleviating neurodegeneration and decreasing the expression of IL-1ß, Caspase 1 and NF-κB in protein or mRNA. Lastly, edaravone and MCC950 both increased the number of Tuj-1 positive neuronal cells peripheral hematoma. CONCLUSIONS: The present study demonstrated that edaravone conducted neuroprotection after ICH partially via suppressing NF-κB-dependent NLRP3 in microglia, which contributed a novel evidence for clinic usage of edaravone after ICH.


Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Edaravone/farmacologia , Inflamassomos/metabolismo , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Caspase 1/metabolismo , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Interleucina-1beta/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais
5.
Eur Radiol ; 30(1): 87-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385050

RESUMO

OBJECTIVES: To develop a radiomics model for predicting hematoma expansion in patients with intracerebral hemorrhage (ICH) and to compare its predictive performance with a conventional radiological feature-based model. METHODS: We retrospectively analyzed 251 consecutive patients with acute ICH. Two radiologists independently assessed baseline noncontrast computed tomography (NCCT) images. For each radiologist, a radiological model was constructed from radiological variables; a radiomics score model was constructed from high-dimensional quantitative features extracted from NCCT images; and a combined model was constructed using both radiological variables and radiomics score. Development of models was constructed in a primary cohort (n = 177). We then validated the results in an independent validation cohort (n = 74). The primary outcome was hematoma expansion. We compared the three models for predicting hematoma expansion. Predictive performance was assessed with the receiver operating characteristic (ROC) curve analysis. RESULTS: In the primary cohort, combined model and radiomics model showed greater AUCs than radiological model for both readers (all p < .05). In the validation cohort, combined model and radiomics model showed greater AUCs, sensitivities, and accuracies than radiological model for reader 2 (all p < .05). Combined model showed greater AUC than radiomics model for reader 1 only in the primary cohort (p = .03). Performance of three models was comparable between reader 1 and reader 2 in both cohorts (all p > .05). CONCLUSIONS: NCCT-based radiomics model showed high predictive performance and outperformed radiological model in the prediction of early hematoma expansion in ICH patients. KEY POINTS: • Radiomics model showed better performance for prediction of hematoma expansion in patients with intracerebral hemorrhage than radiological feature-based model. • Hematomas which expanded in follow-up NCCT tended to be larger in baseline volume, more irregular in shape, more heterogeneous in composition, and coarser in texture. • A radiomics model provides a convenient and objective tool for prediction of hematoma expansion that helps to define subsets of patients who would benefit from anti-expansion therapy.


Assuntos
Hemorragia Cerebral/patologia , Hematoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/diagnóstico por imagem , Métodos Epidemiológicos , Feminino , Hematoma/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
6.
World Neurosurg ; 135: e610-e615, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31870816

RESUMO

BACKGROUND: Noncontrast computed tomography hypodensities (HD) and ultraearly hematoma growth (uHG) are reliable markers for outcome prediction in patients with spontaneous intracerebral hemorrhage (sICH). The present study aimed to assess whether the combination of these 2 markers could improve the prognostic value for sICH. METHODS: We recruited 242 patients with sICH who had been admitted within 6 hours from the onset of symptoms. HD was assessed by 2 independent blinded readers, and uHG was calculated as baseline ICH volume/onset-to-imaging time. We divided the study population into 4 groups: uHG(L) HD(-) (uHG <6.16 mL/hour and HD negative), uHG(L) HD(+) (uHG<6.16 mL/hour and HD positive), uHG(H) HD(-) (uHG ≥6.16 mL/hour and HD negative), and uHG(H) HD(+) (uHG ≥6.16 mL/h and HD positive). The outcome at 90 days was evaluated by the modified Rankin Scale (mRS) score and was dichotomized as good (mRS score 0-3) and poor (mRS score 4-6). The association between the combined indicators and unfavorable outcome was investigated using multivariable logistic regression models. RESULTS: Patients with poor outcomes were more likely to have HD and higher uHG in univariate analysis. In multivariate logistic regression analysis, uHG(H) HD(+) had a higher risk of unfavorable outcomes compared with uHG(L) HD(-) (odds ratio [OR], 5.710; P < 0.001). In addition, the risk of unfavorable outcomes was increased in uHG(H) HD(-) (OR, 2.957, P = 0.044) and uHG(L) HD(+) (OR, 1.924; P = 0.232). The proportions of unfavorable prognoses were 32.6% in uHG(L) HD(-), 48.3% in uHG(L) HD(+), 72.2% in uHG(H) HD(-), and 87.5% in uHG(H) HD(+) (P < 0.001). CONCLUSIONS: The combination of uHG and HD improves the stratification of unfavorable prognoses in patients with sICH.


Assuntos
Hemorragia Cerebral/patologia , Hematoma/patologia , Idoso , Hemorragia Cerebral/diagnóstico por imagem , Feminino , Hematoma/diagnóstico por imagem , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Prognóstico , Estudos Retrospectivos , Tempo de Trombina , Fatores de Tempo , Tomografia Computadorizada por Raios X
7.
Life Sci ; 237: 116929, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610210

RESUMO

LncRNA small nucleolar RNA host gene 3 (Snhg3) has been involved in cell proliferation and migration in malignant cells. However, its role in regulating functions of non-malignant cells has been hardly reported. Here, we found Snhg3 expression was sharply induced in primary brain microvascular endothelial cells (BMVECs) treated with oxygen-and-glucose-deprivation (OGD) plus hemin, an in vitro model of intracerebral hemorrhage (ICH). Downregulation of Snhg3 by siRNA transfection improved cell proliferation and migration abilities and reduced cell apoptosis and monolayer permeability in BMVECs under treatment with OGD plus hemin. Snhg3 overexpression suppressed cell proliferation and migration and increased cell apoptosis and monolayer permeability under normal condition. In ICH rats, downregulation of Snhg3 by siRNA injection improved behavioral and histological manifestations, including number of right turns, limb placement score, integrity of blood-brain barrier (BBB), brain water content and cell apoptosis in vivo. In the mechanism exploration, we found that, TWEAK and Snhg3 displayed a positive correlation with each other. Snhg3 overexpression increased expression of TWEAK protein and its receptor Fn14, that were also induced by OGD plus hemin, activating the downstream neuroinflammatory pathway STAT3 and enhancing the secretion of MMP-2/9. Finally, the TWEAK-siRNA, the Fn14 inhibitor ATA and the STAT3 blocker AG490 were respectively used to treat BMVECs under treatment with OGD plus hemin. Our results showed either TWEAK downregulation, Fn14 inhibition, or STAT3 blockade, could rescue Snhg3-induced impairment of BMVEC functions. In conclusion, the lncRNA Snhg3 contributes to dysfunction of cerebral microvascular cells in ICH rats by activating the TWEAK/Fn14/STAT3 pathway.


Assuntos
Encéfalo/patologia , Hemorragia Cerebral/patologia , Citocina TWEAK/metabolismo , Endotélio Vascular/patologia , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Receptor de TWEAK/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Células Cultivadas , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Circulação Cerebrovascular/fisiologia , Citocina TWEAK/genética , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Masculino , Microvasos/metabolismo , Microvasos/patologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor de TWEAK/genética , Cicatrização
8.
Neurol Res ; 41(11): 1034-1042, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584350

RESUMO

Objectives: To investigate the thrombolysis with recombinant human prourokinase (rhPro-UK) on thromboembolic stroke in rats at different therapeutic time windows (TTW). Methods: Rats were subjected to embolic middle cerebral artery occlusion. RhPro-UK and positive control drugs rt-PA,UK were administered 3 h, 4.5 h, 6 h after inducing thromboem-bolic stroke. Neurological deficit scoring (NDS) was evaluated at 6 h and 24 h after the treatment. The lesion volume in cerebral hemispheres was measured by MRI scanning machine after 6 h of thrombolysis, and the infarct volume was measured by TTC stain, together with hemorrhagic volume quantified by a spectrophotometric assay after 24 h of thrombolysis. Results: RhPro-UK 10, 20 × 104 U/kg significantly improved the NDS after cerebral thromboembolism in rats at 3 h, 4.5 h TTW, and at the 6 h TTW, the NDS was improved by 28.0% (P = 0.0690) and 29.2% (P = 0.0927) at 6 h and 24 h after rhPro-UK 20 ×104 U/kg administration, respectively. RhPro-UK 10, 20 × 104 U/kg significantly reduced the brain lesions measured by MRI at 3 h and 4.5 h TTW. RhPro-UK 10, 20 × 104 U/kg significantly reduced the cerebral infarction measured by TTC at 3 h, 4.5 h TTW. There was no increase in cerebral hemorrhage compared with untreated group after rhPro-UK administration. Conclusions: RhPro-UK had an obvious therapeutic effect on ischemic stroke caused by thrombosis, and could be started within 4.5 h TTW with less side effects of cerebral hemorrhage than that of UK.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Embolia Intracraniana/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Embolia Intracraniana/complicações , Masculino , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Tromboembolia/complicações , Tromboembolia/tratamento farmacológico , Terapia Trombolítica/métodos , Fatores de Tempo
9.
J Biol Regul Homeost Agents ; 33(5): 1359-1367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31659887

RESUMO

To study the expression changes of inflammatory factors heme oxygenase-1 (HO-1), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) in intracerebral hemorrhage (ICH), brain tissues surrounding hematoma were collected from ICH patients. The expressions of HO-1, TNF-α, IL- 1ß, and other genes were examined at different time points of ICH. Changes in HO-1, TNF-α, and IL-1ß positive cell numbers after ICH were detected by immunohistochemical staining. The results showed that the expressions of HO-1, TNF-α, and IL-1ß had no significant changes in brain tissues surrounding hematoma within 6 hours after ICH (P > 0.05). Their expressions during 6-24 hours and 24-72 hours after ICH increased constantly. After reaching the peak, they remained steady or slightly decreased after 72 hours. The dynamic expression changes of HO-1, TNF-α, and IL-1ß were observed and their development trends were interfered timely to alleviate the secondary neurological impairment after ICH, which was significant to prevent ICH.


Assuntos
Encéfalo/metabolismo , Hemorragia Cerebral/patologia , Hematoma/metabolismo , Heme Oxigenase-1/metabolismo , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Encéfalo/patologia , Hematoma/patologia , Humanos
10.
Sensors (Basel) ; 19(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395840

RESUMO

Early, preferably prehospital, detection of intracranial bleeding after trauma or stroke would dramatically improve the acute care of these large patient groups. In this paper, we use simulated microwave transmission data to investigate the performance of a machine learning classification algorithm based on subspace distances for the detection of intracranial bleeding. A computational model, consisting of realistic human head models of patients with bleeding, as well as healthy subjects, was inserted in an antenna array model. The Finite-Difference Time-Domain (FDTD) method was then used to generate simulated transmission coefficients between all possible combinations of antenna pairs. These transmission data were used both to train and evaluate the performance of the classification algorithm and to investigate its ability to distinguish patients with versus without intracranial bleeding. We studied how classification results were affected by the number of healthy subjects and patients used to train the algorithm, and in particular, we were interested in investigating how many samples were needed in the training dataset to obtain classification results better than chance. Our results indicated that at least 200 subjects, i.e., 100 each of the healthy subjects and bleeding patients, were needed to obtain classification results consistently better than chance (p < 0.05 using Student's t-test). The results also showed that classification results improved with the number of subjects in the training data. With a sample size that approached 1000 subjects, classifications results characterized as area under the receiver operating curve (AUC) approached 1.0, indicating very high sensitivity and specificity.


Assuntos
Hemorragia Cerebral/diagnóstico , Imageamento Tridimensional/métodos , Micro-Ondas , Algoritmos , Área Sob a Curva , Estudos de Casos e Controles , Hemorragia Cerebral/patologia , Feminino , Humanos , Aprendizado de Máquina , Masculino , Curva ROC
11.
BMC Res Notes ; 12(1): 497, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405369

RESUMO

OBJECTIVE: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.


Assuntos
Agranulocitose/induzido quimicamente , Alemtuzumab/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Fatores Imunológicos/efeitos adversos , Listeriose/induzido quimicamente , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Agranulocitose/mortalidade , Agranulocitose/patologia , Alemtuzumab/administração & dosagem , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/patologia , Evolução Fatal , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Listeriose/microbiologia , Listeriose/mortalidade , Listeriose/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Pneumonia/microbiologia , Pneumonia/mortalidade , Pneumonia/patologia
12.
Inflammation ; 42(5): 1869-1877, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376096

RESUMO

The Toll-like receptor 4 (TLR4)-mediated neuroinflammation plays a key role in inducing secondary brain injury after intracerebral hemorrhage (ICH). However, how TLR4 is regulated during this pathological process is not well understood. In the present study, by taking advantage of a rat ICH model, we show that miR-140-5p is reversely correlated with TLR4 expression in the peri-hematomal striatum following ICH. In vitro, miR-140-5p directly targets TLR4 and suppresses its expression in a rat neuronal PC12 cell line. Moreover, an intracerebral ventricular injection of miR-140-5p mimics improves neurological function and reduces apoptotic cell death and limits the production of inflammatory cytokines following ICH, indicating that miR-140-5p attenuates brain injury and neuroinflammation in vivo. Furthermore, miR-140-5p suppresses TLR4 expression and inhibits the downstream MyD88/TRIF inflammatory pathway and NF-κB activity following ICH, suggesting that the inhibition of TLR4-mediated neuroinflammation at least in part accounts for the neuroprotective role of miR-140-5 against ICH-induced brain injury in rats. Collectively, these results identify miR-140-5 as a negative regulator of TLR4 and downstream inflammatory pathway following ICH, implicating that miR-140-5 might represent as a potential therapeutic target for alleviating ICH-induced brain injury.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Hemorragia Cerebral/tratamento farmacológico , Inflamação/tratamento farmacológico , MicroRNAs/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Lesões Encefálicas/patologia , Hemorragia Cerebral/patologia , MicroRNAs/uso terapêutico , NF-kappa B/metabolismo , Neuroproteção , Ratos
13.
World Neurosurg ; 132: e520-e528, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31449997

RESUMO

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) comprises 10%-15% of strokes with a high mortality (40%) and low rates of functional independence within 6 months (25%). Minimally invasive parafascicular surgery has emerged as a potentially safer option for ICH management. METHODS: Data from 25 patients who underwent channel-based ICH evacuation were retrospectively collected regarding demographics, clinical presentation, neuroimaging characteristics, follow-up modified Rankin Scale (mRS) score, Glasgow Coma Scale (GCS) score, and disposition. RESULTS: Sixteen patients were male (64%) and 9 were female (36%), with a mean age of 52 years. There were 4 frontal, 1 occipital, and 20 basal ganglia hemorrhages; 15 (60%) showed intraventricular extension. Seventeen ICHs (68%) and 6 of 7 patient deaths (86%) were left sided. The mean volume was 46 cm3 (range, 13.1-101.2 cm3), and the mean clot reduction was 92%. Left-sided ICH (P = 0.014) and the presence of intraventricular hemorrhage (P = 0.038) were associated with worsened postoperative GCS score. Larger hemorrhages were associated with mortality (66 cm3 vs. 38 cm3; P < 0.005). With a mean follow-up time of 5 months, the median follow-up mRS score was 3.5 (vs. 4 preoperatively), and median follow-up GCS was 15 (vs. 10 preoperatively). Patients with higher postoperative mRS scores and lower postoperative GCS were more likely to die. CONCLUSIONS: BrainPath-mediated transsulcal approaches are associated with improved mRS and GCS scores, with low rates of residual hematoma, although further data are needed via controlled studies to determine the importance of hemorrhage location and size, timing of surgical intervention, and long-term patient outcomes.


Assuntos
Hemorragia Cerebral/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Trombectomia/métodos , Adulto , Idoso , Hemorragia Cerebral/patologia , Craniotomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuronavegação/métodos , Estudos Retrospectivos
14.
Neurol Res ; 41(11): 980-990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31378168

RESUMO

Background. As the survival of preterm infants has increased significantly, germinal matrix hemorrhage (GMH) has become an important public health issue. Nevertheless, treatment strategies for the direct neuronal injury are still scarce. The present study aims to analyze the neuroprotective properties of cannabidiol in germinal matrix hemorrhage. Methods. 112 Wistar rat pups (P7) were submitted to an experimental collagenase induced model of GMH. Inflammatory response and neuronal death were analyzed both at the perilesional area as at the distant ipsilateral CA1 hippocampal area. Immunohistochemistry for GFAP and caspase 3 was used. The ipsilateral free water content was assessed for stimation of cerebral edema, and neurodevelopment and neurofunctional tests were conducted. Results. Reduction of reactive astrocytosis was observed both in the perilesional area 24 hours and 14 days after the hemorrhage lesion (p < 0.001) and in the Stratum oriens of the ipsilateral hippocampal CA1 14 days after the hemorrhage lesion (p < 0.05) in the treated groups. Similarly, there was a reduction in the number of Caspase 3-positive astrocytes in the perilesional area in the treated groups 24 hours after the hemorrhage lesion (p < 0.001). Finally, we found a significant increase in the weight of the rats treated with cannabidiol. Conclusion. The treatment of GMH with cannabidiol significantly reduced the number of apoptotic cells and reactive astrocytes in the perilesional area and the ipsilateral hippocampus. In addition, this response was sustained 14 days after the hemorrhage. These results corroborate our hypothesis that cannabidiol is a potential neuroprotective agent in the treatment of germinal matrix hemorrhage.


Assuntos
Apoptose/efeitos dos fármacos , Canabidiol/farmacologia , Hemorragia Cerebral/tratamento farmacológico , Hemorragias Intracranianas/tratamento farmacológico , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Edema Encefálico/complicações , Edema Encefálico/patologia , Canabidiol/administração & dosagem , Hemorragia Cerebral/complicações , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Hemorragias Intracranianas/complicações , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos Wistar
15.
Neurology ; 93(7): e695-e707, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337715

RESUMO

OBJECTIVE: To determine whether patients with TIA or ischemic stroke with coexisting cardiovascular disease (i.e., history of coronary or peripheral artery disease) are still at high risk of recurrent ischemic events despite current secondary prevention guidelines. METHODS: In a population-based study in Oxfordshire, UK (Oxford Vascular Study), we studied consecutive patients with TIA or ischemic stroke for 2002-2014. Patients were treated according to current secondary prevention guidelines and we determined risks of coronary events, recurrent ischemic stroke, and major bleeding stratified by the presence of coexisting cardiovascular disease. RESULTS: Among 2,555 patients (9,148 patient-years of follow-up), those (n = 640; 25.0%) with coexisting cardiovascular disease (449 coronary only; 103 peripheral only; 88 both) were at higher 10-year risk of coronary events than those without (22.8%, 95% confidence interval 17.4-27.9; vs 7.1%, 5.3-8.8; p < 0.001; age- and sex-adjusted hazard ratio [HR] 3.07, 2.24-4.21) and of recurrent ischemic stroke (31.5%, 25.1-37.4; vs 23.4%, 20.5-26.2; p = 0.0049; age- and sex-adjusted HR 1.23, 0.99-1.53), despite similar rates of use of antithrombotic and lipid-lowering medication. However, in patients with noncardioembolic TIA/stroke, risk of extracranial bleeds was also higher in those with coexisting cardiovascular disease, particularly in patients aged <75 years (8.1%, 2.8-13.0; vs 3.4%, 1.6-5.3; p = 0.0050; age- and sex-adjusted HR 2.71, 1.16-6.30), although risk of intracerebral hemorrhage was not increased (age- and sex-adjusted HR 0.36, 0.04-2.99). CONCLUSIONS: As in older studies, patients with TIA/stroke with coexisting cardiovascular disease remain at high risk of recurrent ischemic events despite current management. More intensive lipid-lowering might therefore be justified, but benefit from increased antithrombotic treatment might be offset by the higher risk of extracranial bleeding.


Assuntos
Hemorragia Cerebral/complicações , Ataque Isquêmico Transitório/complicações , Acidente Vascular Cerebral/complicações , Tempo , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/patologia , Feminino , Humanos , Ataque Isquêmico Transitório/patologia , Masculino , Pessoa de Meia-Idade , Risco , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral/patologia
16.
Drug Des Devel Ther ; 13: 1957-1967, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354241

RESUMO

Background: The authors have recently designed a new compound bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and verified that bpV(pis) confers neuroprotection through suppressing PTEN and activating ERK1/2, respectively. Intracerebral hemorrhage (ICH) is the second most common cause of stroke and has severe clinical outcome. In this study, we investigate the effect of bpV(pis) in ICH model both in vivo and in vitro. Materials and methods: The novel drug bpV(pis) was synthesized in the Faculty of Pharmacy, Wuhan University School of Medicine. An ICH model was generated on both SD rats and cells. bpV(pis) was injected into intracerebroventricular or culture media. Western blotting was applied to test the signal pathway. To determine the effect of bpV(pis) on PTEN inhibition and ERK1/2 activation, we measured the phosphorylation level of AKT (a direct downstream target of PTEN that negatively regulates AKT) and ERK1/2. FJC, MTT, and LDH were applied to measure the cell viability. Neurobehavioral tests were performed to measure the effect of bpV(pis). Results: The in vivo results showed that intracerebroventricular administration of bpV(pis) significantly alleviates hematoma, the damage of brain-blood barrier and brain edema. The in vitro results demonstrated that bpV(pis) treatment reduces ICH-induced neuronal injury. Western blotting results identified that bpV(pis) exerts a neuroprotective effect by significantly increasing the phosphorylation level of AKT and ERK1/2 after experimental ICH. Neurobehavioral tests indicate that bpV(pis) promotes functional recovery in ICH animals. Conclusion: This study provides first and direct evidence for a potential role of bpV(pis) in ICH therapy.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Compostos de Vanádio/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Injeções Intraventriculares , Masculino , Exame Neurológico , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Compostos de Vanádio/administração & dosagem
17.
Int Immunopharmacol ; 75: 105771, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352322

RESUMO

OBJECTIVE: Intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatments. And caspase-1-mediated inflammatory response happened during the progression of ICH. Therefore, we aimed to investigate the effects of caspase-1 inhibitor Ac-YVAD-cmk on ICH. MATERIALS AND METHODS: Microglia cells were isolated and activated by thrombin for 24 h. Then the transcript and protein expressions of NLRP3 and inflammatory factors were assessed by RT-PCR and western blotting. Moreover, Ac-YVAD-cmk was injected into the ICH model. The mNSS and brain water content were tested at 24 h post-ICH. Finally, the pathological changes of microglia activation following ICH were discovered by the immunohistochemical and HE staining ways. RESULTS: Ac-YVAD-cmk inhibited the activation of pro-caspase-1 and decreased brain edema, in association with decreasing activated microglia and the expression of inflammation-related factors at 24 h post-ICH. Consequently, Ac-YVAD-cmk reduced the release of mature IL-1ß/IL-18 in perihematoma, improved the behavioral performance, and alleviated microglia in perihematoma region in ICH rats. CONCLUSIONS: These results indicate that caspase-1 could amplify the plural inflammatory responses in the ICH. Administration of Ac-YVAD-cmk has the potential to be a novel therapeutic strategy for ICH.


Assuntos
Clorometilcetonas de Aminoácidos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Caspase 1/imunologia , Inibidores de Caspase/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Inibidores de Caspase/farmacologia , Células Cultivadas , Hemorragia Cerebral/imunologia , Hemorragia Cerebral/patologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley
18.
J Neurol ; 266(9): 2258-2262, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165233

RESUMO

BACKGROUND AND PURPOSE: Moyamoya angiopathy (MMA) is rare outside Asia. Little is known about pathophysiology in European patients. This study aims to elucidate the histopathology of non-Asian MMA and its similarities and differences to those cases from Asia. METHODS: Here, we present a 57-year-old European woman with MMA and describe the post-mortem examination results of the brain and cerebral arteries. RESULTS: Histopathological findings in cerebral blood vessels were identical to those found in Asians. This included thickening and undulation of the internal elastic lamina as well as fibrocellular thickening and proliferation of smooth muscle cells of the intima in the distal segments of the internal carotid arteries and in proximal and middle segments of the anterior and middle cerebral arteries. Collateral vessels showed fragmented internal elastic lamina and thinning of the media with isolated microaneurysms. CONCLUSIONS: Histopathological changes found in this European patient are identical with those described in Asians. Despite suspected different genetic triggers and unknown pathophysiological cascades, MMA in Europeans seems to result in a common final pathway compared with the disease in Asians.


Assuntos
Hemorragia Cerebral/complicações , Hemorragia Cerebral/patologia , Endotélio Vascular/patologia , Doença de Moyamoya/complicações , Doença de Moyamoya/patologia , Hemorragia Cerebral/diagnóstico , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Moyamoya/diagnóstico
19.
EBioMedicine ; 45: 615-623, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31208948

RESUMO

Intracranial haemorrhage (ICH) is a life-threatening type of stroke with high mortality, morbidity, and recurrence rates. However, no effective treatment has been established to improve functional outcomes in patients with ICH to date. Strategies targeting secondary brain injury are of great interest in both experimental and translational studies. The immune system is increasingly considered to be a crucial contributor to ICH-induced brain injury because it participates in multiple phases of ICH, from the early vascular rupture events to brain recovery. Various pathobiological processes that contribute to secondary brain injury closely interact with the immune system, such as brain oedema, neuroinflammation, and neuronal damage. Hence, we summarize the immune response to ICH and recent progress in treatments targeting the immune system in this review. The emerging therapeutic strategies that target the immune system after ICH are a particular focus and have been summarized.


Assuntos
Edema Encefálico/imunologia , Lesões Encefálicas/imunologia , Hemorragia Cerebral/imunologia , Inflamação/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Edema Encefálico/patologia , Edema Encefálico/terapia , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/terapia , Humanos , Sistema Imunitário/patologia , Inflamação/patologia , Inflamação/terapia , Neurônios/imunologia , Neurônios/patologia , Pesquisa Médica Translacional
20.
Dis Model Mech ; 12(5)2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31043432

RESUMO

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors such as neuroblastoma in DS patients and increased vascular anomalies in DS fetuses suggest a potential role of DYRK1A in angiogenic processes, but in vivo evidence is still scarce. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that DYRK1A plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases.


Assuntos
Vasos Sanguíneos/patologia , Sinalização do Cálcio , Técnicas de Inativação de Genes , Proteínas Quinases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Vasos Sanguíneos/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/embriologia , Encéfalo/patologia , Encéfalo/ultraestrutura , Hemorragia Cerebral/patologia , Ácido Egtázico/farmacologia , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Desenvolvimento Embrionário/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Harmina/farmacologia , Espaço Intracelular/metabolismo , Mutação/genética , Fenótipo , Transcriptoma/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/antagonistas & inibidores
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