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BACKGROUND: Remote secondary neurodegeneration is associated with poststroke cognitive impairment (PSCI). Dl-3-n-butylphthalide (NBP) improves PSCI clinically. However, whether it ameliorates PSCI by alleviating secondary neurodegeneration remains uncertain. Nonhuman primates provide more relevant models than rodents for human stroke and PSCI. This study investigated the effects of NBP on PSCI and secondary neurodegeneration in cynomolgus monkeys after permanent left middle cerebral artery occlusion (MCAO). METHODS: Thirteen adult male cynomolgus monkeys were randomly assigned to sham (n=4), MCAO+placebo (n=5), and MCAO+NBP groups (n=4). The MCAO+placebo and MCAO+NBP groups received saline and NBP injections intravenously, respectively, starting at 6-hour postsurgery for 2 weeks, followed by soybean oil and NBP orally, respectively, for 10 weeks after MCAO. Infarct size was assessed at week 4 by magnetic resonance imaging. Working memory and executive function were evaluated dynamically using the delayed response task and object retrieval detour task, respectively. Neuron loss, glia proliferation, and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex, thalamus, and hippocampus were analyzed by immunostaining 12 weeks after MCAO. RESULTS: Infarcts were located in the left middle cerebral artery region, apart from the ipsilateral dorsal lateral prefrontal cortex, thalamus, or hippocampus, with no significant difference between the MCAO+placebo and MCAO+NBP group. Higher success in delayed response task was achieved at weeks 4, 8, and 12 after NBP compared with placebo treatments (P<0.05), but not in the object retrieval detour task (all P>0.05). More neurons and less microglia, astrocytes, CD68-positive microglia, tumor necrosis factor-α, and inducible NO synthase were observed in the ipsilateral dorsal lateral prefrontal cortex and thalamus after 12 weeks of NBP treatment (P<0.05), but not in the hippocampus (P>0.05). CONCLUSIONS: Our findings indicate that NBP improves working memory by alleviating remote secondary neurodegeneration and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex and thalamus after MCAO in cynomolgus monkeys.
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Benzofuranos , Lesiones Encefálicas , Neoplasias Encefálicas , Fármacos Neuroprotectores , Accidente Cerebrovascular , Humanos , Animales , Masculino , Macaca fascicularis , Memoria a Corto Plazo , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológico , Lesiones Encefálicas/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Hipocampo/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Investigating cerebral asymmetries in non-human primates would facilitate to understand the evolutional traits of the human brain specialization related to language and other high-level cognition. However, brain asymmetrical studies of monkeys produced controversial results. Here, we investigated the cerebral asymmetries using a combination of the optimized voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) protocols in monkeys. The study-specific MRI and DTI-based templates were created in 66 adult Macaca fascicularis, and the asymmetrical index of grey and white matter was subsequently examined. The VBM analysis detected the well-known frontal and occipital petalias and confirmed the presence of leftward asymmetry in the ventral frontal cortex. A marked leftward asymmetry of anterior superior temporal gyrus but not posterior portion were found. We also identified grey matter asymmetries in some regions that were not previously reported including rightward anterior cingulate, insular cortex and thalamus, and leftward caudate. In contrast, the results of TBSS analysis for the first time revealed the robust leftwards asymmetries of corpus callosum (splenium and body), internal/external capsule, and white matter in middle temporal gyrus, adjacent thalamus and amygdala whereas the rightwards in uncinate fasciculus, posterior thalamic radiation and cerebral peduncle. These findings provide robust evidence of grey and white matter asymmetries in the brain of monkeys, which may extend the understanding of brain evolution in cerebral specialization.
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Imagen de Difusión Tensora , Sustancia Blanca , Animales , Macaca fascicularis , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagen , LenguajeRESUMEN
Neuronal loss in the ipsilateral thalamus after focal cortical infarction participates in post-stroke cognitive deficits, and enhanced angiogenesis in the thalamus is expected to reduce neuronal damage. We hypothesize that novel translocator protein (TSPO) ligand, 2-Cl-MGV-1, can promote angiogenesis, attenuate neuronal loss in the thalamus, and ameliorate post-stroke cognitive deficits. Cortical infarction was induced by distal middle cerebral artery occlusion (dMCAO) in stroke-prone renovascular hypertensive rats. 2-Cl-MGV-1 or dimethyl sulfoxide was administered 24 h after dMCAO and then for 6 or 13 days. Spatial learning and memory were assessed using the Morris water maze. Neuronal loss, TSPO expression, angiogenesis, and intrinsic pathway were determined by immunofluorescence and immunoblotting 7 and 14 days after dMCAO. Cortical infarction caused post-stroke cognitive deficits and secondary neuronal loss with gliosis in the ipsilateral thalamus within 14 days of dMCAO. Increased angiogenesis and elevated expression of vascular TSPO were detected in the ipsilateral thalamus, and treatment with 2-Cl-MGV-1 enhanced angiogenesis by stimulating the PI3K-AKT-mTOR pathway. The effects of 2-Cl-MGV-1 on angiogenesis coincided with reduced neuronal loss in the thalamus and contributed to improvements in post-stroke cognitive deficits. Our findings suggest that 2-Cl-MGV-1 stimulates angiogenesis, ameliorates neuronal loss in the thalamus, and improves post-stroke cognitive deficits.
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Angiogénesis , Carbamatos , Quinazolinas , Accidente Cerebrovascular , Ratas , Animales , Ratas Sprague-Dawley , Ligandos , Fosfatidilinositol 3-Quinasas/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Accidente Cerebrovascular/metabolismo , Tálamo/metabolismo , CogniciónRESUMEN
The development of omics data and biomedical images has greatly advanced the progress of precision medicine in diagnosis, treatment, and prognosis. The fusion of omics and imaging data, i.e., omics-imaging fusion, offers a new strategy for understanding complex diseases. However, due to a variety of issues such as the limited number of samples, high dimensionality of features, and heterogeneity of different data types, efficiently learning complementary or associated discriminative fusion information from omics and imaging data remains a challenge. Recently, numerous machine learning methods have been proposed to alleviate these problems. In this review, from the perspective of fusion levels and fusion methods, we first provide an overview of preprocessing and feature extraction methods for omics and imaging data, and comprehensively analyze and summarize the basic forms and variations of commonly used and newly emerging fusion methods, along with their advantages, disadvantages and the applicable scope. We then describe public datasets and compare experimental results of various fusion methods on the ADNI and TCGA datasets. Finally, we discuss future prospects and highlight remaining challenges in the field.
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Biología Computacional , Aprendizaje Automático , Biología Computacional/métodosRESUMEN
BACKGROUND AND PURPOSE: Intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke in Asian countries. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse poststroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort. METHODS: We prospectively and consecutively recruited stroke patients from four centers in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using multivariate regression analysis. RESULTS: Among 1593 patients, 116 (63.7%) of 182 patients with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD levels were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD-deficient individuals were more likely to have multiple (≥2 segments) intracranial stenosis (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.25-2.81, p = 0.002). G6PD deficiency increased the risk of ICAS in patients who were male (OR = 1.82, 95% CI = 1.24-2.66, p = 0.002), aged ≥70 years (OR = 2.40, 95% CI = 1.33-4.31, p = 0.004), or hypertensive (OR = 1.88, 95% CI = 1.28-2.77, p = 0.001). CONCLUSIONS: Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.
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Deficiencia de Glucosafosfato Deshidrogenasa , Hipertensión , Arteriosclerosis Intracraneal , Accidente Cerebrovascular , Constricción Patológica , Femenino , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/epidemiología , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Arteriosclerosis Intracraneal/complicaciones , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/epidemiología , Angiografía por Resonancia Magnética , Masculino , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiologíaRESUMEN
Morphological attributes from histopathological images and molecular profiles from genomic data are important information to drive diagnosis, prognosis, and therapy of cancers. By integrating these heterogeneous but complementary data, many multi-modal methods are proposed to study the complex mechanisms of cancers, and most of them achieve comparable or better results from previous single-modal methods. However, these multi-modal methods are restricted to a single task (e.g., survival analysis or grade classification), and thus neglect the correlation between different tasks. In this study, we present a multi-modal fusion framework based on multi-task correlation learning (MultiCoFusion) for survival analysis and cancer grade classification, which combines the power of multiple modalities and multiple tasks. Specifically, a pre-trained ResNet-152 and a sparse graph convolutional network (SGCN) are used to learn the representations of histopathological images and mRNA expression data respectively. Then these representations are fused by a fully connected neural network (FCNN), which is also a multi-task shared network. Finally, the results of survival analysis and cancer grade classification output simultaneously. The framework is trained by an alternate scheme. We systematically evaluate our framework using glioma datasets from The Cancer Genome Atlas (TCGA). Results demonstrate that MultiCoFusion learns better representations than traditional feature extraction methods. With the help of multi-task alternating learning, even simple multi-modal concatenation can achieve better performance than other deep learning and traditional methods. Multi-task learning can improve the performance of multiple tasks not just one of them, and it is effective in both single-modal and multi-modal data.
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Glioma , Redes Neurales de la Computación , Genómica , Humanos , PronósticoRESUMEN
PURPOSE: The purpose of this study was to explore the feasibility and potential advantages of laparoscopic surgery in the treatment of incarcerated obturator hernia (IOH). MATERIALS AND METHODS: Clinical data of 23 patients with IOH who underwent emergency surgery at our hospital from June 2015 to October 2020 were retrospectively analyzed. The clinical characteristics and surgery outcomes were compared between the laparoscopic group, open group, and the previously published data. RESULTS: Twelve patients with IOH were treated by laparoscopic management, while 11 patients with IOH underwent open surgery. There was no statistically significant difference in preoperative general data between the 2 groups, while the laparoscopic group had less intraoperative blood loss, shorter postoperative hospital stay, and lower postoperative complications compared with open group. Furthermore, when compared with the open group reported in previous literature, which showed similar conclusions. CONCLUSION: Laparoscopic surgery for IOH showed more favorable advantages including less intraoperative blood loss, shorter postoperative hospital stay, and lower postoperative complications compared with an open approach, which is a safe and feasible minimally invasive strategy and has certain advantages.
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Hernia Obturadora , Laparoscopía , Estudios de Factibilidad , Hernia Obturadora/complicaciones , Hernia Obturadora/cirugía , Herniorrafia , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
AIMS: The risk of hemoglobin decline induced by low-dose aspirin in glucose-6-phosphate dehydrogenase (G6PD) deficiency remains unknown, and its influence on stroke outcome remains to be investigated. This study aimed to evaluate the effect of G6PD deficiency on hemoglobin level during aspirin treatment and its association with outcome after acute ischemic stroke. METHODS: In total, 279 patients (40 G6PD-deficient and 239 G6PD-normal) with acute ischemic stroke treated with aspirin 100 mg/day from a cohort study were examined. The primary safety endpoint was a hemoglobin decline ≥25 g/L or 25% from baseline within 14 days after aspirin treatment. Poor outcomes were defined as a modified Rankin Scale score ≥2 at 3 months. The χ2 test was used to compare stroke outcomes, and multivariate logistic regression analyses were performed to analyze the association between hemoglobin level and outcomes. RESULTS: The G6PD-deficient group had lower baseline hemoglobin and tended to develop comorbid pulmonary infection more frequently (p < 0.05). The proportion of patients with hemoglobin decline ≥25 g/L or 25% from baseline (15.0% vs. 3.3%; p = 0.006) and anemia (30.0% vs. 14.6%; p = 0.016) after aspirin treatment was higher in the G6PD-deficient group, which was accompanied by a more significant bilirubin increase. The rate of poor functional outcomes at 3 months after acute ischemic stroke was higher in the G6PD-deficient group (Risk ratio = 1.31 [95% confidence interval (CI) = 1.10-1.56]; p = 0.017). Confounder-adjusted analysis showed that lower hemoglobin levels (odds ratio = 0.98 [95% CI = 0.96-0.99]; adjusted p = 0.009) increased the risk of poor functional outcomes. CONCLUSION: Hemoglobin decrease with bilirubin increase after aspirin treatment in patients with G6PD deficiency suggests hemolysis, which may influence stroke prognosis. The risk of hemoglobin decline should be carefully monitored in G6PD-deficient patients with ischemic stroke taking aspirin.
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Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Glucosafosfato Deshidrogenasa/genética , Hemoglobinas/metabolismo , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/genética , Anciano , Anemia/inducido químicamente , Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Estudios de Cohortes , Determinación de Punto Final , Femenino , Deficiencia de Glucosafosfato Deshidrogenasa/tratamiento farmacológico , Humanos , Enfermedades Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The curse of dimensionality, which is caused by high-dimensionality and low-sample-size, is a major challenge in gene expression data analysis. However, the real situation is even worse: labelling data is laborious and time-consuming, so only a small part of the limited samples will be labelled. Having such few labelled samples further increases the difficulty of training deep learning models. Interpretability is an important requirement in biomedicine. Many existing deep learning methods are trying to provide interpretability, but rarely apply to gene expression data. Recent semi-supervised graph convolution network methods try to address these problems by smoothing the label information over a graph. However, to the best of our knowledge, these methods only utilize graphs in either the feature space or sample space, which restrict their performance. We propose a transductive semi-supervised representation learning method called a hierarchical graph convolution network (HiGCN) to aggregate the information of gene expression data in both feature and sample spaces. HiGCN first utilizes external knowledge to construct a feature graph and a similarity kernel to construct a sample graph. Then, two spatial-based GCNs are used to aggregate information on these graphs. To validate the model's performance, synthetic and real datasets are provided to lend empirical support. Compared with two recent models and three traditional models, HiGCN learns better representations of gene expression data, and these representations improve the performance of downstream tasks, especially when the model is trained on a few labelled samples. Important features can be extracted from our model to provide reliable interpretability.
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Aprendizaje Automático Supervisado , Expresión Génica , HumanosRESUMEN
BACKGROUND AND PURPOSE: Aspirin is the first recommended antiplatelet agent to prevention secondary stroke, but its safety and efficacy in stroke patients with glucose-6-phosphate dehydrogenase deficiency remain unclear. We sought to evaluate its safety and efficacy in ischemic stroke patients with and without glucose-6-phosphate dehydrogenase deficiency. METHODS: Patients with ischemic stroke receiving aspirin (100 mg/day) for three months were recruited for a multicenter, prospective, cohort study. Blood glucose-6-phosphate dehydrogenase activity was examined after stroke. Safety outcomes including acute hemolysis, moderate-to-severe bleeding, and death (vascular, all-cause), and efficacy outcome indicated as stroke recurrence were evaluated at three months. Risk factors associated with moderate-to-severe bleeding and all-cause death were determined using multivariate or Cox regression analysis. RESULTS: Among the included 1121 patients, 81 of 130 glucose-6-phosphate dehydrogenase deficient and 576 of 991 glucose-6-phosphate dehydrogenase normal patients received aspirin for three months. Acute hemolysis was observed in one of the glucose-6-phosphate dehydrogenase deficient and in none of the glucose-6-phosphate dehydrogenase normal patients (p = 0.876). The rates of moderate-to-severe bleeding were 2.5% and 0.3% (p = 0.045), and the percentages of all-cause death were 6.2% and 1.4% (p = 0.008) in the glucose-6-phosphate dehydrogenase deficient and glucose-6-phosphate dehydrogenase normal patients. Stroke recurrence rate was similar in the two groups (2.5% vs. 1.7%; p = 0.608). Glucose-6-phosphate dehydrogenase deficiency was significantly associated with increased risk of moderate-to-severe bleeding (adjust p = 0.048) and all-cause death during aspirin use (adjust p = 0.008). CONCLUSIONS: Long-term low-dose aspirin therapy might relate to worse safety outcomes in patients with glucose-6-phosphate dehydrogenase deficiency and large clinical trials are needed to further confirm these findings.
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Isquemia Encefálica , Deficiencia de Glucosafosfato Deshidrogenasa , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Aspirina/uso terapéutico , Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Estudios de Cohortes , Quimioterapia Combinada , Glucosafosfato Deshidrogenasa/uso terapéutico , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/tratamiento farmacológico , Humanos , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Prospectivos , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
BACKGROUND: With the rapid development of sequencing technologies, collecting diverse types of cancer omics data become more cost-effective. Many computational methods attempted to represent and fuse multiple omics into a comprehensive view of cancer. However, different types of omics are related and heterogeneous. Most of the existing methods do not consider the difference between omics, so the biological knowledge of individual omics may not be fully excavated. And for a given task (e.g. predicting overall survival), these methods prefer to use sample similarity or domain knowledge to learn a more reasonable representation of omics, but it's not enough. METHODS: For the purpose of learning more useful representation for individual omics and fusing them to improve the prediction ability, we proposed an autoencoder-based method named MOSAE (Multi-omics Supervised Autoencoder). In our method, a specific autoencoder were designed for each omics according to their size of dimension to generate omics-specific representations. Then, a supervised autoencoder was constructed based on specific autoencoder by using labels to enforce each specific autoencoder to learn both omics-specific and task-specific representations. Finally, representations of different omics that generate from supervised autoencoders were fused in a traditional but powerful way, and the fused representation was used for subsequent predictive tasks. RESULTS: We applied our method over TCGA Pan-Cancer dataset to predict four different clinical outcome endpoints (OS, PFI, DFI, and DSS). Compared with traditional and state-of-the-art methods, MOSAE achieved better predictive performance. We also tested the effects of each improvement, which all have a positive effect on predictive performance. CONCLUSIONS: Predicting clinical outcome endpoints are very important for precision medicine and personalized medicine. And multi-omics fusion is an effective way to solve this problem. MOSAE is a powerful multi-omics fusion method, which can generate both omics-specific and task-specific representation for given endpoint predictive tasks and improve the predictive performance.
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Neoplasias , Humanos , Neoplasias/genética , Medicina de PrecisiónRESUMEN
OBJECTIVE: To assess the risk of glucose-6-phosphate dehydrogenase (G6PD) on stroke prognosis, we compared outcomes between patients with stroke with and without G6PD deficiency. METHODS: The study recruited 1,251 patients with acute ischemic stroke. Patients were individually categorized into G6PD-deficiency and non-G6PD-deficiency groups according to G6PD activity upon admission. The primary endpoint was poor outcome at 3 months defined by a modified Rankin Scale (mRS) score ≥2 (including disability and death). Secondary outcomes included the overall mRS score at 3 months and in-hospital death and all death within 3 months. Logistic regression and Cox models, adjusted for potential confounders, were fitted to estimate the association of G6PD deficiency with the outcomes. RESULTS: Among 1,251 patients, 150 (12.0%) were G6PD-deficient. Patients with G6PD deficiency had higher proportions of large-artery atherosclerosis (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.09-2.17) and stroke history (OR 1.93, 95% CI 1.26-2.90) compared to the non-G6PD-deficient group. The 2 groups differed significantly in the overall mRS score distribution (adjusted common OR 1.57, 95% CI 1.14-2.17). Patients with G6PD deficiency had higher rates of poor outcome at 3 months (adjusted OR 1.73, 95% CI 1.08-2.76; adjusted absolute risk increase 13.0%, 95% CI 2.4%-23.6%). The hazard ratio of in-hospital death for patients with G6PD-deficiency was 1.46 (95% CI 1.37-1.84). CONCLUSIONS: G6PD deficiency is associated with the risk of poor outcome at 3 months after ischemic stroke and may increase the risk of in-hospital death. These findings suggest the rationality of G6PD screening in patients with stroke.
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Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/mortalidad , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico por imagen , Deficiencia de Glucosafosfato Deshidrogenasa/mortalidad , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/mortalidad , Anciano , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Focal cerebral infarction leads to autophagic activation, which contributes to secondary neuronal damage in the ipsilateral thalamus. Although Nogo-A deactivation enhances neuronal plasticity, its role in autophagic activation in the thalamus after ischemic stroke remains unclear. This study aimed to investigate the potential roles of Nogo-A/Nogo-66 receptor 1 (NgR1) in autophagic activation in the ipsilateral thalamus after cerebral infarction. Focal neocortical infarction was established using the middle cerebral artery occlusion (MCAO) method. Secondary damage in the ipsilateral thalamus was assessed by Nissl staining and immunostaining. The expression of Nogo-A, NgR1, Rho-A and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as well as autophagic flux were evaluated by immunofluorescence and immunoblotting. The roles of Nogo-A-NgR1 signaling in autophagic activation were determined by intraventricular delivery of an NgR1 antagonist peptide, NEP1-40, at 24â¯h after MCAO. The results showed that Nogo-A and NgR1 overexpression temporally coincided with marked increases in the levels of Beclin1, LC3-II and sequestosome 1 (SQSTM1)/p62 in the ipsilateral thalamus at seven and fourteen days after MCAO. In contrast, NEP1-40 treatment significantly reduced the expression of Rho-A and ROCK1 which was accompanied by marked reductions of LC3-II conversion as well as the levels of Beclin1 and SQSTM1/p62. Furthermore, NEP1-40 treatment significantly reduced neuronal loss and gliosis in the ipsilateral thalamus, and accelerated somatosensory recovery at the observed time-points after MCAO. These results suggest that blockade of Nogo-A-NgR1 signaling inhibits autophagic activation, attenuates secondary neuronal damage in the ipsilateral thalamus, and promotes functional recovery after focal cerebral cortical infarction.
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Neuronas , Tálamo , Animales , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Proteínas Nogo , Receptor Nogo 1 , Ratas , Ratas Sprague-DawleyRESUMEN
Conflicting evidence exists regarding whether focal cerebral infarction contributes to cerebral amyloid-ß (Aß) deposition, as observed in Alzheimer's disease. In this study, we aimed to evaluate the presence of Aß deposits in the ipsilateral thalamus and hippocampus 12 months post-stroke in non-human primates, whose brains are structurally and functionally similar to that of humans. Four young male cynomolgus monkeys were subjected to unilateral permanent middle cerebral artery occlusion (MCAO), and another four sham-operated monkeys served as controls. All monkeys underwent magnetic resonance imaging examination on post-operative day 7 to assess the location and size of the infarction. The numbers of neurons, astrocytes, microglia and the Aß load in the non-affected thalamus and hippocampus ipsilaterally remote from infarct foci were examined immunohistochemically at sacrifice 12 months after operation. Thioflavin S and Congo Red stainings were used to identify amyloid deposits. Multiple Aß antibodies recognizing both the N-terminal and C-terminal epitopes of Aß peptides were used to avoid antibody cross-reactivity. Aß levels in cerebrospinal fluid (CSF) and plasma were examined using enzyme-linked immunosorbent assay. The initial infarct was restricted to the left temporal, parietal, insular cortex and the subcortical white matter, while the thalamus and hippocampus remained intact. Of note, there were fewer neurons and more glia in the ipsilateral thalamus and hippocampus in the MCAO group at 12 months post-stroke compared to the control group (all P < 0.05). However, there was no sign of extracellular Aß plaques in the thalamus or hippocampus. No statistically significant difference was found in CSF or plasma levels of Aß40 , Aß42 or the Aß40 /Aß42 ratio between the two groups (P > 0.05). These results suggest that significant secondary neuronal loss and reactive gliosis occur in the non-affected thalamus and hippocampus without Aß deposits in the late period after MCAO in non-human primates.
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Péptidos beta-Amiloides/metabolismo , Neuronas/metabolismo , Placa Amiloide/patología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/fisiología , Animales , Isquemia Encefálica/patología , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Hipocampo/patología , Infarto de la Arteria Cerebral Media/patología , Macaca fascicularis , Masculino , Neuroglía/patología , Lóbulo Temporal/metabolismo , Tálamo/patologíaRESUMEN
RATIONALE: Foreign body ingestion is a common clinical event, but serious complication such as perforation is uncommon. Here we present a case of gastrointestinal perforation caused by fish bone, which was treated effectively and successfully by totally laparoscopic management. PATIENT CONCERNS: A 63-year-old man who was admitted to our hospital with epigastric pain for 1 month. Computed tomography of the abdomen at the local hospital revealed a linear, hyperdense, foreign body in the lesser curvature of gastric antrum that had penetrated through the posterior wall of the gastric antrum. DIAGNOSIS: The laparoscopic exploration found that a 2.5âcmâ×â0.3âcm fish bone had penetrated through the posterior wall of the gastric antrum. INTERVENTIONS: A totally laparoscopic surgery was performed to remove the foreign body and repair the perforation eventually. OUTCOMES: After surgery, the patient underwent uneventful recovery and was discharged on postoperative day 7. During the 3 months of follow-up visit, the patient appeared healthy and did not report abdominal symptoms. LESSONS: In this case, the advantages of laparoscopic techniques in the diagnosis and treatment of gastrointestinal perforation caused by foreign body was confirmed, and which may be considered as the primary choice in similar cases.
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Cuerpos Extraños/cirugía , Laparoscopía/métodos , Estómago/cirugía , Animales , Huesos , Peces , Cuerpos Extraños/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estómago/lesiones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Data on the association between socioeconomic status and post-stroke functional outcome in developing countries is lacking. We aimed to evaluate the association in stroke survivors in deprived rural Southern China. METHODS: We conducted door-to-door interviews and collected data using a structured questionnaire in stroke survivors from five fourth-class rural areas of Guangdong Province through a non-government initiated registry from August 2014 to March 2015. Descriptive statistics were used to provide information on the demographic, socioeconomic and clinical characteristics of the selected population. Univariate and multivariate logistic regression were used to examine the relationship of socioeconomic status indexed by self-reported average family income and functional impairment defined as a modified Rankin Scale of 3 to 5. RESULTS: Among the 425 stroke survivors, 52.7% lived below the poverty line set by the local government. About 50% of patients suffered from functional impairment and required assistance in their daily life. Compared with their wealthier counterpart, stroke survivors with lower income were more likely to have functional impairment (OR 2.85, 95% CI 1.93-4.23). The effect size increased and remained significant after adjusting for possible confounding factors (OR 3.17, 95% CI 2.04-4.91). CONCLUSIONS: Poorer patients tend to have poorer post-stroke functional outcome. Primary and secondary strategies targeting underprivileged populations in less-developed areas are thus urgently needed in China.
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Población Rural , Clase Social , Accidente Cerebrovascular/epidemiología , Sobrevivientes , China/epidemiología , Personas con Discapacidad/estadística & datos numéricos , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Renta , Masculino , Persona de Mediana Edad , Pobreza , Sistema de Registros , Encuestas y CuestionariosRESUMEN
BACKGROUND AND PURPOSE: Focal cortical infarction causes neuronal apoptosis in the ipsilateral nonischemic thalamus and hippocampus, which is potentially associated with poststroke cognitive deficits. TSPO (translocator protein) is critical in regulating mitochondrial apoptosis pathways. We examined the effects of the novel TSPO ligand 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2-Cl-MGV-1) on poststroke cognitive deficits, neuronal mitochondrial apoptosis, and secondary damage in the ipsilateral thalamus and hippocampus after cortical infarction. METHODS: One hundred fourteen hypertensive rats underwent successful distal middle cerebral artery occlusion (n=76) or sham procedures (n=38). 2-Cl-MGV-1 or dimethyl sulfoxide as vehicle was administrated 2 hours after distal middle cerebral artery occlusion and then for 6 or 13 days (n=19 per group). Spatial learning and memory were tested using the Morris water maze. Secondary degeneration and mitochondrial apoptosis in the thalamus and hippocampus were assessed using Nissl staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling, JC-1 staining, and immunoblotting 7 and 14 days after surgery. RESULTS: Infarct volumes did not significantly differ between the vehicle and 2-Cl-MGV-1 groups. There were more neurons and fewer glia in the ipsilateral thalamus and hippocampus in the vehicle groups than in the sham-operated group 7 and 14 days post-distal middle cerebral artery occlusion. 2-Cl-MGV-1 significantly ameliorated spatial cognitive impairment and decreased neuronal death and glial activation when compared with vehicle treatment (P<0.05). The collapse of mitochondrial transmembrane potential and cytoplasmic release of apoptosis-inducing factors and cytochrome c was prevented within the thalamus. Caspase cleavage and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling+ or Nissl atrophic cells were reduced within the thalamus and hippocampus. This was accompanied by upregulation of B-cell lymphoma 2 and downregulation of Bax (P<0.05). CONCLUSIONS: 2-Cl-MGV-1 reduces neuronal apoptosis via mitochondrial-dependent pathways and attenuates secondary damage in the nonischemic thalamus and hippocampus, potentially contributing to ameliorated cognitive deficits after cortical infarction.
Asunto(s)
Apoptosis/efectos de los fármacos , Carbamatos/uso terapéutico , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/psicología , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/psicología , Hipocampo/patología , Fármacos Neuroprotectores/uso terapéutico , Quinazolinas/uso terapéutico , Tálamo/patología , Animales , Infarto Cerebral/patología , Disfunción Cognitiva/etiología , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Memoria/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuroglía/patología , Neuronas/patología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores de GABA/biosíntesis , Receptores de GABA/genética , Tálamo/efectos de los fármacosRESUMEN
Focal cerebral cortical infarction causes secondary neurodegeneration in the remote regions, such as the ventroposterior nucleus of the thalamus. Retrograde degeneration of thalamocortical fibers is considered as the principle mechanism, but the exact molecular events remain to be elucidated. This study aimed to investigate whether unfolded protein response (UPR) is activated in thalamic neurons following distal middle cerebral artery occlusion (MCAO) in stroke-prone renovascular hypertensive rats. Immunostaining and immunoblotting were performed to evaluate the expression of Grp78 and its downstream effectors in the thalamus at 3, 7 and 14 days after MCAO. Secondary thalamic degeneration was assessed with Nissl staining and NeuN immunostaining. Neuronal death was not apparent at 3 days post-ischaemia but was evident in the thalamus at 7 and 14 days after MCAO. Grp78 level was reduced in the ipsilateral thalamus at 3 and 7 days after MCAO. In parallel, phosphorylated eIF2α and ATF4 levels were elevated, indicating the activation of UPR. In contrast, ATF6α and CHOP levels were not changed. These results suggest that UPR is activated before neuronal death in the ipsilateral thalamus after MCAO and may represent a key early event in the secondary thalamic degeneration.
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Infarto Cerebral/metabolismo , Hipertensión/metabolismo , Tálamo/metabolismo , Respuesta de Proteína Desplegada/fisiología , Animales , Infarto Cerebral/patología , Hipertensión/patología , Masculino , Ratas , Ratas Sprague-Dawley , Tálamo/patologíaRESUMEN
Gastric cancer including the cardia and non-cardia types is the second frequent cause of cancer-related deaths worldwide. A subset of non-cardia gastric cancer genetic susceptibility loci have been addressed among Asian through genome-wide association studies (GWASs). This study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on non-cardia gastric cancer susceptibility in Chinese populations. We selected long intergenic noncoding RNAs (lincRNAs) located in non-cardia gastric cancer risk-related loci and identified 10 SNPs located within lincRNA exonic regions. We examined whether genetic polymorphisms in lincRNAs exons are associated with non-cardia gastric cancer risk in 438 non-cardia gastric cancer patients and 727 control subjects in Chinese populations using logistic regression. Functional relevance was further examined by biochemical assays. We found that lincRNA-NR_024015 rs8506AA carrier was significantly associated with risk of non-cardia gastric cancer (adjusted odds ratio [OR]â=â1.56, 95%CIâ=â1.03-2.39, compared with the rs8506 AG or GG genotype. Further stratification analysis showed that the risk effect was more pronounced in subgroups of smokers (Pâ=â0.001). Biochemical analysis demonstrated that the G to A base change at rs8506G>A disrupts the binding site for has-miR-526b, thereby influencing the transcriptional activity of lincRNA-NR_024015 and affecting cell proliferation. Our present study established a robust association between the rs8506G>A polymorphism in the lincRNA-NR_024015 exon and the risk of non-cardia gastric cancer.
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Exones/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Pueblo Asiatico/genética , Sitios de Unión/genética , Cardias/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Simulación por Computador , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Factores de Riesgo , Neoplasias Gástricas/patologíaRESUMEN
Platinum-based chemotherapy regimens are often recommended for patients with unresectable thymic carcinoma. In more than 60 cases, however, the systemic chemotherapy provides little benefit. In this report, we described a case of advanced KIT- and VEGF-positive thymic carcinoma with liver and lung metastasis. The patient, a 46-year-old man, exhibited a resistance to cisplatin-based chemotherapy, but responded to the treatment with sorafenib, a molecular target-based therapy. After 4 months of sorafenib therapy, his lung and liver metastases as well as the mediastinal tumor shrank dramatically. Moreover, the tumors showed stable disease for at least 9 months. To the best of our knowledge, it is the first report about a response of advanced thymic carcinoma to sorafenib. The preliminary study suggested that molecular target-based therapy could be an alternative treatment to those chemotherapy-refractory patients.