目的:基于Lasso回归构建癫痫患者认知功能障碍预测模型,并分析该模型的预测效能。方法:采用横断面研究,纳入美国国家健康与营养调查(National Health and Nutrition Examination Survey,NHANES)数据库的癫痫患者,依据数字符号替换测试(d...目的:基于Lasso回归构建癫痫患者认知功能障碍预测模型,并分析该模型的预测效能。方法:采用横断面研究,纳入美国国家健康与营养调查(National Health and Nutrition Examination Survey,NHANES)数据库的癫痫患者,依据数字符号替换测试(digit symbol substitution test,DSST)总分将参与者分为认知功能障碍组(DSST<34分)和认知功能正常组(DSST≥34分)。收集人口学资料、社会经济学特征、体力活动情况、疾病资料以及25-羟基维生素D[25-hydroxyvitamin D,25(OH)D]、神经丝轻链蛋白(neurofilament light chain,NfL)等实验室检测指标,应用Lasso回归筛选非0系数变量,构建多因素Logistic回归模型分析癫痫患者认知功能障碍的影响因素并构建列线图预测模型,应用受试者工作特征(receiver operating characteristic,ROC)曲线、Bootstrap校准曲线和Hosmer-Lemeshow拟合优度检验评价列线图模型对癫痫患者认知功能障碍的预测能力。结果:共纳入282例研究对象,癫痫患者认知功能障碍发生率为32.62%。经Lasso降维处理和Logistic回归共筛选得到血尿酸、NfL、血清25(OH)D和教育程度等癫痫患者认知功能障碍的影响因素。基于上述影响因素构建列线图预测模型,ROC曲线显示模型的曲线下面积为0.833(95%CI:0.780~0.886),特异度为0.804,灵敏度为0.781。Bootstrap校准曲线显示实测概率与列线图预测概率之间具有较高的一致性;Hosmer-Lemeshow拟合优度检验结果也表明列线图模型的拟合程度较好(χ^(2)=7.781,P=0.455)。结论:癫痫患者认知功能障碍的发生受到血尿酸、NfL、血清25(OH)D和教育程度等因素的影响,基于Lasso回归构建的癫痫患者认知功能障碍预测模型显示出良好的预测效能,为临床评估和干预提供了重要依据,有助于提高癫痫患者的预后管理效果。展开更多
目的:创伤后癫痫(post-traumatic epilepsy,PTE)是创伤性脑损伤(traumatic brain injury,TBI)的常见并发症,严重影响患者预后,早期预测PTE风险对临床管理至关重要,相比成人,儿童PTE相关研究较少,且缺乏临床公认的高预测效能模型。本研...目的:创伤后癫痫(post-traumatic epilepsy,PTE)是创伤性脑损伤(traumatic brain injury,TBI)的常见并发症,严重影响患者预后,早期预测PTE风险对临床管理至关重要,相比成人,儿童PTE相关研究较少,且缺乏临床公认的高预测效能模型。本研究旨在构建并验证适用于儿童TBI患者的PTE风险预测列线图模型。方法:系统检索中国知网、万方、中国生物医学文献数据库、维普、Pubmed、Embase和Web of Science数据库中关于儿童PTE危险因素的研究,检索时限为建库至2024年10月。采用Stata 15.0软件进行Meta分析,根据Meta分析结果提取合并效应量具有显著性的风险因素。回顾性收集2019年1月—2023年12月南京医科大学附属儿童医院外科重症监护病房(surgical intensive care unit,SICU)收治的262例TBI患儿,按7∶3比例随机划分为训练队列和内部验证队列,基于Meta分析筛选的危险因素,利用R软件构建多因素Logistic回归模型并绘制列线图。采用受试者工作特征(receiver operating characteristic,ROC)曲线下面积(area under the curve,AUC)评价模型区分度,Hosmer-Lemeshow检验评估校准度,运用决策曲线分析(decision curve analysis,DCA)评估临床实用性。结果:共纳入13项研究,涉及1371819例TBI患儿。Meta分析显示,中国TBI儿童中PTE的发病率为19%(95%CI:17%~20%)。结合Meta分析筛选结果和临床经验,最终纳入8个危险因素构建模型:格拉斯哥昏迷量表(Glasgow coma scale,GCS)评分、开放性脑损伤、早期痫性发作、意识丧失以及异常颅脑影像学表现(颅内血肿、脑挫伤、硬膜下出血、蛛网膜下腔出血),预测模型在训练队列和内部验证队列的AUC分别为0.801(95%CI:0.735~0.867,P<0.05)和0.831(95%CI:0.728~0.934,P<0.05)。Hosmer-Lemeshow拟合优度检验示模型拟合良好(训练队列:P=0.079;验证队列:P=0.082)。DCA显示该模型具有较高临床净获益。结论:本研究基于Meta分析构建的儿童PTE风险预测模型具有良好的区分度、校准度和临床实用性,可作为TBI儿童发生PTE风险评估的有效工具。展开更多
Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various ne...Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
Epilepsy,a common neurological disorder,is characterized by recurrent seizures that can lead to cognitive,psychological,and neurobiological consequences.The pathogenesis of epilepsy involves neuronal dysfunction at th...Epilepsy,a common neurological disorder,is characterized by recurrent seizures that can lead to cognitive,psychological,and neurobiological consequences.The pathogenesis of epilepsy involves neuronal dysfunction at the molecular,cellular,and neural circuit levels.Abnormal molecular signaling pathways or dysfunction of specific cell types can lead to epilepsy by disrupting the normal functioning of neural circuits.The continuous emergence of new technologies and the rapid advancement of existing ones have facilitated the discovery and comprehensive understanding of the neural circuit mechanisms underlying epilepsy.Therefore,this review aims to investigate the current understanding of the neural circuit mechanisms in epilepsy based on various technologies,including electroencephalography,magnetic resonance imaging,optogenetics,chemogenetics,deep brain stimulation,and brain-computer interfaces.Additionally,this review discusses these mechanisms from three perspectives:structural,synaptic,and transmitter circuits.The findings reveal that the neural circuit mechanisms of epilepsy encompass information transmission among different structures,interactions within the same structure,and the maintenance of homeostasis at the cellular,synaptic,and neurotransmitter levels.These findings offer new insights for investigating the pathophysiological mechanisms of epilepsy and enhancing its clinical diagnosis and treatment.展开更多
Complex genetic architecture is the major cause of heterogeneity in epilepsy,which poses challenges for accurate diagnosis and precise treatment.A large number of epilepsy candidate genes have been identified from cli...Complex genetic architecture is the major cause of heterogeneity in epilepsy,which poses challenges for accurate diagnosis and precise treatment.A large number of epilepsy candidate genes have been identified from clinical studies,particularly with the widespread use of next-generation sequencing.Validating these candidate genes is emerging as a valuable yet challenging task.Drosophila serves as an ideal animal model for validating candidate genes associated with neurogenetic disorders such as epilepsy,due to its rapid reproduction rate,powerful genetic tools,and efficient use of ethological and electrophysiological assays.Here,we systematically summarize the advantageous techniques of the Drosophila model used to investigate epilepsy genes,including genetic tools for manipulating target gene expression,ethological assays for seizure-like behaviors,electrophysiological techniques,and functional imaging for recording neural activity.We then introduce several typical strategies for identifying epilepsy genes and provide new insights into gene-gene interactions in epilepsy with polygenic causes.We summarize well-established precision medicine strategies for epilepsy and discuss prospective treatment options,including drug therapy and gene therapy for genetic epilepsy based on the Drosophila model.Finally,we also address genetic counseling and assisted reproductive technology as potential approaches for the prevention of genetic epilepsy.展开更多
文摘目的:基于Lasso回归构建癫痫患者认知功能障碍预测模型,并分析该模型的预测效能。方法:采用横断面研究,纳入美国国家健康与营养调查(National Health and Nutrition Examination Survey,NHANES)数据库的癫痫患者,依据数字符号替换测试(digit symbol substitution test,DSST)总分将参与者分为认知功能障碍组(DSST<34分)和认知功能正常组(DSST≥34分)。收集人口学资料、社会经济学特征、体力活动情况、疾病资料以及25-羟基维生素D[25-hydroxyvitamin D,25(OH)D]、神经丝轻链蛋白(neurofilament light chain,NfL)等实验室检测指标,应用Lasso回归筛选非0系数变量,构建多因素Logistic回归模型分析癫痫患者认知功能障碍的影响因素并构建列线图预测模型,应用受试者工作特征(receiver operating characteristic,ROC)曲线、Bootstrap校准曲线和Hosmer-Lemeshow拟合优度检验评价列线图模型对癫痫患者认知功能障碍的预测能力。结果:共纳入282例研究对象,癫痫患者认知功能障碍发生率为32.62%。经Lasso降维处理和Logistic回归共筛选得到血尿酸、NfL、血清25(OH)D和教育程度等癫痫患者认知功能障碍的影响因素。基于上述影响因素构建列线图预测模型,ROC曲线显示模型的曲线下面积为0.833(95%CI:0.780~0.886),特异度为0.804,灵敏度为0.781。Bootstrap校准曲线显示实测概率与列线图预测概率之间具有较高的一致性;Hosmer-Lemeshow拟合优度检验结果也表明列线图模型的拟合程度较好(χ^(2)=7.781,P=0.455)。结论:癫痫患者认知功能障碍的发生受到血尿酸、NfL、血清25(OH)D和教育程度等因素的影响,基于Lasso回归构建的癫痫患者认知功能障碍预测模型显示出良好的预测效能,为临床评估和干预提供了重要依据,有助于提高癫痫患者的预后管理效果。
文摘目的:创伤后癫痫(post-traumatic epilepsy,PTE)是创伤性脑损伤(traumatic brain injury,TBI)的常见并发症,严重影响患者预后,早期预测PTE风险对临床管理至关重要,相比成人,儿童PTE相关研究较少,且缺乏临床公认的高预测效能模型。本研究旨在构建并验证适用于儿童TBI患者的PTE风险预测列线图模型。方法:系统检索中国知网、万方、中国生物医学文献数据库、维普、Pubmed、Embase和Web of Science数据库中关于儿童PTE危险因素的研究,检索时限为建库至2024年10月。采用Stata 15.0软件进行Meta分析,根据Meta分析结果提取合并效应量具有显著性的风险因素。回顾性收集2019年1月—2023年12月南京医科大学附属儿童医院外科重症监护病房(surgical intensive care unit,SICU)收治的262例TBI患儿,按7∶3比例随机划分为训练队列和内部验证队列,基于Meta分析筛选的危险因素,利用R软件构建多因素Logistic回归模型并绘制列线图。采用受试者工作特征(receiver operating characteristic,ROC)曲线下面积(area under the curve,AUC)评价模型区分度,Hosmer-Lemeshow检验评估校准度,运用决策曲线分析(decision curve analysis,DCA)评估临床实用性。结果:共纳入13项研究,涉及1371819例TBI患儿。Meta分析显示,中国TBI儿童中PTE的发病率为19%(95%CI:17%~20%)。结合Meta分析筛选结果和临床经验,最终纳入8个危险因素构建模型:格拉斯哥昏迷量表(Glasgow coma scale,GCS)评分、开放性脑损伤、早期痫性发作、意识丧失以及异常颅脑影像学表现(颅内血肿、脑挫伤、硬膜下出血、蛛网膜下腔出血),预测模型在训练队列和内部验证队列的AUC分别为0.801(95%CI:0.735~0.867,P<0.05)和0.831(95%CI:0.728~0.934,P<0.05)。Hosmer-Lemeshow拟合优度检验示模型拟合良好(训练队列:P=0.079;验证队列:P=0.082)。DCA显示该模型具有较高临床净获益。结论:本研究基于Meta分析构建的儿童PTE风险预测模型具有良好的区分度、校准度和临床实用性,可作为TBI儿童发生PTE风险评估的有效工具。
基金supported by the National Natural Science Foundation of China,Nos.82471471(to WJ),82471485(to FY)Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation,No.tzjhjw(to WJ)+1 种基金Shaanxi Key Research and Development Plan Project,No.2023-YBSF-353(to XW)the Joint Fund Project of Innovation Research Institute of Xijing Hospital,No.LHJJ24JH13(to ZS)。
文摘Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
基金supported by Basic Research Programs of Science and Technology Commission Foundation of Shanxi Province,No.20210302123486(to WJ).
文摘Epilepsy,a common neurological disorder,is characterized by recurrent seizures that can lead to cognitive,psychological,and neurobiological consequences.The pathogenesis of epilepsy involves neuronal dysfunction at the molecular,cellular,and neural circuit levels.Abnormal molecular signaling pathways or dysfunction of specific cell types can lead to epilepsy by disrupting the normal functioning of neural circuits.The continuous emergence of new technologies and the rapid advancement of existing ones have facilitated the discovery and comprehensive understanding of the neural circuit mechanisms underlying epilepsy.Therefore,this review aims to investigate the current understanding of the neural circuit mechanisms in epilepsy based on various technologies,including electroencephalography,magnetic resonance imaging,optogenetics,chemogenetics,deep brain stimulation,and brain-computer interfaces.Additionally,this review discusses these mechanisms from three perspectives:structural,synaptic,and transmitter circuits.The findings reveal that the neural circuit mechanisms of epilepsy encompass information transmission among different structures,interactions within the same structure,and the maintenance of homeostasis at the cellular,synaptic,and neurotransmitter levels.These findings offer new insights for investigating the pathophysiological mechanisms of epilepsy and enhancing its clinical diagnosis and treatment.
基金supported by the Guangdong Basic and Applied Basic Research Foundation,No.2022A1515111123(to JQ)。
文摘Complex genetic architecture is the major cause of heterogeneity in epilepsy,which poses challenges for accurate diagnosis and precise treatment.A large number of epilepsy candidate genes have been identified from clinical studies,particularly with the widespread use of next-generation sequencing.Validating these candidate genes is emerging as a valuable yet challenging task.Drosophila serves as an ideal animal model for validating candidate genes associated with neurogenetic disorders such as epilepsy,due to its rapid reproduction rate,powerful genetic tools,and efficient use of ethological and electrophysiological assays.Here,we systematically summarize the advantageous techniques of the Drosophila model used to investigate epilepsy genes,including genetic tools for manipulating target gene expression,ethological assays for seizure-like behaviors,electrophysiological techniques,and functional imaging for recording neural activity.We then introduce several typical strategies for identifying epilepsy genes and provide new insights into gene-gene interactions in epilepsy with polygenic causes.We summarize well-established precision medicine strategies for epilepsy and discuss prospective treatment options,including drug therapy and gene therapy for genetic epilepsy based on the Drosophila model.Finally,we also address genetic counseling and assisted reproductive technology as potential approaches for the prevention of genetic epilepsy.
