Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

BACKGROUND: It is inaccurate to reflect the level of dust exposure through working years. Furthermore, identifying a predictive indicator for lung function decline is significant for coal miners. The study aimed to explored whether club cell secretory protein (CC16) levels can reflect early lung function changes. METHODS: The cumulative respiratory dust exposure (CDE) levels of 1,461 coal miners were retrospectively assessed by constructed a job-exposure matrix to replace working years. Important factors affecting lung function and CC16 were selected by establishing random forest models. Subsequently, the potential of CC16 to reflect lung injury was explored from multiple perspectives. First, restricted cubic spline (RCS) models were used to compare the trends of changes in lung function indicators and plasma CC16 levels after dust exposure. Then mediating analysis was performed to investigate the role of CC16 in the association between dust exposure and lung function decline. Finally, the association between baseline CC16 levels and follow-up lung function was explored. RESULTS: The median CDE were 35.13 mg/m³-years. RCS models revealed a rapid decline in forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁), and their percentages of predicted values when CDE exceeded 25 mg/m³-years. The dust exposure level (<5 mg/m³-years) causing significant changes in CC16 was much lower than the level (25 mg/m³-years) that caused changes in lung function indicators. CC16 mediated 11.1% to 26.0% of dust-related lung function decline. Additionally, workers with low baseline CC16 levels experienced greater reductions in lung function in the future. CONCLUSIONS CC16 levels are more sensitive than lung indicators in reflecting early lung function injury and plays mediating role in lung function decline induced by dust exposure. Low baseline CC16 levels predict poor future lung function.
Uteroglobin/blood* ; Humans ; Dust/analysis* ; Occupational Exposure/analysis* ; Male ; Middle Aged ; Adult ; Retrospective Studies ; Lung Injury/chemically induced* ; Coal Mining ; Biomarkers/blood* ; China/epidemiology* ; Air Pollutants, Occupational ; Female

Objective To construct a uricase-deficient mouse model with stable inheritance using the CRISPR/Cas9 system,and evaluate its ability to simulate the disease characteristics of patients with hyperuricemia.Methods Double single guide RNAs(sgRNAs)were designed on both sides of exon 2～4 of the Uox gene.sgRNA and Cas9 mRNA for gene knockout were microinjected into the fertilized eggs of mice.After culture for 2～4 h,the embryos were transferred to surrogate mother mice to produce an F0 generation.Uox-knockout mice were identified by polymerase chain reaction and sequencing analysis.Positive mice were then mated with wild-type(WT)mice to produce an F1 generation,and heterozygous female and male F1 mice were then selected to obtain homozygous F2 mice.Serum and urine levels of uric acid,creatinine,and urea,and serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected and compared between homozygous and wild-type mice.Pathological changes in kidney and liver tissues were observed by hematoxylin and eosin and Masson staining.Results Urine levels of serum uric acid(male:(4116.8±1928.1)μmol/L,P＜0.001;female:(2998.0±547.7)μmol/L,P＜0.01)and serum levels of uric acid(male:(478.4±114.6)μmol/L,P＜0.001;female:(507.7±129.6)μmol/L,P＜0.001),creatinine((91.8±55.6)μmol/L,P＜0.001),urea((28.6±13.9)mmol/L,P＜0.05),ALT((53.3±23.3)U/L,P＜0.01),and AST((203.3±70.3)U/L,P＜0.001)were significantly increased in Uox-/-mice compared with WT mice.Histopathological examination showed moderate hepatocyte degeneration in the liver,moderate-to-severe tubular cystic dilation,degeneration,and fibrosis in the kidney,glomerular hypertrophy and hyperplasia,small-vessel dilation and congestion,and infiltration of stromal monocytes and lymphocytes in Uox-/-mice.Conclusions We successfully established a homozygous uricase-deficient mouse strain using CRISPR/Cas9 technology,as a suitable animal model for research in the field of hyperuricemia.

Objective The medication pattern of doctor Chen Jie in treating functional dyspepsia(FD)in children and the potential mechanism of action of core drug group were explored through data mining and network pharmacology methods.Methods The prescriptions for pediatric FD treated by doctor Chen Jie in the outpatient department of Second Affiliated Hospital of Wenzhou Medical University from January 2020 to December 2024 were collected to establish a prescription database.Excel 2019 and SPSS software were applied to statistically analyze the nature,taste,meridian tropism and frequency of drugs included in the prescriptions,and association rule analysis and cluster analysis were conducted.The potential mechanism of action of the core drug group was explored by using the network pharmacology method.Results A total of 603 prescriptions were included,involving 160 kinds of drugs,with a cumulative frequency of medication reaching 5012 times.Among them,the medicinal nature and flavour were mainly warm and sweet,and channel tropism were mainly the spleen,stomach and lung meridians.The core drug group obtained through association rules and cluster analysis was"Fuchao Baizhu-Fuling-Chenpi".Network pharmacological analysis was conducted on the core drug group,and it was found that its main components included naringenin,atractylenolide Ⅰ,atractylone,and hederagenin,as well as core genes such as AKT1,TNF,IL-6,ESR1,and IL-1β.The main enrichment pathways were lipids and atherosclerosis,advanced glycation end product-advanced glycation end product receptor signaling pathway,cancer pathway,etc..Conclusion Doctor Chen Jie's medication for treating FD in children mainly focuses on invigorating spleen and replenishing qi,regulating qi-flowing for eliminating dampness.The core drug group,"Fuchao Baizhu-Fuling-Chenpi",exerts its effects through multiple components,multiple targets and multiple pathways.

The prevalence of suicidal ideation (SI) and suicide behavior (SB) has gradually risen among adolescents with major depressive disorders in recent years, yet the underlying neurological mechanisms remain unknown. With the advancement of neuroimaging technology, multimodal magnetic resonance imaging (MRI) methods show fundamental value in detecting structural and functional brain abnormalities associated with these conditions. Preliminary studies have revealed alterations in key brain regions, such as the prefrontal cortex, amygdala, and anterior cingulate cortex, in adolescents with major depressive disorders. These findings provide critical insights into the neuropathological basis and underlying mechanisms of SI and SB in adolescent major depressive disorders. This review summarizes recent advances in brain structure and function in adolescents with major depressive disorder who exhibit SI and/or SB using diverse MRI techniques. This paper will provide new insights for the investigation of the neurobiological mechanisms underlying suicidality in adolescents with major depressive disorder, and provide objective neuroimaging evidence for the early identification and individualized intervention for at-risk adolescents.

Objective To construct a uricase-deficient mouse model with stable inheritance using the CRISPR/Cas9 system,and evaluate its ability to simulate the disease characteristics of patients with hyperuricemia.Methods Double single guide RNAs(sgRNAs)were designed on both sides of exon 2～4 of the Uox gene.sgRNA and Cas9 mRNA for gene knockout were microinjected into the fertilized eggs of mice.After culture for 2～4 h,the embryos were transferred to surrogate mother mice to produce an F0 generation.Uox-knockout mice were identified by polymerase chain reaction and sequencing analysis.Positive mice were then mated with wild-type(WT)mice to produce an F1 generation,and heterozygous female and male F1 mice were then selected to obtain homozygous F2 mice.Serum and urine levels of uric acid,creatinine,and urea,and serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected and compared between homozygous and wild-type mice.Pathological changes in kidney and liver tissues were observed by hematoxylin and eosin and Masson staining.Results Urine levels of serum uric acid(male:(4116.8±1928.1)μmol/L,P＜0.001;female:(2998.0±547.7)μmol/L,P＜0.01)and serum levels of uric acid(male:(478.4±114.6)μmol/L,P＜0.001;female:(507.7±129.6)μmol/L,P＜0.001),creatinine((91.8±55.6)μmol/L,P＜0.001),urea((28.6±13.9)mmol/L,P＜0.05),ALT((53.3±23.3)U/L,P＜0.01),and AST((203.3±70.3)U/L,P＜0.001)were significantly increased in Uox-/-mice compared with WT mice.Histopathological examination showed moderate hepatocyte degeneration in the liver,moderate-to-severe tubular cystic dilation,degeneration,and fibrosis in the kidney,glomerular hypertrophy and hyperplasia,small-vessel dilation and congestion,and infiltration of stromal monocytes and lymphocytes in Uox-/-mice.Conclusions We successfully established a homozygous uricase-deficient mouse strain using CRISPR/Cas9 technology,as a suitable animal model for research in the field of hyperuricemia.

Objective The medication pattern of doctor Chen Jie in treating functional dyspepsia(FD)in children and the potential mechanism of action of core drug group were explored through data mining and network pharmacology methods.Methods The prescriptions for pediatric FD treated by doctor Chen Jie in the outpatient department of Second Affiliated Hospital of Wenzhou Medical University from January 2020 to December 2024 were collected to establish a prescription database.Excel 2019 and SPSS software were applied to statistically analyze the nature,taste,meridian tropism and frequency of drugs included in the prescriptions,and association rule analysis and cluster analysis were conducted.The potential mechanism of action of the core drug group was explored by using the network pharmacology method.Results A total of 603 prescriptions were included,involving 160 kinds of drugs,with a cumulative frequency of medication reaching 5012 times.Among them,the medicinal nature and flavour were mainly warm and sweet,and channel tropism were mainly the spleen,stomach and lung meridians.The core drug group obtained through association rules and cluster analysis was"Fuchao Baizhu-Fuling-Chenpi".Network pharmacological analysis was conducted on the core drug group,and it was found that its main components included naringenin,atractylenolide Ⅰ,atractylone,and hederagenin,as well as core genes such as AKT1,TNF,IL-6,ESR1,and IL-1β.The main enrichment pathways were lipids and atherosclerosis,advanced glycation end product-advanced glycation end product receptor signaling pathway,cancer pathway,etc..Conclusion Doctor Chen Jie's medication for treating FD in children mainly focuses on invigorating spleen and replenishing qi,regulating qi-flowing for eliminating dampness.The core drug group,"Fuchao Baizhu-Fuling-Chenpi",exerts its effects through multiple components,multiple targets and multiple pathways.

The prevalence of suicidal ideation (SI) and suicide behavior (SB) has gradually risen among adolescents with major depressive disorders in recent years, yet the underlying neurological mechanisms remain unknown. With the advancement of neuroimaging technology, multimodal magnetic resonance imaging (MRI) methods show fundamental value in detecting structural and functional brain abnormalities associated with these conditions. Preliminary studies have revealed alterations in key brain regions, such as the prefrontal cortex, amygdala, and anterior cingulate cortex, in adolescents with major depressive disorders. These findings provide critical insights into the neuropathological basis and underlying mechanisms of SI and SB in adolescent major depressive disorders. This review summarizes recent advances in brain structure and function in adolescents with major depressive disorder who exhibit SI and/or SB using diverse MRI techniques. This paper will provide new insights for the investigation of the neurobiological mechanisms underlying suicidality in adolescents with major depressive disorder, and provide objective neuroimaging evidence for the early identification and individualized intervention for at-risk adolescents.

Objective: To explore the relationship between dietary behavior, dietary frequency and central precocious puberty (CPP) among children in Wuhan, so as to provide a scientific basis for elucidating the possible and related dietary factors leading to precocious puberty. Methods: From February to December 2023, 100 children with CPP and 100 healthy children were collected in Wuhan Children s Hospital for a case control study. Questionnaires and interviews were used to collect demographic information, child lifestyle, as well as dietary behavior and dietary frequency in the past six months. Conditional Logistic regression model was used to analyze the relationship of children s dietary behavior and dietary frequency with CPP. Results: No associations were found between three dietary behavior, including emotional eating, restrictive eating, and external eating, with CPP at baseline ( P >0.05). In the association analysis of dietary frequency and CPP, the risk of CPP was higher in those who consumed red meat >5 times/week ( OR =1.93, 95% CI =1.01-3.68), carbonated beverages ≥4 times/month ( OR =2.70, 95% CI =1.03-7.08), fruit juices ≥4 times/month ( OR =2.31, 95% CI =1.02-5.25), and nutritional supplementation ( OR =2.77, 95% CI =1.47- 5.22 ), whereas the risk of CPP was lower in those who consumed nuts ≥4 times/month ( OR =0.21, 95% CI =0.08-0.57) ( P < 0.05 ). Conclusion Consumption of higher amounts of red meat, high frequency of carbonated and juice based sugary drinks, and nutrient supplementation may be contributing factors to the development of CPP, whereas regular consumption of nuts is less likely to be associated with the development of CPP.

Objective: To explore the neuroprotective effects of the Shaoyao Gancao decoction (SGD) against excitatory damage in PC12 cells and the role of the Src-NR2-nNOS pathway mediation by SGD in regulating γ-aminobutyric acid (GABA)-glutamate (Glu) homeostasis. Methods: N-Methyl-d-aspartic acid (NMDA) was used to establish a PC12 cell excitability injury model. To investigate the neuroprotective effect of SGD, a cell counting kit-8 (CCK-8) assay was used to determine PC12 cell viability, Annexin V/Propidium Iodide (Annexin V/PI) double staining was used to determine PC12 cell apoptosis, and Ca2+ concentration was observed using laser confocal microscopy. GABA receptor agonists and antagonists were used to analyze the neuroprotective interactions between γ-aminobutyric acid (GABA) and NMDA receptors. Additionally, molecular biology techniques were used to determine mRNA and protein expression in the Src-NR2-nNOS pathway. We analyzed the correlations between the regulatory sites of GABA and NMDA interactions, excitatory neurotoxicity, and brain damage at the molecular level. Results: NMDA excitotoxic injury manifested as a significant decrease in cell activity, increased apoptosis and caspase-3 protein expression, and a significant increase in intracellular Ca2+ concentration. Administration of SGD, a GABAA receptor agonist (muscimol), or a GABAB receptor agonist (baclofen) decreased intracellular Ca2+ concentrations, attenuated apoptosis, and reversed NMDA-induced upregulation of caspase-3, Src, NMDAR2A, NMDAR2B, and nNOS. Unexpectedly, a GABAA receptor antagonist (bicuculline) and a GABAB receptor antagonist (saclofen) failed to significantly increase excitatory neurotoxicity. Conclusions Taken together, these results not only provide an experimental basis for SGD administration in the clinical treatment of central nervous system injury diseases, but also suggest that the Src-NR2A-nNOS pathway may be a valuable target in excitotoxicity treatment.