Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
Organoids/physiology* ; NAV1.2 Voltage-Gated Sodium Channel/genetics* ; Humans ; Anticonvulsants/pharmacology* ; Epilepsy/drug therapy* ; Mutation ; Cerebral Cortex/drug effects* ; Action Potentials/drug effects* ; Carbamazepine/pharmacology*

Objective To investigate the protective effects and underlying mechanisms of sodium butyrate on rats exposed to hypoxia and cold conditions.Methods Fifty-eight male SD rats (aged 7～8 weeks,weighing 240～260 g ) were randomly divided into normoxia normothermia saline control (NNC ) group (n=10),normoxia normothermia sodium butyrate(NNB)group(n=10),hypoxia cold saline control (HCC) group (n=19),and hypoxia cold sodium butyrate (HCB)group (n=19).The intragastric dose of sodium butyrate was 200 mg/kg for the NNB and HCB groups,while the NNC and HCC groups were given normal saline of 5 mL/kg.①After continuous intragastric administration for 7 d,the rats in the HCC and HCB groups were placed in a low-pressure hypoxic chamber to simulate an altitude of 5000 m and exposed to a temperature of 8 ℃ for 7 d.Subsequently,blood samples were collected from the abdominal aorta for blood gas analysis,blood routine test,and detection for serum biochemical indicators.ELISA was used to determine serum inflammatory cytokines and endocrine hormones.The rats in the NNC and NNB groups(n=10)were fed outside the chamber and underwent the same tests in 7 d later to evaluate the protective effects of sodium butyrate on the body.②Core body temperature monitoring was conducted to assess the impact of sodium butyrate on the rmoregulation in rats exposed to hypoxia and cold(n=3).③Hypoxia exercise tolerance of the HCC group and HCB group in a hypoxic chamber (11％O2 )was evaluated for their hypoxia resistance (n=6).Results Compared to the NNC group,the rats in the HCC group exhibited significant decreases in arterial oxygen saturation (SaO2 )and arterial oxygen partial pressure (PaO2 ),serum levels of IL-4,estradiol (E2)and cortisol (F),core temperature,and exercise duration (P<0.05),and had notably increased levels of red blood cell (RBC)count,hemoglobin (HGB),hematocrit (HCT),cardiac troponin (CRDAC-T),uric acid (UA),alanine aminotransferase (ALT),total cholesterol (TC),low-density lipoprotein (LDL),IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF)(P<0.05).Compared to the HCC group,the rats in the HCB group exhibited significant increases in SaO2,PaO2,IL-4,E2,F,corticotropin releasing hormone (CRH)and adrenocorticotropic hormone (ACTH)(P<0.05),remarkably longer exercise duration under hypoxic exposure (P<0.05 ),but decreases in RBC count,serum levels of HGB,HCT,CRDAC-T,UA,ALT,TC,LDL,IL-6,GM-CSF and free thyroxine (FT4 ),and core temperature (P<0.05).Conclusion Sodium butyrate exhibits protective effects on rats exposed to hypoxia and cold conditions,and it is helpful in their adaptation to these hypoxia and cold environments.

Objective:To investigate the spatial distribution pattern of local tumor progression (LTP) for hepatocellular carcinoma (HCC) ≤5 cm after microwave ablation.Methods:A retrospective analysis was performed on 169 HCCs with matched MRI before and after ablation from December 2009 to December 2019. A tumor MRI was reconstructed using three-dimensional visualization technology. LTP was classified as contact or non-contact, early or late stage, according to whether LTP was in contact with the edge of the ablation zone and the occurrence time (24 months). The tumor-surrounded area was divided into eight quadrants by using the eight-quadrant map method. An analysis was conducted on the spatial correlation between the quadrant where the ablative margin (AM) safety boundary was located and the quadrant where different types of LTP occurred. The t-test, or rank-sum test, was used for the measurement data. 2-test for count data was used to compare the difference between the two groups.Results:The AM quadrant had a distribution of 54.4% LTP, 64.2% early LTP stage, and 69.1% contact LTP, suggesting this quadrant was much more concentrated than the other quadrants ( P ?

Objective To explore the mechanism of ginseng in the treatment of periodontitis based on network phar-macology and molecular docking technology.Methods Potential targets of ginseng and periodontitis were obtained through various databases.The intersection targets of ginseng and periodontitis were obtained by using VENNY,the pro-tein-protein interaction network relationship diagram was formed on the STRING platform,the core target diagram was formed by Cytoscape software,and the ginseng-active ingredient-target network diagram was constructed.The selected targets were screened for gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway en-richment analysis.The core targets of ginseng's active in-gredients in treating periodontitis were analyzed by mo-lecular docking technique.Results The 22 ginseng's active ingredients,591 potential targets of ginseng's ac-tive ingredients,2 249 periodontitis gene targets,and 145 ginseng-periodontitis intersection targets were analyzed.Ginseng had strong binding activity on core targets such as vas-cular endothelial growth factor A and epidermal growth factor receptor,as well as hypoxia induced-factor 1(HIF-1)sig-naling pathway and phosphatidylinositol 3-kinase-protein kinase B(PI3K-Akt)signaling pathway.Conclusion Gin-seng and its active components can regulate several signaling pathways such as HIF-1 and PI3K-Akt,thereby indicating that ginseng may play a role in treating periodontitis through multiple pathways.

Gastric cancer is among the most common malignant tumors worldwide.Due to its subtle early symptoms and suboptimal screening rates,a significant proportion of patients are diagnosed with advanced-stage gastric cancer,which adversely influences patient prognosis.In recent years,with the advancement of research,immunotherapy for gastric cancer has made significant strides,demonstrating particularly remarkable efficacy in cases of unresectable and metastatic gastric cancer.This has established it as an effective treatment method following surgery,chemotherapy,radiotherapy,and targeted therapy.Immunotherapy involves artificially modulating the immune system using strategies such as adoptive cell therapy,immune checkpoint inhibitors,and tumor vaccines.Although immunotherapy has broad prospects,it faces many challenges and problems in clinical application.This review delineates the clinical application of immunother-apy in gastric cancer and discusses the extant challenges therein.

Objective:To investigate the cognitive functions of temporal lobe epilepsy (TLE) patients with bilateral asynchronous interictal discharges.Methods:A total of 162 TLE patients who were treated at Zhongshan Hospital, Fudan University, from June 2021 to December 2023 were collected. According to the interictal scalp electroencephalogram, TLE patients were classified to the TLE with bilateral temporal asynchronous interictal epileptiform discharges ( n=51) and TLE with unilateral temporal epileptiform discharges ( n=111). Unilateral TLE patients were divided into TLE with right ( n=48) and left ( n=63) temporal epileptiform discharges. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Digital Span (DS), Verbal Fluency Test (VFT), the third part of Color Word Test (CWT-C), Trail Making Test-B (TMT-B), Symbol Digit Modalities Test (SDMT), Auditory Verbal Learning Test (AVLT), Rey-Osterrieth Complex Figure (ROCF), and Similarity Comprehension Test were performed for the participants. The differences of cognitive functions between patients with bilateral and unilateral temporal discharges were compared. Univariate and multivariate Logistic regression models were used to analyze the risk factors for patients with bilateral temporal asynchronous discharges. Spearman analysis was used to explore the correlation between cognitive function and clinical indicators. Results:In the group of TLE patients with bilateral asynchronous discharges compared to those with unilateral discharges, the completion time of CWT-C [67 (55, 103) s vs 59 (50, 71) s, Z=-2.904, P=0.004], TMT-B [159 (108, 219) s vs 129 (95, 180) s, Z=-2.361, P=0.018] was longer. Additionally, TLE patients with bilateral asynchronous discharges got lower scores of MMSE [28 (26, 29) vs 29 (28, 30), Z=3.098, P=0.002], MoCA [23 (19, 28) vs 27 (23, 28), Z=3.175, P=0.001], AVLT1+2+3 [16.843±6.482 vs 19.162±5.526, t=-2.347, P=0.020], AVLT6 [6 (3, 10) vs 8 (5, 10), Z=3.275, P=0.001], ROCF2 [15 (8, 22) vs 20 (12, 25), Z=2.870, P=0.004], ROCF3 [14 (8, 22) vs 20 (11, 25), Z=2.634, P=0.008], and Similarity Test [13 (8, 18) vs 16 (12, 20), Z=2.387, P=0.017] as well as lower VFT-vegetable and fruit count [15 (13, 19) vs 18 (15, 21), Z=2.402, P=0.016] and SDMT completion count [41 (30, 53) vs 51 (40, 60), Z=3.089, P=0.002]. The multivariate Logistic regression analysis showed that the decrease in AVLT6 scores ( OR=1.546, 95% CI 1.150-2.078, P=0.004) and longer TMT-B time ( OR=1.013, 95% CI 1.001-1.025, P=0.035) were independent risk factors for TLE patients with bilateral asynchronous discharges. Conclusions:Compared to the patients with TLE characterized by unilateral temporal lobe discharges, those with asynchronous discharges in bilateral temporal lobes show statistically significant declines in all domains of cognitive functions, including executive function, memory, and language abilities. Decreased cue recall ability in language memory and prolonged trail-making test in executive function are independent cognitive impairment risk factors for bilateral temporal asynchronous discharges.

15q11-q13 Duplication syndrome is a rare genetic disease of the nervous system, characterized by developmental retardation, intellectual impairments, hypotonia, autism, epilepsy and so on. This article reports a 33-year-old male patient, with the clinical manifestation of early-onset intractable epilepsy and mental retardation. The high-throughout whole exome sequencing showed a 10.53 Mb repeat sequence in the 15q11.2-q13.3 region, further confirming the diagnosis of 15q11-q13 duplication syndrome. The literature reports of the pathogenic mechanism, classification, typical clinical manifestation, seizure features,accessory examination and therapy of the 15q11-q13 duplication syndrome are summarized and reviewed, so as to enhance the understanding of the disease, as well as to improve the diagnosis and treatment level of the clinicians.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

OBJECTIVE To study the effects of Yishen daluo decoction on inflammatory factors and cyclic adenosine monophosphate（cAMP）/protein kinase A （PKA）/cAMP response element binding protein （CREB） signal pathway in experimental autoimmune encephalomyelitis （EAE） model mice by inhibiting the expressions of β-arrestin1， and to explore the mechanism of Yishen daluo decoction in the treatment of EAE. METHODS Sixty mice were randomly divided into normal group， model group， TCM group （Yishen daluo decoction 20 g/kg）， positive control group （prednisone acetate 3.9 mg/kg）， β-arrestin1 siRNA adeno- associated virus （AAV-β） group， AAV-β+TCM group， with 10 mice in each group. Except for normal group， EAE model was made in other groups. AAV-β group and AAV-β+TCM group were injected with AAV-β via tail vein to interfere with the expression of β -arrestin1 protein. Starting from the 8th day of modeling， they were given corresponding drug solution/normal saline intragastrically， once a day， for consecutive 14 days. The neurological function score of mice was detected； the pathological and morphological changes were observed in the brain and spinal cord tissues of mice； the serum levels of inflammatory factors [interleukin-2 （IL-2）， IL-23， interferon-γ （IFN-γ）] in mice were determined； the expressions of β-arrestin1， cAMP， PKA and CREB in brain and spinal cord were detected. RESULTS Compared with normal group， neurological function scores， serum levels of inflammatory factors， and protein expressions of β-arrestin1 in brain and spinal cord were significantly increased （P＜0.05 or P＜ 0.01）； protein expressions of PKA， CREB and cAMP in brain and spinal cord were decreased significantly（P＜0.05 or P＜0.01）. The deep staining of cellular shrinkage and aggregation of inflammatory cells were observed in most neurons of the brain and spinal cord， with varying degrees of demyelinating. Compared with model group， the neurological function scores， pathological changes in brain and spinal cord tissues， and most indicators （except for CREB and cAMP proteins in the brain tissue of AAV-β group） were significantly reversed （P＜0.05 or P＜0.01）.Compared with AAV- β group， the neurological function scores， the levels of IFN-γ in serum and β-arrestin1 in spinal cord were significantly decreased （P＜0.05 or P＜0.01）， PKA and cAMP in brain and spinal cord tissues were significantly increased in AAV- β +TCM group （P＜0.05 or P＜0.01）. CONCLUSIONS Yishen daluo decoction can inhibit the expression of β-arrestin1 in the central nervous system thus activating the cAMP/PKA/CREB signaling pathway， relieving nervous system inflammation， and ultimately alleviates the symptoms of EAE.

Objective:To explore the relationship of infertility-related stress and depression of infertility women, and the effect of coping style and resilience in it.Methods:A cross sectional study was conducted in 230 infertility women who treated with Assisted Reproductive Technology in Reproductive Medical Center of the First Affiliated Hospital of Soochow University using convenience sampling method from April 2020 to April 2021 with self-made general information questionnaire, Fertility Problem Inventory, Simplified Coping Style Questionnaire, 10-item Connor-Davidson Resilience Scale and Patients' Health Questionnaire Depression Scale-9 item. And correlation and effect analysis was conducted.Results:Two hundred and nineteen questionnaires were finally collected, the effective recovery rate was 95.2%(219/230). The score of Fertility Problem Inventory was (136.21 ± 27.38) points, the score of Simplified Coping Style Questionnaire was (34.26 ± 7.66) points, the score of 10-item Connor-Davidson Resilience Scale was (27.50 ± 6.78) points, the score of Patients' Health Questionnaire Depression Scale-9 item was (4.26 ± 3.83) points. Correlation analysis results showed that infertility-related stress of infertility women was positively correlated with negative coping ( r=0.20, P<0.01) and depression ( r=0.26, P<0.01), negative coping was positively correlated with depression ( r=0.23, P<0.01). Effect analysis results showed that negative coping had a partial mediating effect between infertility-related stress and depression, and the mediating effect size was 0.05, accounting for 15.63% of the total effects. Resilience moderated the second half path of the mediation relationship ( β=-0.137, t=-2.11, P<0.05). Conclusions:The infertility-related stress is a positive predictor of depression. Negative coping has a mediating effect between infertility-related stress and depression, and resilience moderates the effect of negative coping on depression.