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

Objective:To explore the efficacy and safety of intense pulsed light (IPL) for facial early linear scars.Methods:The patients who underwent facial plastic surgery and cosmetic suturing at the Department of Plastic and Aesthetic Surgery, the Second Affiliated Hospital of Soochow University from June to December 2023 were included. A randomized self-controlled study was conducted. Each post-operative wound was divided into the treatment and control sides by random number. The treatment side received 3 sessions of IPL treatment at 2-3 d after wound suturing, 6-7 d after suture removal and 6 weeks after surgery, respectively. The control side did not receive IPL treatment. After 3 months follow-up, the Vancouver scar scale (VSS), patient and observer scar assessment scale (POSAS) were used to evaluate the scars on both sides. Adverse reactions were recorded. VSS evaluated scar severity through four items: vascularity (0-3 points), pigmentation (0-3 points), thickness (0-4 points), and pliability (0-5 points), with a total score of 0-15 points. The higher the score, the more serious the scar was. POSAS consisted of observer scar assessment scale (OSAS) and patient scar assessment scale (PSAS), OSAS included vascularity, pigmentation, thickness, surface relief, pliability, surface area and overall opinion. While PSAS included pain, itching, color, thickness, stiffness, irregularity, and overall opinion. Each component was assessed on a scale ranging from 1 to 10, while maximum scores indicated the worst outcome. Statistical analysis was performed using the Graphpad Prism 8.0 software. Normal distributed measurement data were expressed as Mean±SD, and non-normally distributed measurement data were expressed as M( Q1, Q3). Comparisons of VSS, OSAS, PSAS scores between the treatment and control sides were performed using paired sample t-test or paired sample Wilcoxon rank sum test. P<0.05 was considered statistically significant. Results:A total of 23 facial trauma patients with 27 scars formed after debridement and aesthetic suture were enrolled in this study, including 17 males and 6 females, aged (28.2±6.1) years old. The length of the scars were (5.9±1.8) cm. After three sessions of treatment and 3 months follow-up, with regard to VSS, the treatment sides scored vascularity [0(0, 1) vs. 1(1, 1)], thickness [0(0, 0) vs. 0(0, 1)], and total scores [0.5(0, 1) vs. 1(1, 2.75)], which were statistically lower than the control sides (all P<0.05). With regard to OSAS, the treatment sides scored vascularity(2.1±0.9 vs. 3.0±1.0), pigmentation(2.2±0.8 vs. 2.3±0.8), thickness(1.4±0.7 vs. 1.9±0.9), surface relief(1.7±0.6 vs. 2.2±1.1), pliability(1.8±0.8 vs. 2.1±1.1), overall opinion(1.9±0.8 vs. 2.8±1.1) and total scores(12.6±4.4 vs. 16.2±6.2), which were statistically lower than the control sides(all P<0.05).With regard to PSAS, the treatment sides scored scar color(2.9±1.3 vs. 3.9±1.7), thickness(1.8±1.4 vs. 2.4±1.5), overall opinion(2.2±1.0 vs. 3.1±1.3) and total scores(14.3±6.7 vs. 17.7±7.7), which were statistically lower than the control sides(all P<0.05). No adverse reactions such as wound infection, delayed wound healing and blister formation were observed in all patients. Conclusion:IPL is effective in the treatment of early facial scars, which can significantly improve the vascularity, thickness, pigmentation, surface relief and pliability of scars, and improve the scars appearance. This treatment method is safe with few adverse reactions.

Objective:To explore the efficacy and its related factors of rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS).Methods:It was a single-center retrospective study. The clinical data of FRNS/SDNS children first treated with RTX in the First Affiliated Hospital of Sun Yat-sen University from November 1, 2016 to September 1, 2023 were collected. The number of relapse within 1 year before and after RTX treatment, the time to first relapse after RTX treatment, and the time to B-cell reconstitution were analyzed. At the first treatment, a single dose of RTX was given at 375 mg/m 2, with a maximum dose of 500 mg, once a week, for 1 to 4 doses. The count of CD19 + lymphocytes in the peripheral blood of the children was continuously monitored. If B-cell reconstruction was performed, the decision on whether to proceed to the next course of RTX treatment was made based on clinical manifestations. Kaplan-Meier method was used to analyze relapse-free survival rate after receiving RTX. Cox proportional hazards regression model was used to analyze the related factors of relapse after RTX treatment. Results:A total of 98 FRNS/SDNS children receiving RTX treatment were enrolled, including 75 males (76.5%). The age at onset was 4.0 (1.9, 7.1) years and age of receiving RTX was 11.3 (8.5, 13.5) years. There were 90 children (91.8%) achieving complete remission, while 8 patients (8.2%) did not respond to RTX treatment, and 3 patients (3.1%) progressed to end-stage kidney disease after receiving RTX. The relapse-free survival rates at 6 months and 1 year after RTX treatment were 83.3% (75/90) and 57.9% (22/38), respectively. The frequency of relapse 1 year after RTX treatment decreased compared to 1 year before RTX treatment ( Z=-7.398, P<0.001). Compared with children without relapse during the period of B-cell depletion, relapsed children had a higher number of relapse within one year after RTX treatment ( Z=5.246, P<0.001). The time to first relapse after RTX treatment was 8.3 (4.6, 13.9) months in 51 relapse patients. Compared with children receiving 1 dose of RTX in the first course, those receiving 2 or more doses had a longer time to the first relapse ( Z=2.983, P=0.003). There was no statistically significant difference in time to the first relapse between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). The reconstruction time of B cells after the first course of RTX was 6.9 (5.3, 9.0) months. Compared to children receiving one dose of RTX in the first course, those receiving two or more doses had a longer B-cell reconstitution time ( Z=2.739, P=0.006). There was no statistically significant difference in B-cell reconstitution time between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). Univariate Cox regression analysis showed that recurrence after calcineurin inhibitor (CNI) treatment before RTX treatment and the number of recurrence in one year before RTX treatment were correlated factors of recurrence after RTX treatment (both P<0.05). Multivariate Cox regression analysis showed that recurrence after CNI treatment before RTX treatment was an independent correlated factor of relapse after RTX therapy ( HR=3.496, 95% CI 1.245-9.818, P=0.018). Infusion reactions occurred in 10 patients (10.2%) and infections were observed in 24 patients (24.5%) during B cell depletion. No serious adverse events occurred. Conclusions:RTX is well tolerated and effective in treating FRNS/SDNS. Recurrence after CNI treatment before RTX treatment may be an independent related factor of relapse after RTX treatment.

OBJECTIVE To investigate the ameliorative effect and potential mechanism of imperatorin(IMP)on doxorubicin(DOX)resistance in breast cancer.METHODS The effects of maximum non-toxic concentration(100 μg/mL)of IMP combined with different concentrations of DOX(12.5,25,50,75,100 μg/mL)on the proliferation of MCF-7/DOX cells were determined by MTT method.MCF-7/DOX cells were divided into blank control group(1‰ dimethyl sulfoxide),DOX group(50 μg/mL),IMP+DOX group(100 μg/mL IMP+50 μg/mL DOX)and IMP group(100 μg/mL).mRNA and protein expressions of multidrug resistance protein 1(MDR1)and multidrug resistance-associated protein l in each group were measured.The relevant pathways and targets involved in the improvement of DOX resistance in breast cancer cells by IMP were screened and validated by using transcriptome sequencing technology,along with gene ontology(GO)enrichment analyses and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses.RESULTS Compared with DOX alone,the combination of IMP and DOX reduced the half inhibitory concentration of DOX on MCF-7/DOX cells from 81.965 μg/mL to 43.170 μg/mL,the reverse fold was 1.90,and the mRNA expression of MDR1 was significantly down-regulated(P＜0.05).The results of GO enrichment analyses and KEGG pathway enrichment analyses indicated that the reversal of DOX resistance in breast cancer by IMP was mainly associated with the regulation of biological processes such as detoxification,multiple biological processes,and cell killing.The main pathway involved was the p53 signaling pathway,and the key targets mainly included constitutively photomorphogenic protein 1(COP1),cyclin E1(CCNE1),growth arrest and DNA damage-inducible protein 45A(GADD45A)and GADD45B.The results of the verification experiments showed that compared with DOX group,there was a trend of up-regulation of COP1 mRNA,and significant down-regulation of CCNE1,GADD45A,and GADD45B mRNA expression in IMP+DOX group(P＜0.05).CONCLUSIONS The effect of IMP in ameliorating DOX resistance in breast cancer is related to its regulation of COP1,CCNE1,GADD45A and GADD45B targets in the p53 signaling pathway.

Objective:To explore the efficacy and its related factors of rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS).Methods:It was a single-center retrospective study. The clinical data of FRNS/SDNS children first treated with RTX in the First Affiliated Hospital of Sun Yat-sen University from November 1, 2016 to September 1, 2023 were collected. The number of relapse within 1 year before and after RTX treatment, the time to first relapse after RTX treatment, and the time to B-cell reconstitution were analyzed. At the first treatment, a single dose of RTX was given at 375 mg/m 2, with a maximum dose of 500 mg, once a week, for 1 to 4 doses. The count of CD19 + lymphocytes in the peripheral blood of the children was continuously monitored. If B-cell reconstruction was performed, the decision on whether to proceed to the next course of RTX treatment was made based on clinical manifestations. Kaplan-Meier method was used to analyze relapse-free survival rate after receiving RTX. Cox proportional hazards regression model was used to analyze the related factors of relapse after RTX treatment. Results:A total of 98 FRNS/SDNS children receiving RTX treatment were enrolled, including 75 males (76.5%). The age at onset was 4.0 (1.9, 7.1) years and age of receiving RTX was 11.3 (8.5, 13.5) years. There were 90 children (91.8%) achieving complete remission, while 8 patients (8.2%) did not respond to RTX treatment, and 3 patients (3.1%) progressed to end-stage kidney disease after receiving RTX. The relapse-free survival rates at 6 months and 1 year after RTX treatment were 83.3% (75/90) and 57.9% (22/38), respectively. The frequency of relapse 1 year after RTX treatment decreased compared to 1 year before RTX treatment ( Z=-7.398, P<0.001). Compared with children without relapse during the period of B-cell depletion, relapsed children had a higher number of relapse within one year after RTX treatment ( Z=5.246, P<0.001). The time to first relapse after RTX treatment was 8.3 (4.6, 13.9) months in 51 relapse patients. Compared with children receiving 1 dose of RTX in the first course, those receiving 2 or more doses had a longer time to the first relapse ( Z=2.983, P=0.003). There was no statistically significant difference in time to the first relapse between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). The reconstruction time of B cells after the first course of RTX was 6.9 (5.3, 9.0) months. Compared to children receiving one dose of RTX in the first course, those receiving two or more doses had a longer B-cell reconstitution time ( Z=2.739, P=0.006). There was no statistically significant difference in B-cell reconstitution time between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). Univariate Cox regression analysis showed that recurrence after calcineurin inhibitor (CNI) treatment before RTX treatment and the number of recurrence in one year before RTX treatment were correlated factors of recurrence after RTX treatment (both P<0.05). Multivariate Cox regression analysis showed that recurrence after CNI treatment before RTX treatment was an independent correlated factor of relapse after RTX therapy ( HR=3.496, 95% CI 1.245-9.818, P=0.018). Infusion reactions occurred in 10 patients (10.2%) and infections were observed in 24 patients (24.5%) during B cell depletion. No serious adverse events occurred. Conclusions:RTX is well tolerated and effective in treating FRNS/SDNS. Recurrence after CNI treatment before RTX treatment may be an independent related factor of relapse after RTX treatment.

Objective:To explore the efficacy and safety of intense pulsed light (IPL) for facial early linear scars.Methods:The patients who underwent facial plastic surgery and cosmetic suturing at the Department of Plastic and Aesthetic Surgery, the Second Affiliated Hospital of Soochow University from June to December 2023 were included. A randomized self-controlled study was conducted. Each post-operative wound was divided into the treatment and control sides by random number. The treatment side received 3 sessions of IPL treatment at 2-3 d after wound suturing, 6-7 d after suture removal and 6 weeks after surgery, respectively. The control side did not receive IPL treatment. After 3 months follow-up, the Vancouver scar scale (VSS), patient and observer scar assessment scale (POSAS) were used to evaluate the scars on both sides. Adverse reactions were recorded. VSS evaluated scar severity through four items: vascularity (0-3 points), pigmentation (0-3 points), thickness (0-4 points), and pliability (0-5 points), with a total score of 0-15 points. The higher the score, the more serious the scar was. POSAS consisted of observer scar assessment scale (OSAS) and patient scar assessment scale (PSAS), OSAS included vascularity, pigmentation, thickness, surface relief, pliability, surface area and overall opinion. While PSAS included pain, itching, color, thickness, stiffness, irregularity, and overall opinion. Each component was assessed on a scale ranging from 1 to 10, while maximum scores indicated the worst outcome. Statistical analysis was performed using the Graphpad Prism 8.0 software. Normal distributed measurement data were expressed as Mean±SD, and non-normally distributed measurement data were expressed as M( Q1, Q3). Comparisons of VSS, OSAS, PSAS scores between the treatment and control sides were performed using paired sample t-test or paired sample Wilcoxon rank sum test. P<0.05 was considered statistically significant. Results:A total of 23 facial trauma patients with 27 scars formed after debridement and aesthetic suture were enrolled in this study, including 17 males and 6 females, aged (28.2±6.1) years old. The length of the scars were (5.9±1.8) cm. After three sessions of treatment and 3 months follow-up, with regard to VSS, the treatment sides scored vascularity [0(0, 1) vs. 1(1, 1)], thickness [0(0, 0) vs. 0(0, 1)], and total scores [0.5(0, 1) vs. 1(1, 2.75)], which were statistically lower than the control sides (all P<0.05). With regard to OSAS, the treatment sides scored vascularity(2.1±0.9 vs. 3.0±1.0), pigmentation(2.2±0.8 vs. 2.3±0.8), thickness(1.4±0.7 vs. 1.9±0.9), surface relief(1.7±0.6 vs. 2.2±1.1), pliability(1.8±0.8 vs. 2.1±1.1), overall opinion(1.9±0.8 vs. 2.8±1.1) and total scores(12.6±4.4 vs. 16.2±6.2), which were statistically lower than the control sides(all P<0.05).With regard to PSAS, the treatment sides scored scar color(2.9±1.3 vs. 3.9±1.7), thickness(1.8±1.4 vs. 2.4±1.5), overall opinion(2.2±1.0 vs. 3.1±1.3) and total scores(14.3±6.7 vs. 17.7±7.7), which were statistically lower than the control sides(all P<0.05). No adverse reactions such as wound infection, delayed wound healing and blister formation were observed in all patients. Conclusion:IPL is effective in the treatment of early facial scars, which can significantly improve the vascularity, thickness, pigmentation, surface relief and pliability of scars, and improve the scars appearance. This treatment method is safe with few adverse reactions.

A 52-year-old female patient diagnosed with hereditary cerebral small vessel disease(CSVD),with clinical manifestations of recurrent stroke and mild cognitive impairment was reported.There was no history of hypertension or diabetes,and her maternal grandparents were consanguineous.Her maternal grandmother and mother died of cerebral infarction.Cranial magnetic resonance imaging showed multiple lacunar cerebral infarcts,cerebral white matter degeneration and microhemorrhagic foci,and whole exome sequencing reported a heterozygous mutation c.947A＞G in the high-temperature requirement A serine peptidase 1(HTRA1).For patients with CSVD,the family history should be asked,and for patients with suspected hereditary CSVD,the possibility of HTRA1 heterozygous mutations should be considered.Reasonable use of genetic testing methods to screen high-risk families of CSVD patients and further guide treatment.

Brain/diagnostic imaging* ; Head

OBJECTIVE Cognitive deficit is a com-mon comorbidity in temporal lobe epilepsy(TLE)and that is not well controlled by current therapeutics.Currently,how epileptic seizure affects cognitive performance remains largely unclear.The subiculum is the major out-put of the hippocampus,which projects to entorhinal cor-tex and other more distinct brain regions.Physiologically,the subiculum codes spatial working memory and naviga-tion information including place,speed,and trajectory.Importantly,prior studies have noted the importance of the subiculum in the beginning,spreading,and generaliz-ing process of hippocampal seizure.How seizure-activated neurons in subiculum participate in cognitive impairment remains largely elusive.METHODS In this study,we sought to label the subicular seizure-activated c-fos+ neu-rons with a special promoter with enhanced synaptic activity-responsive element E-SARE in the subiculum,combined with chemogenetics and designer receptors exclusively activated by designer drugs(DREADDs),Ca2+ fiber photometry approaches,and behavioral tasks,to reveal the role of these neurons in cognitive impairment in epilepsy.RESULTS We found that chemogenetic inhibi-tion of subicular seizure-tagged c-fos+ neurons(mainly CaMK Ⅱ α+ glutamatergic neurons)alleviates seizure generalization and improves cognitive performance in the hippocampal CA3 kindling TLE model.While inhibition of seizure-labeled c-fos+ GABAergic interneuron shows no effect on seizure and cognition.As a comparison,che-mogenetic inhibition of the whole subicular CaMK Ⅱ α+ neuron impairs cognitive function in na?ve mice in basal condition.Notably,inhibition of subicular seizure-tagged c-fos+ neurons enhances the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks.CONCLUSION Our results dem-onstrate that subicular seizure-activated c-fos+ neurons contribute to cognitive impairment in TLE,suggesting sei-zure-tagged c-fos+ neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

This study aimed to observe the protective effect of momordicine I, a triterpenoid compound extracted from momordica charantia L., on isoproterenol (ISO)-induced hypertrophy in rat H9c2 cardiomyocytes and investigate its potential mechanism. Treatment with 10 μM ISO induced cardiomyocyte hypertrophy as evidenced by increased cell surface area and protein content as well as pronounced upregulation of fetal genes including atrial natriuretic peptide, β-myosin heavy chain, and α-skeletal actin; however, those responses were markedly attenuated by treatment with 12.5 μg/ml momordicine I. Transcriptome experiment results showed that there were 381 and 447 differentially expressed genes expressed in comparisons of model/control and momordicine I intervention/model, respectively. GO enrichment analysis suggested that the anti-cardiomyocyte hypertrophic effect of momordicine I may be mainly associated with the regulation of metabolic processes. Based on our transcriptome experiment results as well as literature reports, we selected glycerophospholipid metabolizing enzymes group VI phospholipase A 2 (PLA2G6) and diacylglycerol kinase ζ (DGK-ζ) as targets to further explore the potential mechanism through which momordicine I inhibited ISO-induced cardiomyocyte hypertrophy.Our results demonstrated that momordicine I inhibited ISO-induced upregulations of mRNA levels and protein expressions of PLA2G6 and DGK-ζ. Collectively, momordicine I alleviated ISO-induced cardiomyocyte hypertrophy, which may be related to its inhibition of the expression of glycerophospholipid metabolizing enzymes PLA2G6 and DGK-ζ.