Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

Objective To investigate the clinical characteristics of patients with clinical and subclinical Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia(PBMAH).Methods A retrospective analysis was performed on the clinical data of 198 patients with Cushing's syndrome caused by PBMAH diagnosed in the First Medical Center of Chinese PLA General Hospital from January 2004 to October 2024.According to clinical manifestations,the patients were classified into clinical type Cushing's syndrome(n=61)and subclinical type Cushing's syndrome(n=137),and the clinical characteristics of the two types were compared.Results The mean age at diagnosis of patients with PBMAH-induced Cushing's syndrome was(53.5±10.4)years,including 118 males and 80 females,with a male-to-female ratio of 1.475:1.Compared with the subclinical type,the clinical type had a higher proportion of females,higher levels of serum cortisol,24-hour urine free cortisol(24 h UFC),and inhibited serum cortisol after low-dose dexamethasone suppression.Additionally,the clinical type had lower plasma ACTH,larger adrenal nodules and a higher risk of surgery(P<0.05)compared with those in subclinical type.The incidences of hypertension,dyslipidemia,obesity,diabetes mellitus,hypokalemia,vitamin D deficiency,osteoporosis,coronary heart disease,and cerebrovascular disease in patients with Cushing's syndrome caused by PBMAH were 87.9%,50.5%,37.1%,36.9%,27.8%,25.9%,18.7%,18.7%and 12.1%,respectively.Among them,compared with subclinical type patients,clinical type patients had higher incidence of hypokalaemia,vitamin D deficiency and osteoporosis(P<0.05),while there were no statistically significant differences in the incidences of other comorbidities between the two types(P>0.05).The results of postoperative follow-up for PBMAH patients showed that the short-term biochemical remission rate of unilateral total adrenalectomy was 41.5%(22/53)and the long-term biochemical remission rate was 32.0%(8/25).The short-term biochemical remission rate of unilateral partial(or nodular)adrenalectomy was 52.9%(9/17),and the long-term biochemical remission rate was 14.3%(1/7).All patients who underwent unilateral total adrenalectomy plus contralateral partial resection developed adrenal insufficiency(3/3),and 1 patient(1/3)relapsed 3.4 years after surgery.Conclusion Clinical and subclinical types of Cushing's syndrome caused by PBMAH have their distinct clinical characteristics.Surgery is an effective treatment for PBMAH,but a certain proportion of patients fail to achieve biochemical remission after non-bilateral total adrenalectomy.

Objective: To investigate the application value of computed tomography (CT) examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma (ESCC). Methods: A total of 477 patients with primary thoracic ESCC who underwent surgical treatment in the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to December 2017 were collected. All of them underwent McKeown esophagectomy plus complete two-field or three-field lymph node dissection. Picture archiving and communication system were used to measure the largest cardia-left gastric lymph node short diameter in preoperative CT images. The postoperative pathological diagnosis results of cardia-left gastric lymph node were used as the gold standard. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CT lymph node short diameter in detecting the metastasis of cardia-left gastric lymph node in thoracic ESCC, and determine the optimal cut-off value. Results: The median short diameter of the largest cardia-left gastric lymph node was 4.1 mm in 477 patients, and the largest cardia-left gastric lymph node short diameter was less than 3 mm in 155 cases (32.5%). Sixty-eight patients had cardia-left gastric lymph node metastases, of which 38 had paracardial node metastases and 41 had left gastric node metastases. The lymph node ratios of paracardial node and left gastric node were 4.0% (60/1 511) and 3.3% (62/1 887), respectively. ROC curve analysis showed that the area under the curve of CT lymph node short diameter for evaluating cardia-left gastric lymph node metastasis was 0.941 (95% CI: 0.904-0.977; P<0.05). The optimal cut-off value of CT examination of the cardia-left gastric lymph node short diameter was 6 mm, and the corresponding sensitivity, specificity and accuracy were 85.3%, 91.7%, and 90.8%, respectively. Conclusion: CT examination of lymph node short diameter can be a good evaluation of cardia-left gastric lymph node metastasis in thoracic ESCC, and the optimal cut-off value is 6 mm.
Humans ; Esophageal Squamous Cell Carcinoma/pathology* ; Cardia/surgery* ; Esophageal Neoplasms/pathology* ; Lymphatic Metastasis/pathology* ; Lymph Nodes/pathology* ; Lymph Node Excision ; Tomography, X-Ray Computed/methods* ; Esophagectomy/methods* ; Retrospective Studies

Objective: To investigate the application value of computed tomography (CT) examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma (ESCC). Methods: A total of 477 patients with primary thoracic ESCC who underwent surgical treatment in the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to December 2017 were collected. All of them underwent McKeown esophagectomy plus complete two-field or three-field lymph node dissection. Picture archiving and communication system were used to measure the largest cardia-left gastric lymph node short diameter in preoperative CT images. The postoperative pathological diagnosis results of cardia-left gastric lymph node were used as the gold standard. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CT lymph node short diameter in detecting the metastasis of cardia-left gastric lymph node in thoracic ESCC, and determine the optimal cut-off value. Results: The median short diameter of the largest cardia-left gastric lymph node was 4.1 mm in 477 patients, and the largest cardia-left gastric lymph node short diameter was less than 3 mm in 155 cases (32.5%). Sixty-eight patients had cardia-left gastric lymph node metastases, of which 38 had paracardial node metastases and 41 had left gastric node metastases. The lymph node ratios of paracardial node and left gastric node were 4.0% (60/1 511) and 3.3% (62/1 887), respectively. ROC curve analysis showed that the area under the curve of CT lymph node short diameter for evaluating cardia-left gastric lymph node metastasis was 0.941 (95% CI: 0.904-0.977; P<0.05). The optimal cut-off value of CT examination of the cardia-left gastric lymph node short diameter was 6 mm, and the corresponding sensitivity, specificity and accuracy were 85.3%, 91.7%, and 90.8%, respectively. Conclusion: CT examination of lymph node short diameter can be a good evaluation of cardia-left gastric lymph node metastasis in thoracic ESCC, and the optimal cut-off value is 6 mm.
Humans ; Esophageal Squamous Cell Carcinoma/pathology* ; Cardia/surgery* ; Esophageal Neoplasms/pathology* ; Lymphatic Metastasis/pathology* ; Lymph Nodes/pathology* ; Lymph Node Excision ; Tomography, X-Ray Computed/methods* ; Esophagectomy/methods* ; Retrospective Studies

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

Objective To explore the clinical value of second polar body (Pb2) exclusion monitoring by timelapse in predicting the fertilization and embryo development efficiency for intracytoplasmic sperm injection ( ICSI). Methods A retrospective research was performed on 278 patients treated with ICSI, the clinical data and Time-lapse monitoring embryo culture data were collected and analyzed, to explore the exclusion of Pb2 after ICSI and the relationship between the specific exclusion time and the outcome of fertilization and embryo development. Results The average time of Pb2 exclusion after ICSI was ( 3. 03 ± 1. 21) hours; The fertilization rate, 2 pronucleus(PN) fertilization rate and 5 days ( D5) blastocyst formation rate in the Pb2 exclusion group were significantly higher than those in the without Pb2 exclusion group (99.95% vs f. 75%, P < 0 . 001; 97.18% vs 0.66%, P< 0.001; 60.50% vs 16.67%, P < 0 . 0 5 ) ; The 2PN fertilization rate in Pb2 exclusion time >3-4 hours group was significantly higher than that in 0-2 hours group and >5 hours group (98.80% vs 9 3 . 8 1 % , P<0. 05; 98.80% vs 95.40%, P<0. 0 5 ) ; The exclusion time of Pb2 was significantly correlated with the average number of blastomeres in D3 embryos (P<0. OOf). The D5 blastocyst formation rate of 3-4 hours group was significantly lower than that of > 2-3 hours group ( 56. 23% vs 67. 23%, P < 0. 05 ) , > 4-5 hours group was significantly lower than 0-2 hours group and >2-3 hours group ( 46. 6f % vs 62. 30% , P<0. 05; 46. 6f % vs 67. 23% , P< 0. 05) , and D5 blastocyst formation rate of >5 hours group was 7. f 4 % , which were significantly lower than that of the other four groups (P<0. 05). The fonnation rate of D5 high-quality blastocysts in 3-4 hours group was significantly lower than 0-2 hours group and > 2-3 hours group ( 9. 92% vs 16. 39% , P<0. 05; 9. 92% vs 20. 72% , P<0. 05) , and D5 highquality blastocysts formation rate in > 4-5 hours group was significantly lower than that in > 2-3 hours group (11. 02% vs 20.72%, P<0. 05). Conclusion Monitoring Pb2 exclusion by Time-lapse can accurately predict fertilization outcome. The time of Pb2 exclusion is significantly correlated with embiyo development potential. It is a valuable morphological index to predict fertilization and embiyo development outcome in ICSI.

OBJECTIVE This study aims to elucidate the mechanism of action of Isoliquiritigenin(ILG)in the treatment of Dia-betic Encephalopathy(DE)based on network pharmacological analysis and in-vitro experiments.METHODS The potential targets of ILG were predicted using the HERB database and SwissTargetPrediction database.DE-associated disease targets were obtained from GeneCards,OMIM,and PharmGkb,and the intersecting targets between ILG and DE were identified using the Venny software.A PPI network was constructed using the STRING database,and core targets were screened out using Cytoscape software.GO function and KEGG pathway enrichment analyses were undertaken using R 4.0.3,followed by validation via molecular docking techniques and in vitro experiments.RESULTS 65 intersecting targets between ILG and DE were identified in this study.Topological analysis yielded eight core targets namely,EGFR,ESR1,PTGS2,PPARG,GSK3β,CDK2,PIK3R1,and F3.GO function and KEGG pathway en-richment analyses revealed that ILG antagonizes DE through several biological processes which impact numerous cellular components and molecular functions such as response to lipopolysaccharides,protein phosphorylation,protein kinase activity,and serine/threo-nine/tyrosine kinase activity.Pathways implicated included the PI3K-Akt signaling pathway,protein polysaccharide signaling pathway in cancer,and endocrine resistance pathway.The molecular docking results showed that all eight core targets had a good binding with ILG,especially with GSK3β,with a binding energy of-7.22 kcal·mol-1.In vitro experiments indicated that ILG could improve high glucose-induced cell damage and activate the PI3K/AKT/GSK3β signaling pathway.CONCLUSION ILG is likely to exert its effects on GSK3β to regulate the PI3K/AKT/GSK3β signaling pathway,thereby alleviating DE.

OBJECTIVES: To evaluate myocardial injury in neonates born to pregnant women with pregnancy complicated by severe preeclampsia by myocardial work indices. METHODS: A prospective cohort study was performed on 25 preterm infants born to the pregnant women with severe preeclampsia from June 2020 to April 2021 (severe preeclampsia group), and 25 preterm infants born to the pregnant women without severe complications in pregnancy were enrolled as the control group. Echocardiography was performed within 24 hours and at 48-72 hours and 14-28 days after birth to measure conventional parameters. Two-dimensional speckle-tracking echocardiography was performed to construct a noninvasive left ventricular pressure-strain loop based on two-dimensional myocardial strain and left ventricular systolic pressure noninvasively measured, so as to calculate myocardial work indices. RESULTS: Compared with the control group, the severe preeclampsia group had significant reductions in left ventricular global work index and global constructive work within 24 hours after birth (P<0.05), a significant reduction in left ventricular global work efficiency and a significant increase in global waste work at 48-72 hours after birth (P<0.05), and a significant reduction in left ventricular global work efficiency at 14-28 days after birth (P<0.05). CONCLUSIONS Subclinical myocardial injury persists in the neonatal period in preterm infants born to pregnant women with severe preeclampsia.
Echocardiography/methods* ; Female ; Humans ; Infant ; Infant, Newborn ; Infant, Premature ; Pre-Eclampsia ; Pregnancy ; Pregnant Women ; Prospective Studies

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.
Animals ; Anxiety/etiology* ; Chronic Pain/etiology* ; GABAergic Neurons ; Gyrus Cinguli/metabolism* ; Hyperalgesia/metabolism* ; Pancreatitis, Chronic/pathology* ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Trinitrobenzenesulfonic Acid/toxicity*

ObjectiveTo evaluate the safety and comfort of hepatic artery infusion chemotherapy （HAIC） via distal transradial access （dTRA） in patients with liver cancer. MethodsPatients with advanced liver cancer who received HAIC via dTRA or transfemoral access （TFA） at the Department of Interventional Radiology， the First Affiliated Hospital of Sun Yat-sen University， were enrolled. The patients underwent dTRA or TFA for onetime and crossed-over subsequently. The patients received HAIC using FOLFOX4 regimen. Postcatheterization questionaire was used to compare the effects of the two vessel accesses on patients’ quality of life. Procedure-related adverse events were also recorded. ResultsAmong the 18 cases enrolled for HAIC， 9 underwent crossover from dTRA to TFA and the the remaining 9 from TFA to dTRA. During HAIC via dTRA， we only found grade 1 or grade 2 procedure-related adverse events such as 2 access site hematoma， 3 persistent pain at access site and 1 left palm numbness. No grade 3 or grade 4 procedure-related adverse event was found. Post dTRA ultrasound revealed no proximal radial artery occlusion. Significant difference in catheterization time between dTRA and TFA accesses was found （4 min vs. 3 min， P < 0.05）. All comfort scores were higher with dTRA as compared to TFA and patients preferred dTRA （7.89 vs. 2.72， P < 0.001）. The compression time for dTRA access was significantly shorter than TFA access （2 h vs. 7 h， P < 0.05）. ConclusionsdTRA approach is safe and tolerable， which is beneficial to improve the quality of life and comfort of patients with liver cancer when undergoing HAIC.