[This corrects the article DOI: 10.11909/j.issn.1671-5411.2017.08.005.].

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 protective effects of the ANXA1(Annexin A1)mimetic peptide Ac2-26 on mice with severe heatstroke(HS)and its underlying mechanisms.Methods Twenty-four adult healthy male C57BL/6J mice weighing 20-25 g were randomly divided into four groups using a simple random sampling method:control group(Con group),Con+Ac2-26 group,severe heatstroke group(HS group),and severe heatstroke+Ac2-26 group(HS+Ac2-26 group),with 6 mice in each group.Mice in Con+Ac2-26 group and HS+Ac2-26 group were injected intraperitoneally with Ac2-26(6 mg/kg),and the remaining mice of two groups were injected intraperitoneally with normal saline of equivalent volume.One hour after drug administration,mice in HS group and HS+Ac2-26 group were placed in a high-temperature and high-humidity simulated environment[(37.0±0.5)℃,75%±5%humidity],while mice in Con group and Con+Ac2-26 were kept in a room temperature and humidity environment[(24±0.5)℃and 40±5%humidity]throughout the experiment.The anal temperature of the mice was recorded every 5 minutes;when the anal temperature of mice in HS group and HS+Ac2-26 group reached 42℃,they were removed from the high-temperature environment and placed in a room temperature environment for 6 hours of rewarming,after which blood samples of mice in each group were collected.Flow cytometry was used to detect the proportion of neutrophils and the expression levels of Cd11b and Cd62L(molecules related to neutrophil activation).Enzyme-linked immunosorbent assay(ELISA)was used to measure the plasma levels of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6),IL-10,and IL-4.Hematoxylin-eosin staining(HE staining)was performed to observe the pathological changes in lung,kidney and liver tissues.Furthermore,RNA sequencing(RNA-seq)was conducted to detect changes in neutrophil gene expression.Results Compared with Con group,Con+Ac2-26 group showed no significant increase in neutrophil proportion,decreased expression of CD62L and CD11b,no significant changes in cytokine levels,and no obvious pathological changes in lung,kidney,or liver tissues.Compared with HS group,the time for mice in HS+Ac2-26 group to reach an anal temperature of 42℃and the time to develop hypothermia after model establishment were both prolonged(P<0.05);the proportion of neutrophils was reduced(P<0.05);the plasma levels of pro-inflammatory cytokines TNF-α and IL-6 were decreased(P<0.05);and the plasma level of anti-inflammatory cytokine IL-10 was increased(P<0.05).HE staining results showed that compared with HS group,HS+Ac2-26 group had a reduced range of inflammatory cell infiltration in lung,kidney,and liver tissues.RNA-seq results revealed that compared with HS group,HS+Ac2-26 group had decreased expression levels of molecules related to the oxidative phosphorylation signaling pathways and neutrophil extracellular trap(NETs).Conclusion Annexin A1 mimetic peptide Ac2-26 may reduce the pro-inflammatory response and alleviate the heatstroke-induced organ histopathologic damage in heatstroke mice by inhibiting oxidative phosphorylation in heat-stressed cells and NETs formation.

Objective To investigate the status of population dynamics and distribution changes of Aedes aegypti in Guangdong Province.Methods Continuous monitoring was conducted from May 2018 to July 2024 in Wushi Town and Qishui Town,Leizhou City,Zhanjiang City,Guangdong Province.Additionally,a survey of the distribution of Ae.aegypti along the Leizhou Peninsula coast was carried out.Results The density of Ae.aegypti in Zhanjiang showed a gradual decline from 2018 to 2024.The last detection of adult Ae.aegypti in Wushi Town was in September 2021,and the last larva was found in October 2023.No Ae.aegypti was detected in Qishui Town during surveys from 2021 to 2024.A survey of 18 coastal villages in the Leizhou Peninsula revealed no detections of Ae.aegypti.Conclusions This study provides a basis for understanding the distribution and population density fluctuations of Ae.aegypti,assessing its invasion risk,and scientifically conducting relevant prevention and control efforts.

Objective:To determine the total and age-specific cut-off values of total prostate specific antigen (tPSA) and the ratio of free PSA divided total PSA (fPSA/tPSA) for screening prostate cancer in China.Methods:Based on the Chinese Colorectal, Breast, Lung, Liver, and Stomach cancer Screening Trial (C-BLAST) and the Tianjin Common Cancer Case Cohort (TJ4C), males who were not diagnosed with any cancers at baseline since 2017 and received both tPSA and fPSA testes were selected. Based on Cox regression, the overall and age-specific (＜60, 60-＜70, and ≥70 years) accuracy and optimal cut-off values of tPSA and fPSA/tPSA ratio for screening prostate cancer were evaluated with time-dependent receiver operating characteristic curve (tdROC) and area under curve (AUC). Bootstrap resampling was used to internally validate the stability of the optimal cut-off value, and the PLCO study was used to externally validate the accuracy under different cut-off values.Results:A total of 5 180 participants were included in the study, and after a median follow-up of 1.48 years, a total of 332 prostate cancer patients were included. In the total population, the tdAUC of tPSA and fPSA/tPSA screening for prostate cancer were 0.852 and 0.748, respectively, with the optimal cut-off values of 5.08 ng/ml and 0.173, respectively. After age stratification, the age specific cut-off values of tPSA in the <60, 60-<70, and ≥70 age groups were 3.13, 4.82, and 11.54 ng/ml, respectively, while the age-specific cut-off values of fPSA/tPSA were 0.153, 0.135, and 0.130, respectively. Under the age-specific cut-off values, the sensitivities of tPSA screening for prostate cancer in males <60, 60-70, and ≥70 years old were 92.3%, 82.0%, and 77.6%, respectively, while the specificities were 84.7%, 81.3%, and 75.4%, respectively. The age-specific sensitivities of fPSA/tPSA for screening prostate cancer were 74.4%, 53.3%, and 55.9%, respectively, while the specificities were 83.8%, 83.7%, and 83.7%, respectively. Both bootstrap's internal validation and PLCO external validation provided similar results. The combination of tPSA and fPSA/tPSA could further improve the accuracy of screening.Conclusion:To improve the screening effects, it is recommended that age-specific cut-off values of tPSA and fPSA/tPSA should be used to screen for prostate cancer in the general risk population.

Purpose::The incidence of heatstroke (HS) is not particularly high; however, once it occurs, the consequences are serious. It is reported that calcitonin gene-related peptide (CGRP) is protective against brain injury in HS rats, but detailed molecular mechanisms need to be further investigated. In this study, we further explored whether CGRP inhibited neuronal apoptosis in HS rats via protein kinase A (PKA)/p-cAMP response element-binding protein (p-CREB) pathway.Methods::We established a HS rat model in a pre-warmed artificial climate chamber with a temperature of (35.5 ± 0.5) °C and a relative humidity of 60% ± 5%. Heatstress was stopped once core body temperature reaches above 41 °C. A total of 25 rats were randomly divided into 5 groups with 5 animals each: control group, HS group, HS+CGRP group, HS+CGRP antagonist (CGRP8-37) group, and HS+CGRP+PKA/p-CREB pathway blocker (H89) group. A bolus injection of CGRP was administered to each rat in HS+CGRP group, CGRP8-37 (antagonist of CGRP) in HS+CGRP8-37 group, and CGRP with H89 in HS+CGRP+H89 group. Electroencephalograms were recorded and the serum concentration of S100B, neuron-specific enolase (NSE), neuron apoptosis, activated caspase-3 and CGRP expression, as well as pathological morphology of brain tissue were detected at 2 h, 6 h, and 24 h after HS in vivo. The expression of PKA, p-CREB, and Bcl-2 in rat neurons were also detected at 2 h after HS in vitro. Exogenous CGRP, CGRP8-37, or H89 were used to determine whether CGRP plays a protective role in brain injury via PKA/p-CREB pathway. The unpaired t-test was used between the 2 samples, and the mean ± SD was used for multiple samples. Double-tailed p < 0.05 was considered statistically significant. Results::Electroencephalogram showed significant alteration of θ (54.50 ± 11.51 vs. 31.30 ± 8.71, F = 6.790, p = 0.005) and α wave (16.60 ± 3.21 vs. 35.40 ± 11.28, F = 4.549, p = 0.020) in HS group compared to the control group 2 h after HS. The results of triphosphate gap terminal labeling (TUNEL) showed that the neuronal apoptosis of HS rats was increased in the cortex (9.67 ± 3.16 vs. 1.80 ± 1.10, F= 11.002, p = 0.001) and hippocampus (15.73 ± 8.92 vs. 2.00 ± 1.00, F = 4.089, p = 0.028), the expression of activated caspase-3 was increased in the cortex (61.76 ± 25.13 vs. 19.57 ± 17.88, F = 5.695, p = 0.009) and hippocampus (58.60 ± 23.30 vs. 17.80 ± 17.62, F = 4.628, p = 0.019); meanwhile the expression of serum NSE (5.77 ± 1.78 vs. 2.35 ± 0.56, F = 5.174, p = 0.013) and S100B (2.86 ± 0.69 vs. 1.35 ± 0.34, F= 10.982, p = 0.001) were increased significantly under HS. Exogenous CGRP decreased the concentrations of NSE and S100B, and activated the expression of caspase-3 (0.41 ± 0.09 vs. 0.23 ± 0.04, F = 32.387, p < 0.001) under HS; while CGRP8-37 increased NSE (3.99 ± 0.47 vs. 2.40 ± 0.50, F = 11.991, p = 0.000) and S100B (2.19 ± 0.43 vs. 1.42 ± 0.30, F = 4.078, p = 0.025), and activated the expression caspase-3 (0.79 ± 0.10 vs. 0.23 ± 0.04, F= 32.387, p < 0.001). For the cell experiment, CGRP increased Bcl-2 (2.01 ± 0.73 vs. 2.15 ± 0.74, F= 8.993, p < 0.001), PKA (0.88 ± 0.08 vs. 0.37 ± 0.14, F= 20.370, p < 0.001), and p-CREB (0.87 ± 0.13 vs. 0.29 ± 0.10, F= 16.759, p < 0.001) levels; while H89, a blocker of the PKA/p-CREB pathway reversed the expression. Conclusions::CGRP can protect against HS-induced neuron apoptosis via PKA/p-CREB pathway and reduce activation of caspase-3 by regulating Bcl-2. Thus CGRP may be a new target for the treatment of brain injury in HS.

Objective To investigate the risk factors for bronchopulmonary dysplasia(BPD)in twin preterm infants with a gestational age of<34 weeks,and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.Methods A retrospective analysis was performed for the twin preterm infants with a gestational age of<34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020.According to their conditions,they were divided into group A(both twins had BPD),group B(only one twin had BPD),and group C(neither twin had BPD).The risk factors for BPD in twin preterm infants were analyzed.Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.Results A total of 904 pairs of twins with a gestational age of<34 weeks were included in this study.The multivariate logistic regression analysis showed that compared with group C,birth weight discordance of>25%between the twins was an independent risk factor for BPD in one of the twins(OR=3.370,95%CI:1.500-7.568,P<0.05),and high gestational age at birth was a protective factor against BPD(P<0.05).The conditional logistic regression analysis of group B showed that small-for-gestational-age(SGA)birth was an independent risk factor for BPD in individual twins(OR=5.017,95%CI:1.040-24.190,P<0.05).Conclusions The development of BPD in twin preterm infants is associated with gestational age,birth weight discordance between the twins,and SGA birth.

Objective To investigate the protective effects and mechanisms of dexmedetomidine(Dex)on kidney donors after warm ischemia and cold ischemia in rats.Methods A total of twenty-one male SD rats were randomly allocated into the control group,the model group(0 μmol/L Dex group)and the Dex group(1 μmol/L Dex group),with 7 rats in each group.All the rats were killed by bloodletting,the kidneys were extracted after 30 minutes of warm ischemia,and the kidneys of the control group were directly fixed or preserved at-80 ℃.The kidney donors of the model group and the Dex group were respectively refrigerated in the university of Wisconsin organ preserva-tion solution containing 0 μmol/L Dex and 1 μmol/L Dex at 4 ℃ for 24 hours,to simulate the cold ischemia state of the kidney donors.HE staining was performed to observe the morphological changes and the tissue injury score was conducted.The activity of N-acetyl-β-D-glucosaminase(NAG)was determined by colorimetry,the apoptosis level was detected by TUNEL,the expression level of receptor-interacting protein kinase 3(RIPK3)was detected by Western blot,and the expression level of phosphorylation mixed lineage kinase domain like protein(pMLKL)was determined by immunofluorescence method.Results In the control group,there were no obvious abnormalities in glomerular or renal tubules.In the model group,some renal tubules were dilated and tubular epithelial cells were flattened.Compared with the model group,the damage of renal tubules in the Dex group was alleviated.Compared with the control group,kidney injury score,NAG activity,TUNEL positive cell number,pMLKL and RIPK3 expression levels were increased in the model group and the Dex group(P＜0.05).Compared with the model group,kidney injury score,NAG activity,TUNEL positive cell number,and pMLKL expression level were decreased in the Dex group(P＜0.05).Conclusion Dex has protective effects on kidney donors after warm ischemia and cold ischemia,and its mechanism is related to reducing apoptosis and inhibiting necroptosis.

Coronary perforation is when a contrast agent or blood flows outside a blood vessel through a tear in a coronary artery.In this case,we reported a case of percutaneous coronary intervention for coronary calcified lesions,which led to iatrogenic coronary perforation and cardiac tamponade after the use of Shockwave balloon to treat intracoronary calcified nodules,and the management of PCI-related CAP was systematically reviewed through the literature.

Objective:To determine the total and age-specific cut-off values of total prostate specific antigen (tPSA) and the ratio of free PSA divided total PSA (fPSA/tPSA) for screening prostate cancer in China.Methods:Based on the Chinese Colorectal, Breast, Lung, Liver, and Stomach cancer Screening Trial (C-BLAST) and the Tianjin Common Cancer Case Cohort (TJ4C), males who were not diagnosed with any cancers at baseline since 2017 and received both tPSA and fPSA testes were selected. Based on Cox regression, the overall and age-specific (＜60, 60-＜70, and ≥70 years) accuracy and optimal cut-off values of tPSA and fPSA/tPSA ratio for screening prostate cancer were evaluated with time-dependent receiver operating characteristic curve (tdROC) and area under curve (AUC). Bootstrap resampling was used to internally validate the stability of the optimal cut-off value, and the PLCO study was used to externally validate the accuracy under different cut-off values.Results:A total of 5 180 participants were included in the study, and after a median follow-up of 1.48 years, a total of 332 prostate cancer patients were included. In the total population, the tdAUC of tPSA and fPSA/tPSA screening for prostate cancer were 0.852 and 0.748, respectively, with the optimal cut-off values of 5.08 ng/ml and 0.173, respectively. After age stratification, the age specific cut-off values of tPSA in the <60, 60-<70, and ≥70 age groups were 3.13, 4.82, and 11.54 ng/ml, respectively, while the age-specific cut-off values of fPSA/tPSA were 0.153, 0.135, and 0.130, respectively. Under the age-specific cut-off values, the sensitivities of tPSA screening for prostate cancer in males <60, 60-70, and ≥70 years old were 92.3%, 82.0%, and 77.6%, respectively, while the specificities were 84.7%, 81.3%, and 75.4%, respectively. The age-specific sensitivities of fPSA/tPSA for screening prostate cancer were 74.4%, 53.3%, and 55.9%, respectively, while the specificities were 83.8%, 83.7%, and 83.7%, respectively. Both bootstrap's internal validation and PLCO external validation provided similar results. The combination of tPSA and fPSA/tPSA could further improve the accuracy of screening.Conclusion:To improve the screening effects, it is recommended that age-specific cut-off values of tPSA and fPSA/tPSA should be used to screen for prostate cancer in the general risk population.