The aim of this study is to investigate the protective effect of idebenone (IDE) combined with borneol (BO) against Parkinson's disease (PD). In this study, wild-type AB zebrafish and transgenic Tg ( vmat2: GFP) zebrafish with green fluorescence labeled dopamine neurons were used to establish the PD model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). Following drug treatment, the behavioral performance and dopamine neuron morphology of zebrafish were evaluated, and regulation of dopamine signaling pathway-related genes was determined using RT-qPCR. The results showed that IDE combined with BO improved the behavioral disorders of zebrafish such as bradykinesia and shortening movement distance, also effectively reversed the damage of MPTP-induced dopaminergic neurons. At the same time, the expression of dopamine synthesis and transportation-related genes was up-regulated, and the normal function of the signal transduction pathway was restored. The combination showed a better therapeutic effect compared to the IDE monotherapy group. This study reveals the protective mechanism of IDE combined with BO on the central nervous system for the first time, which provides an important experimental basis and theoretical reference for clinical combination strategy in PD treatment.
Animals ; Zebrafish ; Signal Transduction/drug effects* ; Animals, Genetically Modified ; Dopamine/metabolism* ; Neuroprotective Agents/pharmacology* ; Disease Models, Animal ; Camphanes/pharmacology* ; Ubiquinone/pharmacology* ; Parkinson Disease/drug therapy* ; Dopaminergic Neurons/metabolism*

Objective To explore the inhibitory effect ORY-1001,a lysine-specific histone demethylase 1(LSD1)inhibitor,on growth of glioblastoma(GBM)and the underlying mechanism.Methods We analyzed LSD1 expressions in GBM and normal brain tissues based on data from TCGA and HPA databases.Female BALB/c mouse models bearing xenografts derived from U87 cells or cells with lentivirus-mediated LSD1 silencing or Notch overexpression were treated with saline or 400 μg/kg ORY-1001 by gavage every 7 days,and GBM formation and survival time of the mice were recorded.The effect of ORY-1001 on GBM cell viability was assessed,and its effect on LSD1 expression was analyzed with Western blotting.The genes and pathways associated with LSD1 were analyzed using bioinformatics methods.Western blotting and qRT-PCR were used to detect Notch/HES1 pathway expression after LSD1 silencing and ORY-1001 treatment.The impact of ORY-1001 on viability of U87 cells with Notch1 silencing or overexpression was assessed,and the regulatory effects of ORY-1001 on Notch/HES1 pathway were analyzed using chromatin immunoprecipitation assay.Results A high expression of LSD1 in GBM was negatively correlated with patient survival(P<0.001).ORY-1001 and LSD1 silencing obviously reduced tumor burden and prolonged the survival time of GBM-bearing mice.ORY-1001 treatment significantly inhibited the viability and dose-dependently decreased LSD1 expression in GBM cells,and such inhibitory effect of ORY-1001 was attenuated by LSD1 silencing.The Notch pathway enriched the differential genes related to LSD1,and Notch/HES1 pathway expression was significantly down-regulated after LSD1 silencing and ORY-1001 treatment.Notch1 overexpression significantly attenuated the anti-tumor effect of ORY-1001 on GBM.Mechanistically,ORY-1001 disrupted the interaction between LSD1 and the Notch pathway target genes including Notch3,HES1 and CR2.Conclusion ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice.

Objective To explore the inhibitory effect ORY-1001,a lysine-specific histone demethylase 1(LSD1)inhibitor,on growth of glioblastoma(GBM)and the underlying mechanism.Methods We analyzed LSD1 expressions in GBM and normal brain tissues based on data from TCGA and HPA databases.Female BALB/c mouse models bearing xenografts derived from U87 cells or cells with lentivirus-mediated LSD1 silencing or Notch overexpression were treated with saline or 400 μg/kg ORY-1001 by gavage every 7 days,and GBM formation and survival time of the mice were recorded.The effect of ORY-1001 on GBM cell viability was assessed,and its effect on LSD1 expression was analyzed with Western blotting.The genes and pathways associated with LSD1 were analyzed using bioinformatics methods.Western blotting and qRT-PCR were used to detect Notch/HES1 pathway expression after LSD1 silencing and ORY-1001 treatment.The impact of ORY-1001 on viability of U87 cells with Notch1 silencing or overexpression was assessed,and the regulatory effects of ORY-1001 on Notch/HES1 pathway were analyzed using chromatin immunoprecipitation assay.Results A high expression of LSD1 in GBM was negatively correlated with patient survival(P<0.001).ORY-1001 and LSD1 silencing obviously reduced tumor burden and prolonged the survival time of GBM-bearing mice.ORY-1001 treatment significantly inhibited the viability and dose-dependently decreased LSD1 expression in GBM cells,and such inhibitory effect of ORY-1001 was attenuated by LSD1 silencing.The Notch pathway enriched the differential genes related to LSD1,and Notch/HES1 pathway expression was significantly down-regulated after LSD1 silencing and ORY-1001 treatment.Notch1 overexpression significantly attenuated the anti-tumor effect of ORY-1001 on GBM.Mechanistically,ORY-1001 disrupted the interaction between LSD1 and the Notch pathway target genes including Notch3,HES1 and CR2.Conclusion ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice.

Objective:To investigate the effect of mitochondrial division of GABAergic neurons in substantia nigra pars reticulata(SNr)on motor dysfunction in mice with acute hepatic encephalopathy(AHE).Methods:AHE mice model was established by intraperitoneal injection of thioacetamide(TAA).The changes of liver lobules in AHE mice were observed by hematoxylin-eosin(HE)staining.The changes of serum aspartate aminotransferase(AST),alanine aminotransferase(ALT)and blood ammonia in AHE mice were detected by biochemical detection kit.Then,the motor function of AHE mice was observed by rod fatigue test,elevated cross maze test and open field test.Furthermore,the changes of mitochondrial area,perimeter,roundness and other morphological indicators in SNr of AHE mice were ob-served and analyzed by transmission electron microscopy.The expression of mitochondrial division and fusion related molecules in SNr of AHE mice was observed by Western Blot.Then,the expression of mitochondrial dynamic related protein 1(DRP1)in SNr of AHE mice was targeted by AAV virus.The mitochondrial membrane potential(MMP),ATP and reactive oxygen species(ROS)in SNr were detected by fluorescence enzyme marker,and the changes of motor function of mice were observed.Results:Compared with the control group,the motor function of AHE mice was signifi-cantly decreased,the mitochondrial division of SNr was significantly enhanced,and the expression of mitochondrial divi-sion related proteins was significantly increased.The MMP in SNr of AHE mice was significantly decreased,the ATP of cells was decreased,and the ROS was increased.After targeted inhibition of DRP1 expression in SNr of AHE mice,the movement was improved;further observation found that after the mitochondrial division in SNr of AHE mice was inhibi-ted,the MMP was significantly increased,the ATP of cells was increased,and the ROS was decreased,which demon-strated that the mitochondrial function was significantly improved.Conclusion:Targeted inhibition of mitochondrial di-vision of GABAergic neurons in SNr of AHE mice can improve mitochondrial morphology and function,thus alleviating their movement disorders.

Objective:To investigate the precipitating and aggravating factors in patients with fibromyalgia (FMS) compared to patients with rheumatoid arthritis (RA).Methods:This study was conducted from January 2015 to November 2021, using a cross-sectional survey research method, based on references to develop a patient-reported "onset and exacerbation triggers questionnaire", and surveyed patients with FMS and RA at the same time, and counted the types and proportions of onset and exacerbation triggers in the two groups of patients and used the chi-square test to make comparisons between the groups.Results:A total of 415 patients with FMS and 200 patients with RA participated the survey. 146 patients with FMS (35.2%) and 38 patients with RA (19.0%) reported morbidity triggers. Experiencing physical injury (71, 17.1%), wind-cold/cold-dampness (30 patients, 7.2%), mental stress (26, 6.2%), and exercise fatigue (10 patients, 2.4%) were the common morbidity triggers for FMS. More FMS patients reported to have experienced physical injuries and mental stress before the onset of the disease compared to RA patients [8.2%(17/200), χ2=5.41, P=0.020; 1.5%(3/200), χ2=6.82, P=0.009]. Exacerbation triggers were reported by 319 patients with FMS (76.9%) and 137 patients with RA (68.5%), in the order of weather changes (219 patients, 52.7%), physical labor (192 patients, 46.2%), mood swings (147 patients, 35.4%), sleep deprivation (145 patients, 34.9%), and mental stress (130 patients, 31.3%). The proportion of FMS patients with symptom exacerbation due to physical labor [46.2%(192/415)], mood swings[35.4%(147/415)], sleep deprivation[34.9%(145/415)], mental stress[31.3%(130/415)], and infection [9.3%(39/415)] was significantly higher than that of RA patients [35.0%(70/200), χ2=7.00, P=0.008; 19.5%(39/200), χ2=16.22, P<0.001; 13.5%(27/200), χ2=30.79, P<0.001; 17.5%(35/200), χ2=13.14, P<0.001; 3.0%(6/200), χ2=8.15, P=0.004). Conclusion:More than a third of FMS patients reported precipitating factors, and nearly four fifths FMS patients reported at least one aggravating trigger. FMS patients are likely to be more sensitive to environmental changes and perceived stress than RA patients.

ObjectiveTo understand the use of antibiotics in inpatients and the incidence and trend of hospital infections， to explore the implementation effect of comprehensive management measures， and to provide reference for hospitals to use antibiotics reasonably. MethodsBased on the hospital infection monitoring and management system， a retrospective analysis and comparison were conducted on the use of antibiotics， submission of microbial test samples， and incidence of hospital infections among inpatients in a tertiary hospital from 2012 to 2021. ResultsFrom 2012 to 2021， the use of antibiotics showed a downward trend， from 50.82% in 2012 to 41.29% in 2021. At the same time， the use rate of restricted and special antibiotics had also decreased， and the use rate of restricted and special antibiotics in patients without hospital infection was significantly lower than that in patients with hospital infection， and the microbial testing rate was also on the rise. The annual incidence rate of hospital infection was 0.69%‒1.92%， and the annual case-time prevalence rate was 0.79%‒2.17%. The annual average rate of the above two in 10 years was 1.18% and 1.34%， respectively. The results of the exponential smoothing model also showed that the utilization rate of antibiotics was decreasing and the incidence of nosocomial infection was stable. ConclusionLarge general hospitals took comprehensive management measures to strengthen the management of rational use of antibiotics， which led to a decline in the use rate of antibacterial drugs for inpatients and an increase in the rate of microbial examination. At the same time， the overall incidence of hospital infection was relatively stable， suggesting that the comprehensive management measures of antibacterial drugs in hospitals had achieved certain results. The current measures need to be optimized in the future to continuously improve the management level of rational use of antibacterial drugs.

Objective:To investigate the changes of mitochondria in the substantia nigra pars reticulata(SNr)in a mouse model of acute hepatic encephalopathy(AHE),and the effects of mitochondrial division inhibitor Mdivi-1 on the motor function and mitochondrial function of SNr in AHE mice.Methods:The mouse model of AHE was established by intraperitoneal injection of thioacetamide(TAA)and treated with Mdivi-1.The changes of serum aspartate aminotrans-ferase(AST),alanine aminotransferase(ALT),and blood ammonia were detected by biochemical detection kits.Open field test,rotor-rod fatigue test and elevated plus maze test were performed to observe the motor function of AHE mice.Mitochondrial membrane potential(MMP),cellular reactive oxygen species(ROS)and ATP of SNr were detected by commercial kits.Results:Compared with the control group,the levels of AST,ALT and blood ammonia in AHE mice were increased.The total movement distance of the mice in the open field was reduced,and the movement time of the rotor-rod fatigue test and the elevated plus maze test were shortened.In SNr,mitochondria became smaller and rounder,mitochondrial fission increased,MMP decreased,cellular ROS increased,and ATP production decreased.After treat-ment with Mdivi-1,the levels of AST,ALT and blood ammonia in AHE mice were decreased.In the open field,the total movement distance of mice increased,the movement time of rotorrod fatigue test and elevated plus maze test increased,the mitochondria of SNr were larger,with decreased roundness,decreased mitochondrial division,increased MMP,decreased cellular ROS,and increased ATP production.Conclusion:Mdivi-1 can improve movement disorders in AHE mice by repairing mitochondrial in the SNr.

Objective:To evaluate the feasibility of artificial intelligence (AI) diagnosis of pulmonary nodules on virtual non-contrast(VNC) images derived from dual-layer detector spectral CT.Methods:Totally 52 patients who underwent non-contrast and dual-phase enhanced chest CT scan from May 2022 to November 2022 were enrolled in this study. The VNC images of lung were reconstructed based on venous phase data. CT values and image noise of lung parenchyma, signal-to-noise ratio (SNR) were measured. The dose-length product (DLP) of each scan was recorded and the effective dose ( E) was calculated. All of the objective indicators of image quality and radiation dose were compared by Paired t test. Image quality was evaluated subjectively by two radiologists and compared with Wilcoxon non-parametric test. Wilcoxon symbolic rank test was used to compare the sensitivity and false positive detection rate (FPDR) of AI diagnosis between two groups. Results:Compared with TNC, the noise of venous VNC image was decreased by 13.8%, SNR increased by 14.9%, and both of DLP and E decreased by 33.3% ( t=5.82, -5.35, 22.93, 22.92, P <0.05). There were no significant differences in CT values and subjective scores between 2 groups ( P >0.05). For different types of pulmonary nodules, there was no statistical difference in the sensitivity of AI diagnosis between two groups ( P >0.05). For solid nodules with diameter ≤4 mm and all pulmonary nodules in general, FPDR in VNC group was slightly increased with statistical significance ( Z=-2.03, -3.09, P<0.05), while for other types of pulmonary nodules, there was no statistical difference ( P >0.05). Conclusions:The VNC images of thoracic venous phase based on spectral CT can significantly reduce the radiation dose of patients while the image quality and the AI diagnostic sensitivity of pulmonary nodules remain unchanged, and the FPDR without significantly increase. And it could replace TNC for daily routine.

OBJECTIVE: To explore the laboratory phenotype and molecular pathogenesis in a Chinese pedigree affected with Hereditary coagulation factor Ⅻ (FⅫ) deficiency. METHODS: A male proband admitted to Ningbo No.2 Hospital on July 17, 2021 due to chronic gastritis and members of his pedigree (7 individuals from three generations) were selected as the study subjects. Prothrombin time (PT), activated partial thromboplastin time (APTT), FⅧ activity (FⅧ: C), FⅨ activity (FⅨ: C), FⅪ activity (FⅪ: C), FⅫ activity (FⅫ: C), and FⅫ antigen (FⅫ: Ag) were determined. All of the exons, exon-intronic boundaries, as well as the 5'- and 3'-untranslated regions of the F12 gene were subjected to Sanger sequencing. Candidate variants were verified by cloning sequencing. The effect of candidate variants on the protein function was analyzed by bioinformatics software. RESULTS: The proband, a 47-year-old male, had significantly prolonged APTT (180.0 s) and decreased FⅫ:C and FⅫ:Ag levels (< 1%). His father, mother, brother and two sons also showed certain degrees of reduction. Genetic testing revealed that the proband has harbored compound heterozygous variants of the F12 gene, namely c.1092_1093insC (p.Lys365Glnfs*69) in exon 10 and c.1792_1796delGTCTA (p.Val579Hisfs*32) in exon 14. His mother and elder son were heterozygous for the c.1092_1093ins variant, whilst his father, brother, and younger son were heterozygous for the c.1792_1796delGTCTA variant. Analysis of the promoter region of exon 1 also showed that the proband and both sons had harbored a 46T/T polymorphism, whilst other family members were 46C/T. Bioinformatic analysis suggested that the p.Val579 is a highly conserved site. Protein model analysis showed that, with the p.Val579Hisfs*32 variant, a benzene ring was added and the hydrogen bond of surrounding amino acids was changed. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1792_1796delGTCTA was classified as a pathogenic variant (PVS1+PM2_Supporting+PM4). CONCLUSION The c.1092_1093insC (p.Lys365Glnfs*69) and c.1792_1796delGTCTA (p.Val579Hisfs*32) compound heterozygous variants of the F12 gene probably underlay the decreased FXII levels in this pedigree. Above finding has also enriched the mutational spectrum for FⅫ deficiency.
Male ; Humans ; Aged ; Middle Aged ; Pedigree ; East Asian People ; Exons ; Introns ; Family ; Factor XII Deficiency/genetics* ; 3' Untranslated Regions ; Factor XII/genetics*

Objective:To evaluate the status of position management of anesthesia specialist nurses in China.Methods:From January 2022 to March 2022, a cross-sectional survey was conducted using a self-made questionnaire through convenience sampling to assess the current situation of position management of anesthesia specialist nurses in tertiary hospitals in mainland China.Results:A total of 154 questionnaires were distributed, 137 of which were recovered, the response rate was 89%, and 36 questionnaires were excluded. The survey involved 101 tertiary hospitals in 25 provincial administrative regions in China, and 90% of hospitals were general hospitals. Eighty-three percent of hospitals had separate anesthesia care units, anesthesia specialist nurses accounted for ≥ 10% of nurse anesthetists in 53% of hospitals. Ninety-four percent of hospitals had the position management system of specialist nurses, more than 50% of hospitals had position responsibility and hierarchical management systems and showed difference in position benefits. Less than 50% of hospitals had employed and full-time anesthesia specialist nurses. Fifty percent of hospitals conformed to the advocacy scope of anesthesia specialist nurse service. Fifty-five percent of hospitals carried out the qualification certification of anesthesia specialist nurses, and 37% of hospitals were the training bases for anesthesia specialist nurses. Ninety-six percent of hospitals formulated the development plan of anesthesia specialist nurses.Conclusions:The position management of anesthesia specialist nurses has begun to take shape in tertiary hospitals in China at present, but the institutional system of position management and specialized management need to be strengthened.