PURPOSE: To investigate the protective effect of sub-hypothermic mechanical perfusion combined with membrane lung oxygenation on ischemic hypoxic injury of yorkshire brain tissue caused by traumatic blood loss. METHODS: This article performed a random controlled trial. Brain tissue of 7 yorkshire was selected and divided into the sub-low temperature anterograde machine perfusion group (n = 4) and the blank control group (n = 3) using the random number table method. A yorkshire model of brain tissue injury induced by traumatic blood loss was established. Firstly, the perfusion temperature and blood oxygen saturation were monitored in real-time during the perfusion process. The number of red blood cells, hemoglobin content, NA⁺, K⁺, and Ca²⁺ ions concentrations and pH of the perfusate were detected. Following perfusion, we specifically examined the parietal lobe to assess its water content. The prefrontal cortex and hippocampus were then dissected for histological evaluation, allowing us to investigate potential regional differences in tissue injury. The blank control group was sampled directly before perfusion. All statistical analyses and graphs were performed using GraphPad Prism 8.0 Student t-test. All tests were two-sided, and p value of less than 0.05 was considered to indicate statistical significance. RESULTS: The contents of red blood cells and hemoglobin during perfusion were maintained at normal levels but more red blood cells were destroyed 3 h after the perfusion. The blood oxygen saturation of the perfusion group was maintained at 95% - 98%. NA⁺ and K⁺ concentrations were normal most of the time during perfusion but increased significantly at about 4 h. The Ca²⁺ concentration remained within the normal range at each period. Glucose levels were slightly higher than the baseline level. The pH of the perfusion solution was slightly lower at the beginning of perfusion, and then gradually increased to the normal level. The water content of brain tissue in the sub-low and docile perfusion group was 78.95% ± 0.39%, which was significantly higher than that in the control group (75.27% ± 0.55%, t = 10.49, p < 0.001), and the difference was statistically significant. Compared with the blank control group, the structure and morphology of pyramidal neurons in the prefrontal cortex and CA1 region of the hippocampal gyrus were similar, and their integrity was better. The structural integrity of granulosa neurons was destroyed and cell edema increased in the perfusion group compared with the blank control group. Immunofluorescence staining for glail fibrillary acidic protein and Iba1, markers of glial cells, revealed well-preserved cell structures in the perfusion group. While there were indications of abnormal cellular activity, the analysis showed no significant difference in axon thickness or integrity compared to the 1-h blank control group. CONCLUSIONS Mild hypothermic machine perfusion can improve ischemia and hypoxia injury of yorkshire brain tissue caused by traumatic blood loss and delay the necrosis and apoptosis of yorkshire brain tissue by continuous oxygen supply, maintaining ion homeostasis and reducing tissue metabolism level.
Animals ; Perfusion/methods* ; Disease Models, Animal ; Brain Injuries/etiology* ; Swine ; Male ; Hypothermia, Induced/methods*

OBJECTIVE: To investigate the genetic causal relationship of leukocyte telomere length (LTL) with prostatitis, orchitis and epididymitis by two-sample Mendelian randomization (MR). METHODS: Using LTL as the exposure factor and prostatitis, orchitis and epididymitis as outcome factors, we mined the Database of Genome-Wide Association Studies (GWAS). Then, we analyzed the causal relationship of LTL with prostatitis, orchitis and epididymitis by Mendelian randomization using inverse variance weighting (IVW) as the main method and weighted median and MR-Egger regression as auxiliary methods, determined the horizontal multiplicity by MR-Egger intercept test, and conducted sensitivity analysis using the leaving-one-out method. RESULTS: A total of 121 related single nucleotide polymorphisms (SNPs) were identified in this study. IVW showed LTL to be a risk factor for prostatitis (OR = 1.383, 95% CI: 1.044－1.832, P = 0.024), and for orchitis and epididymitis as well (OR = 1.770, 95% CI: 1.275－2.456, P = 0.000 6). CONCLUSION Genetic evidence from Mendelian randomized analysis indicates that shortening of LTL reduces the risk of prostatitis, orchitis and epididymitis.
Humans ; Male ; Mendelian Randomization Analysis ; Epididymitis/genetics* ; Prostatitis/genetics* ; Polymorphism, Single Nucleotide ; Leukocytes ; Orchitis/genetics* ; Genome-Wide Association Study ; Telomere ; Risk Factors

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

OBJECTIVES: To investigate the mechanism through which N-acetylneuraminic acid (Neu5Ac) exacerbates hypoxia/reoxygenation (H/R) injury in rat cardiomyocytes (H9C2 cells). METHODS: H9C2 cells were cultured in hypoxia and glucose deprivation for 8 h followed by reoxygenation for different durations to determine the optimal reoxygenation time. Under the optimal H/R protocol, the cells were treated with 0, 5, 10, 20, 30, 40, 50, and 60 mmol/L Neu5Ac during reoxygenation to explore the optimal drug concentration. The cells were then subjected to H/R injury followed by treatment with Neu5Ac, Fer-1 (a ferroptosis inhibitor), or both. The changes in SOD activity, intracellular Fe²⁺ and lipid ROS levels in the cells were evaluated, and the cellular expressions of Nrf2, GPX4, HO-1, FSP1, and xCT proteins were detected using Western blotting. RESULTS: Following hypoxia and glucose deprivation for 8 h, the cells with reoxygenation for 6 h, as compared with other time lengths of reoxygenation except for 9 h, showed the lowest expression levels of Nrf2, GPX4, HO-1, and FSP1 proteins (P<0.001). Neu5Ac treatment of dose-dependently decreased the viability of the cells with H/R injury with an IC₅₀ of 30.07 mmol/L. Reoxygenation for 3 h with normal glucose supplementation and a Neu5Ac concentration of 30 mmol/L were selected as the optimal conditions in the subsequent experiments. The results showed that Neu5Ac could significantly increase SOD activity, Fe²⁺ and lipid ROS levels and reduce Nrf2, GPX4, HO-1, and FSP1 protein expressions in H9C2 cells with H/R injury, but its effects were significantly attenuated by treatment with Fer-1. CONCLUSIONS Neu5Ac exacerbates ferroptosis of myocardial cells with H/R injury by inhibiting the Nrf2 axis to promote the production of ROS and lipid ROS.
Ferroptosis/drug effects* ; Myocytes, Cardiac/cytology* ; Animals ; NF-E2-Related Factor 2/metabolism* ; Rats ; N-Acetylneuraminic Acid/pharmacology* ; Cell Hypoxia ; Reactive Oxygen Species/metabolism* ; Cell Line ; Myocardial Reperfusion Injury/metabolism*

OBJECTIVES: This study aimed to investigate the potential mediating role of plasma phosphorylated tau217 (p-tau217) in the association between periodontitis and mild cognitive impairment (MCI). METHODS: In this case-control study, patients diagnosed with MCI in the Neurology Department of the First Affiliated Hospital of Shandong Second Medical University from November 2023 to May 2024 were selected as the case group (MCI group). Cognitively normal (CN) volunteers, matched for age and education level and recruited from the physical examination center during the same period, served as the control group (CN group). The general demographic data of the study participants were collected. The Beijing versions of the Montreal Cognitive Assessment (MoCA), clinical dementia rating (CDR), and activities of daily living scale (ADL) were used to assess neuropsychological functions. Clinical periodontal examinations were conducted, the periodontal inflamed surface area (PISA) was calculated, and the periodontitis stage was determined in accordance with the 2018 classification. Fasting elbow venous blood samples were collected in the morning, and blood biochemical indicators were measured. Plasma p-tau217 levels were detected using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using t-test, Mann-Whitney U test, chi-square test, partial correlation analysis, multivariate Logistic regression analysis, multiple linear regression analysis, restricted cubic spline (RCS) regression analysis, and mediation effect analysis. RESULTS: Among the 192 participants, 96 belong to the MCI group and 96 to the CN group. The prevalence of periodontitis was 63.5% in the MCI group and 43.8% in the CN group, with a statistically significant difference (χ²=7.561, P=0.006). The plasma p-tau217 levels in the MCI group were significantly higher than those in the CN group [7.00 (4.27-9.65) ng/mL versus 2.02 (0.80-3.81) ng/mL, Z=-8.108, P<0.001]. Partial correlation analysis revealed that plasma p-tau217 levels were positively correlated with all the clinical periodontal indices (all P<0.001). After adjustments for baseline covariates, multivariate Logistic regression indicated that periodontitis was an independent risk factor for MCI. Patients with periodontitis had a 1.977-fold higher MCI risk than those without periodontitis (OR=1.977, 95%CI: 1.088-3.594, P=0.025). Moreover, the MCI risk for stage Ⅰ/Ⅱ periodontitis and stage Ⅲ/Ⅳ periodontitis was 1.878 times (OR=1.878, 95%CI: 1.029-3.425, P=0.040) and 2.625 times (OR=2.625, 95%CI: 1.073-6.246, P=0.035) higher than that for patients without periodontitis, respectively. Trend test showed that the MCI risk increased with periodontitis severity (P_trend=0.016). After adjustments for baseline covariates, multiple linear regression analysis showed that periodontitis was an independent risk factor for increased plasma p-tau217 levels (β=3.309, 95%CI: 2.363-4.254, P<0.001). Compared with patients without periodontitis, those with stage Ⅰ/Ⅱ periodontitis (β=1.838, 95%CI: 0.869-2.806, P<0.001) and stage Ⅲ/Ⅳ periodontitis (β=5.539, 95%CI: 4.442-6.636, P<0.001) had significantly higher plasma p-tau217 levels. In addition, trend test indicated that plasma p-tau217 levels increased with periodontitis severity (P_trend<0.001). After adjustments for baseline covariates, RCS regression analysis further revealed that PISA had a positive linear dose-response relationship with MCI risk (P_overall=0.002, P_nonlinear=0.344) and plasma p-tau217 levels (P_overall<0.001, P_nonlinear=0.140). After adjustments for baseline covariates, mediation analysis showed that plasma p-tau217 mediated the association between periodontitis and MCI, with a mediation proportion of 13.99% (95% Bootstrap CI: 0.38%-49.39%, P=0.038). CONCLUSIONS Periodontitis was independently positively associated with MCI risk, and plasma p-tau217 plays a mediating role in this association.
Humans ; Cognitive Dysfunction/complications* ; tau Proteins/blood* ; Periodontitis/complications* ; Case-Control Studies ; Male ; Female ; Phosphorylation ; Aged ; Middle Aged ; Activities of Daily Living

Objective It compared the power consumption and electrical parameters between Thulium fiber laser devices(TFL)and Holmium laser devices(HoL)in transurethral enucleation of prostate(TUEP).Methods A sin-gle surgeon conducted TUEP by THL or HoL in 10 patients respectively.The enucleation efficiency,the laser energy output and the electric parameters were recorded and analyzed.Results The data from both groups of surgeries were tested for normal distribution,and the t-test found that the difference in the enucleation efficiency between the two surgeries was not statistically significant(P=0.818),and the energy consumption indexes of the two devices were comparable.The difference in the total kilojoules of laser emission between the two lasers during surgery was not statistically significant(P=0.148),but the power consumption of the thulium laser was about one-tenth of that of the holmium laser(P＜0.001),suggesting that the former utilised electrical energy significantly more efficiently than the latter.The maximum current of the HoL was significantly higher than that of the TFL(P＜0.001),requiring a spe-cial high-power power outlet.Conclusion TFL was superior to HoL in terms of lower power consumption,higher en-ergy-efficient and electrical convenient in transurethral enucleation of the prostate.

OBJECTIVE To investigate the potential mechanism of procyanidin on rats with gingivitis by regulating phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt）/vascular endothelial growth factor （VEGF） signaling pathway. METHODS The rat model of gingivitis was constructed by sewing the neck of the first maxillary molar with silk thread+applying maltose on the gum+feeding with 20% sucrose solution and soft food. Forth-eight model rats were randomly divided into model group， procyanidin group （160 mg/kg）， 740Y-P group （PI3K/Akt signaling pathway activator， 0.02 mg/kg）， and procyanidin+ 740Y-P group （procyanidin 160 mg/kg+740Y-P 0.02 mg/kg）， with 12 rats in each group； another 12 rats were selected as control group； each medication group was treated with corresponding drugs intragastrically or/and intraperitoneally， once a day， for 7 consecutive days. Twenty-four hours after the last administration， the gingival index of rats was measured； the levels of interleukin- 18 （IL-18）， inducible nitric oxide synthase （iNOS） and alkaline phosphatase （ALP） in gingival crevicular fluid， as well as the levels of superoxide dismutase （SOD）， catalase （CAT） and reactive oxygen species （ROS） in gingival tissues of rats were detected； the pathological changes in gingival tissues were observed； the expression levels of PI3K/Akt/VEGF signaling pathway- related proteins in gingival tissues of rats were detected. RESULTS Compared with control group， the gingival tissues of rats in the model group had severe pathological damage，which was manifested as local tissue expansion and congestion， new capillaries， degeneration and loss of collagen fibers and disorder of arrangement， and a large number of inflammatory cell infiltration in the gingival sulcus wall. The gingival index， the levels of IL-18， iNOS， ALP in gingival crevicular fluid， the level of ROS in gingival tissues， the phosphorylations of PI3K and Akt， as well as the protein expression of VEGF in gingival tissues were significantly increased； the levels of SOD and CAT in gingival tissues of rats in model group were significantly decreased （P＜0.05）. Compared with model group， the pathological damage to the gingival tissues of rats in procyanidin group was reduced， and all quantitative indicators were significantly improved （P＜0.05）； 740Y-P could reverse the improvement effect of procyanidin on various indicators （P＜0.05）. CONCLUSIONS Procyanidin may alleviate gingival tissue damage， and improve gingival inflammation and oxidative stress in rats with gingivitis by inhibiting PI3K/Akt/VEGF signaling pathway.

BACKGROUND:At present,effective preventive and therapeutic measures for hypertrophic scar are still limited.In contrast,most of botanical herbs have few side effects and abundant sources,offering new ideas and approaches for the prevention and treatment for hypertrophic scar. OBJECTIVE:To explore the potential molecular mechanism of plant-derived β-sitosterol on hypertrophic scar fibroblasts by network pharmacology and molecular docking techniques and to initially verify it by cytological experiments. METHODS:Through the network pharmacology,the relevant database and software were used to screen the drug targets of β-sitosterol and obtain the hypertrophic scar-related disease targets.The potential(intersection)targets of β-sitosterol on hypertrophic scar were obtained.Cytoscape software and STRING database were used to construct the"drug-target-disease"network and protein-protein interaction network,and screen out the core targets in the protein-protein interaction network.Gene ontology(GO)biological function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses of intersection targets were conducted through the DAVID database,and the signaling pathways and core target genes closely related to the intersection targets were further identified through literature analysis.AutoDock software was used to perform the molecular docking of β-sitosterol and core target proteins.In vitro cellular assays were used to verify the effects of β-sitosterol on proliferation,apoptosis,cell cycle distribution and mRNA expression of core target genes in human hypertrophic scar fibroblasts. RESULTS AND CONCLUSION:There were 56 intersection targets of β-sitosterol and hypertrophic scar and 10 core targets were identified in the protein-protein interaction network,including tyrosine kinase,mitogen-activated protein kinase 3(MAPK3),cysteine protease 3(CASP3),apolipoprotein E,estrogen receptor 1,sterol regulatory element-binding transcription factor 1,peroxisome proliferator-activated receptor alpha,C-reactive protein,intercellular adhesion molecule 1,and catalase.Combined with the literatures and the functional analysis of the KEGG and GO,the MAPK signaling pathway was further identified to be closely related to the intersection targets,and MAPK3(ERK1-MAPK),CASP3,P53 and tumor necrosis factor were identified as the core targets.The molecular docking results indicated that β-sitosterol was well bound to the core target proteins.Cellular assays showed that 100 μmol/L β-sitosterol inhibited hypertrophic scar fibroblast proliferation,decreased mitochondrial membrane potential and induced apoptosis(P<0.01),increased the proportion of G1-phase cells and decreased the proportion of S-phase cells(P<0.05),upregulated the mRNA expression of CASP3,P53 and tumor necrosis factor(P<0.05),and downregulated the mRNA expression of MAPK3(P<0.001).To conclude,β-sitosterol may induce cell apoptosis in hypertrophic scar fibroblasts by activating the tumor necrosis factor pathway and upregulating the expression of CASP3 and P53,while inhibiting the ERK-MAPK pathway to arrest cell cycle and thus reduce the proliferation of hypertrophic scar fibroblasts.

BACKGROUND:Hypertrophic scar is a skin fibrosis disease characterized by excessive proliferation of fibroblasts,epidermal thickening,and stratum corneum dysfunction.At present,the pathogenesis of Hypertrophic scar is still unclear. OBJECTIVE:To screen the core(Hub)genes and important signaling pathways in hypertrophic scar-related datasets based on bioinformatics,and then verify them by cell experiments to predict small molecule drugs that may have therapeutic effects on hypertrophic scar. METHODS:Datasets related to hypertrophic scar were searched from Gene Expression Omnibus(GEO)database,and differentially expressed genes were identified by R software analysis.Gene ontology and KEGG enrichment analyses were performed for differentially expressed genes.Protein-protein interaction network of differentially expressed genes was constructed using String online platform.Then,the key genes and core modules in the protein-protein interaction network were screened by Cytohubba and MCODE plugin-in Cytoscape software respectively,and the Hub genes were obtained by the intersection of the above key genes and the genes that formed the core module.Real-time fluorescent quantitative PCR was used to verify the difference in Hub gene mRNA expression between human hypertrophic scar and normal skin epidermal stem cells.The histological data from the Human Protein Atlas were used to verify the differences in the expression and distribution of Hub gene-encoded proteins in the two kinds of human tissues.Finally,the potential drugs for hypertrophic scar were predicted by the connectivity map database. RESULTS AND CONCLUSION:Among the identified differentially expressed genes,102 genes were up-regulated and 702 genes were down-regulated.Gene ontology and KEGG analysis showed that the enriched signaling pathways and biological processes were mainly involved in tight junction,arachidonic acid metabolism,extracellular matrix receptor interaction,epidermal development and keratinization.Eight Hub genes were found to be closely related to the mevalonate pathway that regulates cholesterol metabolism,including HMGCS1,DHCR7,MSMO1,FDPS,MVK,HMGCR,MVD and ACAT2.Compared with the normal skin group,the mRNA expression of HMGCS1,DHCR7,MSMO1,FDPS,HMGCR,MVD and ACAT2 in the hypertrophic scar group decreased significantly(P＜0.05),while MVK mRNA expression had no significant change(P＞0.05).Except for MVK,the expression levels of other Hub gene-encoded proteins in normal skin tissue were higher than those in hypertrophic scar tissue(P＜0.05).The top 10 candidate drugs included protein kinase A inhibitor(H-89),serine protease inhibitor(Dabigatran-Etexilate),FLT3 inhibitor(sunitinib),among which resveratrol and β-sitosterol are plant extracts.To conclude,Hub genes closely related to mevalonate metabolism may affect the structure and function of the epidermis by regulating lipid metabolism,which may an important pathogenesis of hypertrophic scar.The small-molecule compounds identified in this study can be used as candidate drugs for the treatment of hypertrophic scar.

Objective It compared the power consumption and electrical parameters between Thulium fiber laser devices(TFL)and Holmium laser devices(HoL)in transurethral enucleation of prostate(TUEP).Methods A sin-gle surgeon conducted TUEP by THL or HoL in 10 patients respectively.The enucleation efficiency,the laser energy output and the electric parameters were recorded and analyzed.Results The data from both groups of surgeries were tested for normal distribution,and the t-test found that the difference in the enucleation efficiency between the two surgeries was not statistically significant(P=0.818),and the energy consumption indexes of the two devices were comparable.The difference in the total kilojoules of laser emission between the two lasers during surgery was not statistically significant(P=0.148),but the power consumption of the thulium laser was about one-tenth of that of the holmium laser(P＜0.001),suggesting that the former utilised electrical energy significantly more efficiently than the latter.The maximum current of the HoL was significantly higher than that of the TFL(P＜0.001),requiring a spe-cial high-power power outlet.Conclusion TFL was superior to HoL in terms of lower power consumption,higher en-ergy-efficient and electrical convenient in transurethral enucleation of the prostate.