OBJECTIVES: To investigate the regulatory role of the NLRP3 signaling pathway in hepatocyte pyroptosis in nonalcoholic steatohepatitis (NASH) under hypoxia. METHODS: Twenty-four male C57BL/6 mice were randomized equally into hypoxic control (A), hypoxic NASH model (B), hypoxic NASH+NLRP3 inhibitor (C), and hypoxic NASH+caspase-1 inhibitor (D) groups. In groups B-D, the mice were fed a methionine choline-deficient (MCD) diet under hypoxic conditions (to simulate a 5000 m altitude) for 6 weeks; the mice in groups C and D received intraperitoneal injections of the respective inhibitors every other day. RESULTS: Compared with those in group A, the mice in group B showed significantly elevated serum levels of FBG, TC, TG, ALT and AST, increased liver lipid content, inflammatory cell infiltration and collagen fiber deposition, and enhanced hepatic expressions of NLRP3, caspase-1, IL-1β and GSDMD proteins, with obvious swelling, cristae breakage, vacuolization, and outer membrane disruption of the mitochondria, ribosome loss in the cytoplasm, destruction of the nuclear membrane, and pathological changes of the rough endoplasmic reticulum. Treatment with NLRP3 inhibitor and caspase-1 inhibitor both significantly lowered serum levels of TC, TG, ALT and AST (but without significantly affecting FBG) in the mouse models, and reduced liver lipid content, inflammatory cell infiltration, collagen deposition, and expression levels of NLRP3, caspase-1, GSDMD and IL-1β. The treatments also significantly improved pathological changes in the mitochondria, ribosomes and endoplasmic reticulum in liver tissues of the mice. CONCLUSIONS NLRP3 signaling pathway plays a key role in promoting hepatocyte pyroptosis in NASH mice under hypoxic condition, and inhibiting this pathway can effectively reduce liver inflammation, suggesting its potential as a therapeutic target for NASH treatment.
Animals ; Non-alcoholic Fatty Liver Disease/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Pyroptosis ; Mice, Inbred C57BL ; Male ; Hepatocytes/pathology* ; Signal Transduction ; Mice ; Hypoxia/metabolism* ; Caspase 1/metabolism* ; Interleukin-1beta/metabolism* ; Liver/metabolism*

OBJECTIVE To analyze the cost-effectiveness of abemaciclib， palbociclib and ribociclib combined with aromatase inhibitors （AI） in first-line treatment of hormone receptor-positive （HR+） advanced breast cancer from the perspective of Chinese medical system. METHODS The 20-year disease course of the patients was simulated by the partitioned survival model， and the simulation period was determined to be 4 weeks， the model output was the total cost and quality-adjusted life year （QALY）， the cost and effect were discounted at a discount rate of 5%. A network meta-analysis was constructed by systematically searching relevant clinical trials to obtain the efficacy parameters of abemaciclib， palbociclib and ribociclib combined with AI. Survival fitting and extrapolation were performed based on the survival curve of the placebo group in MONALEESA-2 trial. Cost-effectiveness was assessed by incremental cost-effectiveness ratio （ICER） and incremental net monetary benefit （INMB）， with a willingness-to-pay threshold of 3 times China’s per capita gross domestic product （GDP） in 2023； one-way sensitivity analysis and probability sensitivity analysis were used to detect the influence of parameters on the results and the robustness of the incremental analysis results. RESULTS In the 20-year simulation， compared with palbociclib+AI scheme， the ICER of ribociclib+AI scheme was 58 558.38 yuan/QALY and the INMB was 62 988.20 yuan. Compared with ribociclib+AI scheme， the ICER of abemaciclib+AI scheme was 264 928.34 yuan/QALY and the INMB was 344.84 yuan. One-way sensitivity analysis showed that the incremental analysis results of abemaciclib+AI scheme compared to ribociclib+AI scheme were not robust. Probabilistic sensitivity analysis confirmed that the probability of ribociclib+AI scheme becoming the most economical was the highest when the threshold was 1-3 times China’s per capita GDP in 2023. CONCLUSIONS Ribociclib+AI scheme is more likely to be the most economical first-line treatment than abemaciclib+AI scheme and palbociclib+AI scheme in Chinese patients with HR+ advanced breast cancer when threshold is 1-3 times China’s per capita GDP in 2023.

Objective To investigate the international occupational classification of rehabilitation-therapy professionals,and analyze the core competencies,to improve the occupational system of rehabilitation-therapy professionals in China. Methods According to Standard Country or Area Codes for Statistical Use that prepared by the Statistics Division of the United Nations and Human Development Index of each country or area,the occupational classification of rehabil-itation-therapy professionals in the International Labour Organization(ILO)and 17 typical countries or areas was compared,and rehabilitation competency framework(RCF)was used to analyze the core competencies. Results The occupational classification or similar documents of ILO and 15 countries or areas were obtained.Except China categorizing rehabilitation-therapy professionals as technicians,all the documents set detailed occupations of rehabilitation-therapy professionals such as physical therapist and speech therapist as formal full-time occupa-tion;and ILO and 14 countries or areas defined these detailed occupations as professional occupation.The core competencies of technicians only involved a very small number of competencies and activities in RCF,while the core competencies of detailed occupations of rehabilitation-therapy professionals covered the vast majority of competencies and activities in RCF.There were differences in RCF competencies and activities involved in the core competencies of detailed occupations of rehabilitation-therapy professionals. Conclusion The core competencies are different between rehabilitation-therapy professionals and technicians,and among different detailed occupations of rehabilitation-therapy professionals.It is important for China to establish the detailed occupations of rehabilitation-therapy professionals as formal full-time occupation.The education re-lated to therapy and rehabilitation in China is gradually aligning with international standards,legislation on occu-pational qualification admission for rehabilitation-therapy professionals should be carried out,and make the reha-bilitation-therapy professionals to be professional occupation.

Dependovirus/genetics* ; Microglia ; Cells, Cultured ; Transduction, Genetic

Objective:To compare the clinical effects between Dynesys dynamic stabilization with microendoscopic discectomy (MED) and posterior lumbar interbody fusion (PLIF) treatment for the degenerative lumbar spinal stenosis in the elder, and to evaluate clinical advantages of Dynesys with MED according to enhanced recovery after surgery (ERAS).Methods:All of 79 cases (male 31, female 48) who suffered from the degenerative lumbar spinal stenosis were include mean age 67.32±5.88 years (from 60 to 81 years) during January 2012 to December 2017. Thirty-nine patients received Dynesys dynamic stabilization with MED (Dynesys group) and 40 cases undergone PLIF (fusion group). The operative time, blood loss, drainage, length of hospital stay, and complications were compared between the two groups. The visual analog scale (VAS), Oswestry disability index (ODI) were used to assess efficacy. The range of motion (ROM) of the lumbar spine and the adjacent segment by dynamic radiographs between two groups were reviewed to evaluate radiological results.Results:The fusion group was larger than Dynesys group in operation time (271.00±57.19 min vs. 193.85±32.17 min), blood loss (458.25±136.85 ml vs. 316.41±87.64 ml), drainage (143.12±47.46 ml vs. 101.67±31.23 ml) and length of hospital stay (15.70±3.01 d vs. 13.38±2.72 d) with statistics differences ( P<0.05). There was a significant difference in VAS and ODI between the two groups at the final follow-up, and Dynesys group was superior to the fusion group (VAS: 1.51±1.21 vs. 2.40±1.48, t=2.910, P=0.005; ODI: 11.90%±6.15% vs. 17.73%±6.85%, t=3.974, P<0.001). The lumbar ROM of Dynesys group increased comparing with the fusion group at post-operation one year (19.21°±6.08° vs. 14.08°±5.80°, t=0.425, P<0.001) and final follow-up (20.56°±6.37° vs. 16.33°±6.94°, t=2.828, P=0.006). ROM of the adjacent segment increased in fusion group at final follow-up (7.45°±2.45°) compared to pre-operation (4.68°±1.98°) and post-operation one year (4.83±1.43°) with significant difference ( F=24.437, P<0.001). The rate of epidural damage, delayed union, surface infection, internal fixation loose, thrombus, pulmonary infection, bedsore, reoperation of the fusion group were all higher than Dynesys group. Conclusion:The Dynesys with MED demonstrated better clinical and radiological results than fusion for degenerative lumbar spinal stenosis. As a method of safety and efficiency, the Dynesys and MED can speed up postoperative recovery of elderly patients in line with ERAS.

Objective To evaluate the clinical application and effect of computerized digital sur -gical assisted design and manufacture for reconstruction of mandibular defect with vascularied iliac crest flap graft .Methods CT was used to scan the craniofacial and maxillofacial region of mandibular ameloblastoma patient ,and then the 3D model of the maxillofacial skeleton was reconstructed using the computerized digital surgical aid design to simulate the focal resection and the mandibular defect reconstruction with the iliac crest flap .Surgical guides were prepared by 3D printing to assist focal re-section and bone reshaping .Postoperatively ,clinical and CT examinations were performed to observe the restoration of the patient's facial appearance and occlusal relationship ,as well as wound healing and graft survival .Results Postoperative review results showed that the bone graft survived well ,and the anastomosed bone was formed .The wound in the surgery area healed .No recurrence of the tumor was found after clinical and CT examination .The maxillofacial appearance was well restored ,and the re-sidual occlusal relationship recovered well .Conclusions The use of computerized digital surgical aided design combined with 3D printing technology can effectively simplify the mandibular segmental defect repair and reconstruction and optimize the postoperative repair effect .

Objective To explore the role of computer-aided design and manufacturing technology (CAD/CAM technology) in the repair of mandibular defects using the fibular osteomyocutaneous free flap.Methods Eight patients with a portion of mandible defect due to various reasons were subjected to preoperative CT scan,obtaining CT data of the mandible and the fibular bone to be transplanted.The original and the reconstructed skull model,as well as the mandible and fibula osteotomy guide plates,was printed using CAD/CAM technology.The titanium plates were preformed using the reconstructed skull model,and the operation was performed with the help of guide plates and a preformed titanium plate.The patients were followed up for 6 to 24 months to evaluate the operation effect.Results Two in 8 cases had flap necrosis caused by immune rejection of the implant,and one case had flap necrosis due to poor postoperative blood glucose control.The other 5 patients healed at the primary site and the fibular myocutaneous flap survived well.There were no serious complications in the donor and recepient site.The patients' satisfaction was high.Conclusions The reconstruction of mandible with the aid of CAD/CAM technique has the advantages of accelerating the operation process,shortening the operation time,improving the accuracy of mandibular amputation and fibular shaping,promotlng postoperative function and morphology recovery.

OBJECTIVE: To establish the cell model using human leukemia cell line HL-60 for exposure of coke oven emissions( COE) in vitro and to explore the mechanism of COE-induced acute toxicity in HL-60 cells. METHODS: HL-60 cells were collected in their logarithmic growth phase and cultured in medium that had final concentrations of COE in 2. 5,5. 0,10. 0 and 20. 0 mg / L for 24 hours. Cell survival rate was examined by CCK-8 assay. The cytotoxicity was evaluated using lactate dehydrogenase release assay. Reactive oxygen species( ROS) production was determined by the 2',7'-dichlorofluorescein diacetate and nitroblue tetrazolium method. The activation of nuclear factor-κB( NF-κB) pathway was evaluated by western blot. RESULTS: With the increasing exposure concentrations of COE,the cytotoxicity of HL-60 cells increased( P < 0. 01),the cell survival rate decreased( P < 0. 01),intracellular ROS decreased( P < 0. 01),whereas extracellular ROS increased( P < 0. 01). These changes had a dose-effect relationship. The levels of phospho-nuclear factor-kappa B p65 and phospho-inhibitor of kappa Bα were higher in all the COE-treated cells compared with untreated cells( P < 0. 05),with no dose-effect relationship. CONCLUSION: COE could cause acute toxicity in HL-60 cells in a doseeffect relationship. The mechanism may be related to the COE-induced in-balanced ROS release and removal,leading to the activation of NF-κB pathway. HL-60 cells can be used as a common cell line for COE hematotoxicity analysis.

OBJECTIVE To establish an in vitro test method and to evaluate the genotoxicity of chemicals using primary cultured mouse hepatocytes and the changes in phosphorylated histone H2AX(γH2AX)expression levels to provide a more reliable marker of the identification of genotoxicity. METHODS Hepatocytes were isolated from BALB/c mice by an improved two-step collagenase diges?tion method and then cultured in sandwich configuration. The primary cultured hepatocytes were treat?ed with various concentrations of four known genotoxic agents bleomycin(BLM),benzo(a)pyrene〔B (a)p〕,styrene and styrene-7,8-oxide(SO)within the range of 40 μmol · L-1 and two non-genotoxic agents azathioprine(Aza)and ciclosporin A(CsA)at different time points within 24 h. The cytotoxicity induced by these toxicants was assessed by CCK-8 assay. Then,the changes in γH2AX expression levels in treated cells were determined by flow cytometry. RESULTS The four genotoxic agents could be detected and two non-genotoxic agents could not be detected by this method. The γH2AX expression level was the highest when hepatocytes were exposed to BLM and SO for 3 h,or B(a)p and styrene for 6 h(P<0.01). The production of γH2AX was 25.67,18.36,12.43 and 14.25 for the four types of genotoxic agents,respectively,and was approximately 19,13,9 and 11 times that of the vehicle control group(P<0.01)at the optimum time point and concentration. There was a significant positive corre?lation between the indicated concentrations of genotoxic chemicals and γH2AX expression levels(P<0.01). In addition,the production ofγH2AX indicated no marked increase in two non-genotoxic agents such as Aza and CsA in comparison with the control group. CONCLUSION This test method can effec?tively distinguish genotoxic agents from non-genotoxic agents,and direct genotoxic agents from indirect genotoxic agents in the absence of S9. γH2AX might be a reliable marker for the identification of the potential genotoxicity of chemicals.

OBJECTIVETo analyze the risk factors of postoperative complications in gastric carcinoma patients complicated with liver cirrhosis.

METHODSA retrospective research of 41 gastric cancer patients with liver cirrhosis who underwent surgical therapy was performed. The multivariate Logistic regression analysis was carried out to determine risk factors of postoperative complications.

RESULTSThere were no postoperative death in this cohort. Twenty-seven(65.9%) patients developed postoperative complications. As determined by the Logistic regression analysis, Child-Pugh score(OR=27.96, 95% CI:1.16-672.23), albumin level(OR=17.98, 95% CI:1.28-253.36) and intraoperative blood loss(OR=10.60, 95% CI:1.21-92.82) were independent risk factors of postoperative complications.

CONCLUSIONAs for gastric cancer patients with liver cirrhosis, positive perioperative management, adjustment of Child-Pugh classifications score, following damage control principle during operation and reducing the intraoperative bleeding may decrease the morbidity of postoperative complications.