Objective To investigate the effects of exosome(Exo)secreted by cholangiocarcinoma(CCA)cells under hypoxic conditions on the proliferation,migration,invasion,and Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)pathway of CCA cells.Methods Exo secreted by CCA cells was extracted and identified.Exo under normoxic and hypoxic conditions were co-cultured with CCA cells and divided into normal oxygen group,hypoxic group,hypoxic+inhibitor group,and blank group.The proliferation,migration,and invasion abilities of CCA cells were tested separately.Immunoblotting was applied to detect the expression levels of relevant proteins.Results Exo carrying fluorescent dye 3,3'-dioctadecyloxacarbocyanine perchlorate was detected in CCA cytoplasm.Compared with blank group,the number of clone formation,cell migration and invasion cells in normoxic group increased,the expression of proliferating cell nuclear antigen(PCNA),matrix metallopeptidase(MMP)-2,MMP-9,neural cadherin(N-Cadherin),Vimentin,phosphorylated JAK2(p-JAK2)/JAK2,phosphorylated STAT3(p-STAT3)/STAT3 increased,and the expression of epithelial cadherin(E-Cadherin)decreased(P＜0.05);Compared with normal oxygen group,the number of clone formation,cell migration and invasion cells in hypoxia group increased,the expression of PCNA,MMP-2,MMP-9,N-Cadherin,Vimentin,p-JAK2/JAK2 and p-STAT3/STAT3 increased,and the expression of E-Cadherin decreased(P＜0.05).Compared with hypoxia group,the number of clone formation,cell migration and invasion cells in hypoxia+inhibitor group decreased,the expression of PCNA,MMP-2,MMP-9,N-Cadherin,Vimentin,p-JAK2/JAK2 and p-STAT3/STAT3 decreased,and the expression of E-Cadherin increased(P＜0.05).Conclusion Exo secreted by CCA cells under hypoxic conditions promote proliferation,migration,invasion,and epithelial mesenchymal transition of CCA cell by activating the JAK2/STAT3 pathway.

Objective:To evaluate the clinical effect of derotational distal femoral osteotomy (DDFO) combined with medial patellofemoral ligament (MPFL) reconstruction assisted by digital orthopedic technique in the treatment of recurrent patellar dislocation with enlarged femoral anteversion angle (FAA).Methods:TThe clinical data of 18 patients (4 men and 14 women; mean age 22.1±0.7 years; range, 18-26 years) with recurrent patellar dislocation (FAA≥30°) admitted to Digital Orthopedic Technology Clinical Application Center in Tianjin hospital from May 2022 to December 2023 were retrospectively analyzed. The average number of patella dislocations were 3.6±0.4 (range, 2-8 times), with a mean symptom duration of 4.3±0.4 years (range, 2-7 years). According to Dejour classification of femoral trochlea dysplasia, there were 5 cases of type A, 3 cases of type B, 6 cases of type C and 4 cases of type D. All patients underwent 3D CT scanning and digital modeling before operation. Based on the modeling results, personalized osteotomy and orthopedic integration guide were designed and printed to direct intraoperative DDFO and MPFL reconstruction. Radiological parameters, knee function and complications were assessed during follow-up. Knee function assessments included visual analogue scale (VAS), Intemational Knee Documentation Committee Knee Form (IKDC), Kujala, Lysholm and Tegner score. The radiological parameters included FAA, patellar tilt angle (PTA), tibial tuberosity-trochlear groove distance (TT-TG) and caton-deschamps index (CDI).Results:All patients underwent surgery and were followed up for 15.4±2.8 months (range, 12-20 months). Complications occurred in 3 patients, including deep venous thrombosis in 2 cases and wound effusion in 1 case. No other complications such as wound infection, nerve injury, vascular injury, fracture nonunion or patella dislocation were recorded. The VAS score improved from 5.4±0.3 preoperatively to 2.1±0.2 at one year postoperatively. The IKDC score improved from 44.4±2.7 to 79.2±1.9 points. The Kujala score improved from 51.8±2.6 to 86.1±1.6, the Lysholm from 49.8±2.5 to 84.9±1.5, and the Tegner score from 2.2±0.2 to 4.1±0.2. The FAA decreased from 39.7°±1.2° to 14.9°±0.2°, the PTA from 33.1°±2.6° to 12.6°±1.4°, and the TT-TG from 20.2±0.6 to 13.9±0.4 mm. The differences between time of all the above-mentioned parameters were statistically significant ( P<0.05). The CDI remained stable, which changed from 1.03±0.02 preoperatively to 1.07±0.01 one year after operation ( P>0.05). Conclusions:After the application of DDFO combined with MPFL reconstruction assist by personalized osteotomy and orthopedic integrated guide, the patient's knee function and imaging parameters were significantly improved at one-year follow-up. In the treatment of recurrent patellar dislocation with enlarged FAA, good early clinical efficacy could be achieved with this operation.

Objective:To evaluate the clinical effectiveness of high tibial osteotomy (HTO) assisted by digital orthopedic techniques in the treatment of varus knee osteoarthritis secondary to tibial fracture malunion.Methods:The clinical data were retrospectively analyzed of the 16 patients who had been admitted to Clinical Application Center of Digital Orthopedic Technology, Tianjin Hospital for varus knee osteoarthritis secondary to tibial fracture malunion from April 2022 to October 2023. There were 6 men and 10 women, with an age of (56.3±1.6) years and a mean body mass index of (23.8±0.9) kg/m 2. HTO was performed for all the patients using patient-specific instrumentation integrated osteotomy and orthopedic guide which was designed and printed with digital orthopedic techniques. If preoperative imaging indicated symptomatic meniscus injury (tear), intraarticular free body, or intercondylar fossa stenosis in a patient, arthroscopic clearance was first conducted before subsequent performance of HTO at one stage. Clinical effectiveness was evaluated by measuring and comparing hip-knee-ankle angle (HKA), medial proximal tibial angle (MPTA), posterior tibial slope (PTS), lower limb weight-bearing line (WBL) ratio, Western Ontario and McMaster University (WOMAC) osteoarthritis index, visual analogue scale (VAS) pain score and knee range of motion (ROM) before surgery and 12 months after surgery. Results:The operative time was (41.3±2.1) min and intraoperative fluoroscopy was performed only once in all the patients. All the wounds healed by the first stage with no such complications as hinge point fracture, wound infection, vascular injury, nerve injury, delayed union or nonunion of fracture, lower limb deep venous thrombosis, loosening of internal fixation, or plate rupture. The follow-up time for the 16 patients was (16.3±0.7) months. At 12 months after surgery, the HKA (179.5°±0.5°), MPTA (91.7°±0.5°), WBL ratio (61.2%±0.4%), WOMAC osteoarthritis index [(12.8±0.8) points], VAS pain score [(1.8±0.3) points] and knee ROM (121.8°±1.8°) were significantly better than those before surgery [166.6°±1.3°, 81.8°±0.4°, 29.6%±1.0%, (38.4±2.1) points, (4.8±0.3) points, and 110.5°±2.1°] ( P < 0.05). There was no significant difference in PTS between pre-surgery and 12 months after surgery ( P > 0.05). Conclusions:When HTO is used to treat varus knee osteoarthritis secondary to tibial fracture malunion, assistance of digital orthopedic techniques can improve HKA, MPTA, lower limb alignment, and knee ROM to reduce and recover knee function for the patients.

Objective:To evaluate the clinical effect of derotational distal femoral osteotomy (DDFO) combined with medial patellofemoral ligament (MPFL) reconstruction assisted by digital orthopedic technique in the treatment of recurrent patellar dislocation with enlarged femoral anteversion angle (FAA).Methods:TThe clinical data of 18 patients (4 men and 14 women; mean age 22.1±0.7 years; range, 18-26 years) with recurrent patellar dislocation (FAA≥30°) admitted to Digital Orthopedic Technology Clinical Application Center in Tianjin hospital from May 2022 to December 2023 were retrospectively analyzed. The average number of patella dislocations were 3.6±0.4 (range, 2-8 times), with a mean symptom duration of 4.3±0.4 years (range, 2-7 years). According to Dejour classification of femoral trochlea dysplasia, there were 5 cases of type A, 3 cases of type B, 6 cases of type C and 4 cases of type D. All patients underwent 3D CT scanning and digital modeling before operation. Based on the modeling results, personalized osteotomy and orthopedic integration guide were designed and printed to direct intraoperative DDFO and MPFL reconstruction. Radiological parameters, knee function and complications were assessed during follow-up. Knee function assessments included visual analogue scale (VAS), Intemational Knee Documentation Committee Knee Form (IKDC), Kujala, Lysholm and Tegner score. The radiological parameters included FAA, patellar tilt angle (PTA), tibial tuberosity-trochlear groove distance (TT-TG) and caton-deschamps index (CDI).Results:All patients underwent surgery and were followed up for 15.4±2.8 months (range, 12-20 months). Complications occurred in 3 patients, including deep venous thrombosis in 2 cases and wound effusion in 1 case. No other complications such as wound infection, nerve injury, vascular injury, fracture nonunion or patella dislocation were recorded. The VAS score improved from 5.4±0.3 preoperatively to 2.1±0.2 at one year postoperatively. The IKDC score improved from 44.4±2.7 to 79.2±1.9 points. The Kujala score improved from 51.8±2.6 to 86.1±1.6, the Lysholm from 49.8±2.5 to 84.9±1.5, and the Tegner score from 2.2±0.2 to 4.1±0.2. The FAA decreased from 39.7°±1.2° to 14.9°±0.2°, the PTA from 33.1°±2.6° to 12.6°±1.4°, and the TT-TG from 20.2±0.6 to 13.9±0.4 mm. The differences between time of all the above-mentioned parameters were statistically significant ( P<0.05). The CDI remained stable, which changed from 1.03±0.02 preoperatively to 1.07±0.01 one year after operation ( P>0.05). Conclusions:After the application of DDFO combined with MPFL reconstruction assist by personalized osteotomy and orthopedic integrated guide, the patient's knee function and imaging parameters were significantly improved at one-year follow-up. In the treatment of recurrent patellar dislocation with enlarged FAA, good early clinical efficacy could be achieved with this operation.

Objective To investigate the effects of exosome(Exo)secreted by cholangiocarcinoma(CCA)cells under hypoxic conditions on the proliferation,migration,invasion,and Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)pathway of CCA cells.Methods Exo secreted by CCA cells was extracted and identified.Exo under normoxic and hypoxic conditions were co-cultured with CCA cells and divided into normal oxygen group,hypoxic group,hypoxic+inhibitor group,and blank group.The proliferation,migration,and invasion abilities of CCA cells were tested separately.Immunoblotting was applied to detect the expression levels of relevant proteins.Results Exo carrying fluorescent dye 3,3'-dioctadecyloxacarbocyanine perchlorate was detected in CCA cytoplasm.Compared with blank group,the number of clone formation,cell migration and invasion cells in normoxic group increased,the expression of proliferating cell nuclear antigen(PCNA),matrix metallopeptidase(MMP)-2,MMP-9,neural cadherin(N-Cadherin),Vimentin,phosphorylated JAK2(p-JAK2)/JAK2,phosphorylated STAT3(p-STAT3)/STAT3 increased,and the expression of epithelial cadherin(E-Cadherin)decreased(P＜0.05);Compared with normal oxygen group,the number of clone formation,cell migration and invasion cells in hypoxia group increased,the expression of PCNA,MMP-2,MMP-9,N-Cadherin,Vimentin,p-JAK2/JAK2 and p-STAT3/STAT3 increased,and the expression of E-Cadherin decreased(P＜0.05).Compared with hypoxia group,the number of clone formation,cell migration and invasion cells in hypoxia+inhibitor group decreased,the expression of PCNA,MMP-2,MMP-9,N-Cadherin,Vimentin,p-JAK2/JAK2 and p-STAT3/STAT3 decreased,and the expression of E-Cadherin increased(P＜0.05).Conclusion Exo secreted by CCA cells under hypoxic conditions promote proliferation,migration,invasion,and epithelial mesenchymal transition of CCA cell by activating the JAK2/STAT3 pathway.

Objective:To evaluate the clinical effectiveness of high tibial osteotomy (HTO) assisted by digital orthopedic techniques in the treatment of varus knee osteoarthritis secondary to tibial fracture malunion.Methods:The clinical data were retrospectively analyzed of the 16 patients who had been admitted to Clinical Application Center of Digital Orthopedic Technology, Tianjin Hospital for varus knee osteoarthritis secondary to tibial fracture malunion from April 2022 to October 2023. There were 6 men and 10 women, with an age of (56.3±1.6) years and a mean body mass index of (23.8±0.9) kg/m 2. HTO was performed for all the patients using patient-specific instrumentation integrated osteotomy and orthopedic guide which was designed and printed with digital orthopedic techniques. If preoperative imaging indicated symptomatic meniscus injury (tear), intraarticular free body, or intercondylar fossa stenosis in a patient, arthroscopic clearance was first conducted before subsequent performance of HTO at one stage. Clinical effectiveness was evaluated by measuring and comparing hip-knee-ankle angle (HKA), medial proximal tibial angle (MPTA), posterior tibial slope (PTS), lower limb weight-bearing line (WBL) ratio, Western Ontario and McMaster University (WOMAC) osteoarthritis index, visual analogue scale (VAS) pain score and knee range of motion (ROM) before surgery and 12 months after surgery. Results:The operative time was (41.3±2.1) min and intraoperative fluoroscopy was performed only once in all the patients. All the wounds healed by the first stage with no such complications as hinge point fracture, wound infection, vascular injury, nerve injury, delayed union or nonunion of fracture, lower limb deep venous thrombosis, loosening of internal fixation, or plate rupture. The follow-up time for the 16 patients was (16.3±0.7) months. At 12 months after surgery, the HKA (179.5°±0.5°), MPTA (91.7°±0.5°), WBL ratio (61.2%±0.4%), WOMAC osteoarthritis index [(12.8±0.8) points], VAS pain score [(1.8±0.3) points] and knee ROM (121.8°±1.8°) were significantly better than those before surgery [166.6°±1.3°, 81.8°±0.4°, 29.6%±1.0%, (38.4±2.1) points, (4.8±0.3) points, and 110.5°±2.1°] ( P < 0.05). There was no significant difference in PTS between pre-surgery and 12 months after surgery ( P > 0.05). Conclusions:When HTO is used to treat varus knee osteoarthritis secondary to tibial fracture malunion, assistance of digital orthopedic techniques can improve HKA, MPTA, lower limb alignment, and knee ROM to reduce and recover knee function for the patients.

Objective:To investigate the effect and mechanism of short-chain fatty acids (SCFAs) on the side-effect of tacrolimus on blood glucose.Methods:The C57BL/6 mice were treated with tacrolimus orally (10 mg/kg, tacrolimus group), tacrolimus plus 150 mmol/L sodium butyrate and isovalerate mixed solution (SCFAs group), broad-spectrum antibiotics (antibiotic group), and tacrolimus plus broad-spectrum antibiotics (tac&abx group). After 8 weeks intervention, the fasting blood glucose (FBG), oral glucose tolerance test (OGTT), hemoglobin A1C (HbA1c) were tested as indicators of glucose metabolism, and the gut microbiota, SCFAs concentration in the ileocecal, serum glucagon-like peptide-1 (GLP-1), fasting serum insulin, and GLP-1 expression in intestinal mucosa were performed for intestinal-glucose metabolism mechanism.Results:The FBG and HbA1c were significantly increased in tacrolimus group[(7.31±0.97)mmol/L, (8.34±1.12)%] than control group [(5.23±0.30)mmol/L, (4.32±0.80)%, all P<0.05], which remained normal in antibiotic group [(4.92±0.31)mmol/L, (5.61±0.98)%)], tac&abx group[(5.95±0.37)mmol/L, (4.56±0.26)%] and SCFAs groups [(5.87±0.68)mmol/L, (5.07±1.79)%]. The OGTT in the tacrolimus group showed glucose tolerance impairment, while other groups remained normal. The ileocecal butyric acid and isovaleric acid concentrations in the tacrolimus group were (722.3±262.2) μg/g and (10.0±5.1)μg/g, lower than the control group[ (1 321.3±165.5) μg/g, (19.7±3.6)μg/g, P<0.05]. The above acids in the SCFAs group remained normal as in the control group [(1 375.7±451.6) μg/g, (24.5±11.5)μg/g)]. The fasting serum insulin in the tacrolimus group decreased significantly to (3.2 ± 0.6)mIU/L, compared with control[ (4.4±0.9) mIU/L]and SCFAs groups [(7.0±1.1) mIU/L]. The GLP-1 test indicated a significant decrease in the tacrolimus group[ (4.7±2.9)pg/ml, P<0.05] compared with the SCFAs group and control group [(42.5±19.9) pg/ml, (33.1±9.1) pg/ml]. Conclusions:Tacrolimus affects glucose metabolism through the SCFAs-associated GLP-1 pathway in the intestine, and oral supplementation with mixed SCFAs provides a new insight for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Joint deformity and dysfunction can occur in the late stage of the disease,which is seriously harmful to human health. Anti-inflammatory factors (AIC), as a protective factor, together with pro-inflammatory factors (PIC) play important roles in the pathogenesis and progression of RA. It is widely accepted by the majority of scholars that the decrease of AIC and the increase of PIC in RA can aggravate the systemic and local inflammatory reactions and accelerate the articular cartilage and subchondral bone destruction, resulting in further progress of RA. A new generation of biological therapy for RA targeting at AIC is in the ascendant. Therefore ,it is important to understand the role of AIC in the pathogenesis of RA. From the perspective of the relationship between AIC and RA and the mechanism, this article reviews the research progress in this field, which provides new concepts for the diagnosis and treatment of RA.