Cannabidiol (CBD), a non-psychoactive cannabinoid, shows great promise in treating methamphetamine (METH) addiction. Nonetheless, the molecular target and the mechanism through which CBD treats METH addiction remain unexplored. Herein, CBD was shown to counteract METH-induced locomotor sensitization and conditioned place preference. Additionally, CBD mitigated the adverse effects of METH, such as cristae loss, a decline in ATP content, and a reduction in membrane potential. Employing an activity-based protein profiling approach, a target fishing strategy was used to uncover CBD's direct target. ATP5A1, a subunit of ATP synthase, was identified and validated as a CBD target. Moreover, CBD demonstrated the ability to ameliorate METH-induced ubiquitination of ATP5A1 via the D376 residue, thereby reversing the METH-induced reduction of ATP5A1 and promoting the assembly of ATP synthase. Pharmacological inhibition of the ATP efflux channel pannexin 1, blockade of ATP hydrolysis by a CD39 inhibitor, and blocking the adenosine A1 receptor (A1R) all attenuated the therapeutic benefits of CBD in mitigating METH-induced behavioral sensitization and CPP. Moreover, the RNA interference of ATP5A1 in the ventral tegmental area resulted in the reversal of CBD's therapeutic efficacy against METH addiction. Collectively, these data show that ATP5A1 is a target for CBD to inhibit METH-induced addiction behaviors through the ADO-A1R signaling pathway.

OBJECTIVE: To investigate the effect of acetylcorynoline (Ace) for promoting functional recovery of injured spinal cord in rats and explore the underlying mechanism. METHODS: Rat models of spinal cord injury (SCI) were treated with intraperitoneal injection of different concentrations of Ace, with the sham-operated rats as the control group. After the treatment, the changes in motor function of the rats and the area of spinal cord injury were assessed with BBB score and HE staining, and the changes in pro-inflammatory cytokine levels and microglial activation were determined using PCR, ELISA and immunofluorescence staining. In a lipopolysaccharide (LPS)-treated BV2 cell model, the effects of different concentrations of Ace or DMSO on microglial activation and inflammatory cytokine production were observed. Network pharmacology analysis was performed to predict the target protein and signaling mechanism that mediated the inhibitory effect of Ace on microglia activation, and AutoDock software was used for molecular docking between Ace and the target protein. A signaling pathway blocker (Osimertinib) was used to verify the signaling mechanism in rat models of SCI and LPS-treated BV2 cell model. RESULTS: In rat models of SCI, Ace treatment significantly increased the BBB score, reduced the area of spinal cord injury, and lowered the number of activated microglia cells and the levels of pro-inflammatory cytokines (P < 0.05). The cell experiments showed that Ace treatment significantly lower the level of cell activation and the production of inflammatory cytokines in LPS-treated BV2 cells (P < 0.05). Network pharmacology analysis suggested that EGFR was the main target of Ace, and they bound to each other via hydrogen bonds as shown by molecular docking. Western blotting confirmed that Ace inhibited the activation of the EGFR/MAPK signaling pathway in injured mouse spinal cord tissue and in LPS-treated BV2 cells, and its inhibitory effect was comparable to that of Osimertinib. CONCLUSION In rat models of SCI, treatment with Ace can inhibit microglia-mediated inflammatory response by regulating the EGFR/MAPK pathway, thus promoting tissue repair and motor function recovery.
Mice ; Animals ; Rats ; Recovery of Function ; Lipopolysaccharides ; Microglia ; Molecular Docking Simulation ; Spinal Cord Injuries ; Signal Transduction ; Cytokines ; ErbB Receptors

Objective To study the stability of plate-assisted intramedullary nailing for fixing proximal third tibiafractures, compare and observe biomechanical characteristics of anterolateral or posteromedial plate-assisted intramedullary nailing after fixation of proximal third tibia fractures. Methods Eight artificial tibia of 4th-generation sawbones were divided into two groups based on location of the assisted plate, namely, anterolateral plate group and posteromedial plate group, with 4 specimens in each group. Each two locking bolts were fixed to theintramedullary nail proximally and distally, and each three bicortical screws were fixed to the plate proximally and distally. The specimens were osteotomized with a 10-mm defect which located 0. 5 cm to the proximal locking bolt of intramedullary nail or 5-6 cm distally to the knee joint line, in order to simulate an AO/ OTA 41-A2 type proximal third tibia fracture after fixation of intramedullary nail. After osteotomy was finished, axial compression test, three point bending test, cyclic loading and overstress test were conducted by mechanical testing machine. The results of axial stiffness and three-point stiffness between two groups were compared and analyzed. Results Axial compression test showed that the average axial stiffness in posteromedial plate group was lower than that in anterolateral plate group, but no significantly statistical differences were found between the two groups. Three point bending test showed that the average bending stiffness in posteromedial plate group was significantly higher than that in anterolateral plate group when stimulating either varus stress (plate located at pressure side of the fracture, t = 3. 679, P<0. 05) or valgus stress (plate located at tension side of the fracture, t = 8. 975, P<0. 05). Conclusions Plate-assisted intramedullary nailing for fixation of proximal third tibia fractures can minimize the angulation malalignment, improve the stability of nailed proximal tibial fragment and allow the early weight bearing. Both anterolateral and posteromedial plate-assisted intramedullary nail can provide satisfactory axial stability for proximal third tibia fractures, while posteromedial plate-assisted intramedullary nail shows better bending stability than anterolateral plate in countering varus or valgus stress deformity. This study provides an essential basis for clinical decision making about plate-assisted intramedullary nailing for fixing proximal third tibia fractures.

OBJECTIVE: Through a retrospective large sample analysis of copy number variants in single center, we explored the technical standards for the interpretation and reporting of constitutional copy-number variants (CNVs) jointly proposed by the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) in 2019, analyzing its impact on CNVs ratings and the improvement in the consistency of the classification of CNVs in clinical laboratories. METHODS: 236 CNVs that assessed as pathogenic, uncertain significant (including likely pathogenic, uncertain and likely benign) by the 2011 ACMG guidelines between August 2018 and December 2019 in our center were re-analyzed. Four working group members of the center reclassified and evaluated 235 CNVs according to 2019 ACMG guidelines. RESULTS: The consistency of clinical significance classification of CNVs was 91% and the α test coefficient was 0.98 among four working group members. Compared with the 2011 and 2019 ACMG technical standards for the CNVs classification, evaluation of pathogenicity and uncertain significant is basically consistent. 90% (45/50) of likely pathogenic and likely benign CNVs were Re-evaluated as variants of uncertain significance, and the difference is significant. CONCLUSION The new version ACMG/ClinGen guidelines for the evaluation of CNVs developed semi-quantitative point-based scoring system and help to improve the consistency in clinical classifications. It can also make the interpretation of CNVs more standardized and transparent.
DNA Copy Number Variations ; Genetic Testing ; Genetic Variation ; Genome, Human ; Humans ; Mutation ; Retrospective Studies

Objective:To evaluate the clinic efficacy of channel bone grafting [preservation of the sclerotic bone at the broken nonunion ends and fixation with limited contact dynamic compression plate (LC-DCP)] in the treatment of postoperative atrophic nonunion of middle clavicular fracture.Methods:The 41 patients were retrospectively analyzed who had been treated at Department of Orthopaedics and Traumatology, Xi'an Hong-Hui Hospital for atrophic nonunion after internal fixation of middle clavicular fracture from June 2015 to December 2019. They were 23 males and 18 females, with a mean age of 47.6 years (from 28 to 63 years). The left side was affected in 25 cases and the right side in 16 cases. The time interval between initial fracture surgery and nonunion surgery averaged 18.5 months (from 9 to 40 months). Thirty-six cases had undergone one operation and 5 cases 2 operations before admission. The length of bone defect was measured during operation. All nonunions were treated with construction of a graft channel, iliac bone graft and LC-DCP internal fixation above the clavicle. The upper limb function of the affected side was evaluated by the Disabilities of Arm, Shoulder and Hand (DASH) 12 months after operation.Results:The 41 patients were followed up for an average of 13.6 months (from 12 to 15 months). A bone defect ≤2.0 cm was found in 25 cases and that >2.0 cm in 16 ones. Nonunion healed in all patients after an average time of 14 weeks (from 12 to 16 weeks). One patient reported continuous pain in the donor area after operation and the other developed deep venous thrombosis at the right lower limb. The DASH upper limb scores at 12 months after operation averaged 14.7.Conclusion:Channel bone grafting is a feasible clinical treatment of postoperative atrophic nonunion of middle clavicular fracture, because it preserves the sclerotic bone at the broken nonunion ends, reduces the amount of iliac bone graft and leads to fine clinic efficacy.

Inflammatory bowel diseases (IBD) are a kind of non-specific inflammatory disease that occurs in gastrointestinal tract. Abnormal immune regulation is a key factor in its pathogenesis. The acquired immune regulation is mediated by helper T cells (Th), which is reported to play an important role in the pathogenesis of IBD. Th17 is a subtype of CD4 + T cells that could specifically produce interleukin-17 (IL-17) and other related cytokines. In this paper, we review the immune modulation of Th17 and its related cytokines in IBD.

Objective:To compare the early clinical efficacy between reaming after distal tibia cortical fenestration combined with antibiotic-loaded calcium sulphate and trench grooving combined with polymethyl methacrylate (PMMA) for the treatment of chronic tibial osteomyelitis after intramedullary nail fixation.Methods:A retrospective analysis was conducted in the 20 patients who had been surgically treated for chronic tibial osteomyelitis after intramedullary nail fixation at Department of Trauma Orthopaedics, Honghui Hospital from January 2019 to January 2021. According to the surgical methods, they were divided into a reaming group and a grooving group. In the reaming group, there were 6 males and 3 females with an age of (47.6±11.4) years; in the grooving group, there were 9 males and 2 females with an age of (49.2±13.9) years. The 2 groups were compared in terms of duration of infection, operation time, intraoperative blood loss, bacterial culture results, total hospital stay, time for inflammatory indexes to return to normal, time for weight-bearing, complication rate, infection control rate, and good to excellent rate by Johner-Wruhs joint function scoring.Results:There was no significant difference in the preoperative general data between the 2 groups, showing they were comparable ( P > 0.05). All patients were followed up for 12 to 25 months after operation. There were no significant differences in the duration of infection, operation time, intraoperative blood loss, bacterial culture results, time for inflammatory indexes to return to normal, complication rate, infection control rate, or Johner-Wruhs scoring between the 2 groups ( P > 0.05). The total hospital stay [(11.7 ± 4.7) d] and weight-bearing time [(5.8 ± 1.6) weeks] for the reaming group were significantly shorter than those for the grooving group [(16.8 ± 4.6) d and (8.1 ± 2.9) weeks] ( P < 0.05). Conclusion:In the treatment of chronic tibial osteomyelitis after intramedullary nail fixation, compared with conventional trench grooving combined with PMMA, reaming after distal tibia cortical fenestration combined with antibiotic-loaded calcium sulphate can not only obtain satisfactory outcomes by infection control but also shorten the treatment cycle by allowing the patients to start early weight bearing.

Objective:To investigate the effect of life review therapy on spiritual comfort and dignity among patients with advanced bladder cancer, to provide reference for the improvement of quality of death outcomes.Methods:A total of 60 patients with advanced bladder cancer who were admitted to the Cancer Hospital of the University of Chinese Academy of Sciences from March 2018 to January 2020 were selected as the research objects. Randomly divided all the patients into the control group and the experimental group, 30 cases in each group. The control group was given routine end-of-life care, and the experimental group was given 5 times of life review therapy on the basis of the control group. The effect of the intervention was evaluated by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being Scale(FACIT-Sp-12) and the Patient Dignity Inventory (PDI).Results:Finally, there were 28 cases in the experimental group and 29 cases in the control group. After the intervention, the scores of peace, meaning and belief demensions and total scores in FACIT-Sp-12 in the experimental group were (10.61 ± 2.23), (11.14 ± 1.90), (10.67 ± 1.79) and (32.36 ± 3.28), respectively, which was significantly higher than those in the control group (8.34 ± 2.24), (10.03 ± 1.49), (8.66 ± 1.89) and (27.03 ± 3.61), the differences were statistically significant ( t values were 2.45-5.82, all P<0.05). The psychological state, dependence, mental peace, social support demension scores and total scores of PDI in the experimental group were (8.64 ± 2.06), (3.14 ± 0.89), (4.21 ± 0.79), (2.43 ± 0.69) and (28.46 ± 4.98), which were significantly lower than those in the control group (10.34 ± 2.93), (4.17 ± 1.17), (4.93 ± 1.33), (3.17 ± 1.07) and (34.01 ± 4.79), the differences were statistically significant ( t values were 2.48-4.28, all P<0.05). Conclusions:Life review therapy can promote spiritual comfort and alleviate dignity destroyed in patients with advanced bladder cancer.

Objective:To characterize the biomechanical performance of our self-designed novel blocking screws in the treatment of distal tibial fractures.Methods:Thirty artificial composite tibial bones were used to create models of unstable distal tibial fracture (AO type 43-A3) which were randomized into 3 even groups ( n=10) according to modes of fixation. Group A was subjected to fixation with intramedullary nails only with merely preset holes reserved for the blocking screws, group B to fixation with intramedullary nails plus conventional anteroposterior blocking screws, and group C to fixation with intramedullary nails plus novel lateral blocking screws. In all the 3 groups, a lateral bending stress test was conducted to record the maximum transversal displacement of the intramedullary nail, a fatigue test to observe the structural abnormality in the model and an axial stress test to record the maximum axial displacement of the intramedullary nail-bone structure. The 3 groups were compared in structural abnormality, the maximum transversal displacement of the intramedullary nail and the maximum axial displacement of the intramedullary nail-bone structure. Results:The lateral bending stress tests showed the maximum transversal displacements were (5.02±1.03) mm; (4.19±0.64) mm and (4.18±0.65) mm in groups A, B and C; compared with group A, the maximum transversal displacement decreased by 16.6%( P=0.027) in group B and decreased by 16.8%( P=0.025) in group C, showing significant differences but there was no significant difference in the maximum transversal displacement between groups B and C ( P=0.978). In the fatigue test, all models showed no structural abnormality under cyclic loading. In the axial stress test, the maximum axial displacements of the intramedullary nail-bone structure were, respectively, (5.69±0.75) mm, (5.31±0.61) mm and (5.51±0.65) mm in groups A, B and C, showing no statistically significant difference among the 3 groups ( P>0.05). Conclusion:Our self-designed novel blocking screws can be a new means in clinical application, because they are similar to conventional blocking screws in increasing the stability of nail-bone construct and other biomechanical performance.

Objective:To evaluate short-term clinical efficacy of femoral neck system (FNS) for treatment of femoral neck fractures in young and middle-aged patients.Methods:A retrospective analysis was conducted of the 70 middle-aged and young patients who had been surgically treated for femoral neck fractures at Department of Trauma Orthopaedics, Honghui Hospital from January to November 2020. Of them, 32 cases were fixated by FNS; they were 16 males and 16 females, with an age of (49.4±11.0) years, including 10 cases of type Ⅱ, 12 cases of type Ⅲ and 10 cases of type Ⅳ by the Garden classification. The other 38 patients were fixated by cannulated compression screws (CCS); they were 19 males and 19 females, with an age of (48.8±10.1) years, including 12 cases of type Ⅱ, 15 cases of type Ⅲ and 11 cases of type Ⅳ by the Garden classification. The 2 groups were compared in terms of operation time, intraoperative blood loss, fracture reduction, fracture union time, weight-bearing time, complications, Barthel index at 3 months after surgery, and hip function at 6 months after surgery.Results:There was no statistically significant difference in preoperative general information or follow-up time between the 2 groups, showing comparability between groups ( P>0.05). There was no significant difference in operation time, intraoperative blood loss or fracture reduction quality between the 2 groups ( P>0.05). In the FNS group, weight-bearing time [(11.4±3.4) weeks] and fracture healing time [(3.1±0.9) months] were significantly shorter than those in the CCS group [(16.4±3.9) weeks and (3.6±0.9) months], rate of complications (12.5%, 4/32) was significantly lower than that in the CCS group (34.2%, 13/38), Barthel index at 3 months after operation (98.1±2.8) and Harris hip score at 6 months after operation (96.8±4.0) were significantly higher than those in the CCS group (93.8±4.1 and 93.6±6.7) ( P<0.05). Conclusion:In the treatment of femoral neck fractures in young and middle-aged patients, compared with CCS fixation, FNS fixation can obtain better short-term curative effects, due to its advantages of shorter bone union and weight-bearing time, a decreased rate of complications and early functional recovery of daily activities.