BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged

Neurodegenerative disorders (NDDs) are prevalent chronic conditions characterized by progressive synaptic loss and pathological protein alterations. Increasing evidence suggested that mitochondrial quality control (MQC) serves as the key cellular process responsible for clearing misfolded proteins and impaired mitochondria. Herein, we provided a comprehensive analysis of the mechanisms through which MQC mediates the onset and progression of NDDs, emphasizing mitochondrial dynamic stability, the clearance of damaged mitochondria, and the generation of new mitochondria. In addition, traditional Chinese medicines (TCMs) and their active monomers targeting MQC in NDD treatment have been demonstrated. Consequently, we compiled the TCMs that show great potential in the treatment of NDDs by targeting MQC, aiming to offer novel insights and a scientific foundation for the use of MQC stabilizers in NDD prevention and treatment.

Objective:To analyze the changing trend of intracerebral hemorrhage (ICH) incidence among residents with different characteristics during 9 years of comprehensive hypertension prevention and control (hypertension prevention and control) in Tengzhou from 2013 to 2021.Methods:From January 1, 2013 to December 31, 2021, the new ICH cases collected by the Center for Disease Control and Prevention in Tengzhou City were analyzed to calculate the incidence of ICH, and the trend of its distribution was analyzed among residents with different ages, sexes, and between urban and rural areas. The registered population information came from Tengzhou Public Security Bureau. Age and sex standardized incidence was calculated based on the 7th National Population Census in 2020. The Cochran-Armitage test was used to analyze the time and age trends of the incidence.Results:The overall ICH crude and standardized incidence in Tengzhou City decreased from 97.30/100 000 to 52.13/100 000 ( Z=-9.93, P<0.001) and 119.30/100 000 to 50.69/100 000 ( Z=-15.40, P<0.001) from 2013 to 2021, and both elevated to form a single peak in 2020, with 22.58% ( χ 2=24.02, P<0.001) and 18.09% ( χ 2=17.08, P<0.001) higher than in 2019, respectively. The trends in male and female incidence over the same period were similar to the overall trends, and the incidence was higher in males than in females in all years. The incidence of ICH increased with age in all years. The difference of increase in male incidence rate in 2020 was statistically significant in three age groups ≥45 years compared with 2019 (36.29%, 23.57% and 16.18%, respectively, χ 2=6.73, 4.65, 4.00, P<0.001). The incidence of ICH decreased by 70.07% and 36.23% ( Z=18.44, 5.22, P<0.001) in urban and rural areas respectively from 2013 to 2021, whereas increased by 34.15% ( χ 2=10.88, P<0.01) and 22.08% ( χ 2=18.63, P<0.001) in 2020 compared with 2019 separately. Conclusions:The incidence of ICH in Tengzhou from 2013 to 2021 showed a significant downward trend, with the decrease in the incidence of ICH in women exceeding that in men. The decrease in the incidence of ICH in urban areas exceeded that in rural areas, and male morbidity seemingly had a younger trend.

To investigate the feasibility and safety of endoscopic trans-gastric cholecystolithotomy(ETGC) combined with endoscopic retrograde cholangiopancreatography (ERCP) for cholecystolithiasis and choledocholithiasis. Data of patients with cholecystolithiasis and choledocholithiasis who underwent ETGC after ERCP in Zhongshan Hospital Affiliated to Fudan University from November 2018 to April 2019 were analyzed. Six patients with cholecystolithiasis and choledocholithiasis, 4 males and 2 females, were included in this study.The interval between ERCP and ETGC ranged from 1 to 77 days (median 5 days). All the 6 patients successfully completed ETGC after ERCP, with a surgical success rate of 100%. All the patients had multiple cholecystolithiasis and one patient was complicated with gallbladder polyps.The ETGC operation time was 22-100 min (median 65 min), and the length of hospital stay was 3-9 d (median 6.5 d). Two patients had dull pain in the upper abdomen and increased body temperature after surgery. Abdominal ultrasound in one patient suggested local effusion in the right upper abdomen.Both patients improved after conservative treatment.None of the patients had cholecystitis and cholangitis related symptoms such as right upper abdominal pain or fever during postoperative follow-up, and the follow-up rate was 100%with median follow-up time of 18 month.All the 6 patients underwent abdominal ultrasound examination after surgery. No recurrence occurred in 5 patients. One of the patients showed cholesterol crystals in the gallbladder wall and bile mud deposition.ETGC combined with ERCP is safe and feasible for cholecystolithiasis and choledocholithiasis.

Objective:To study the beneficial effect of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on sleep disorder and other non-motor symptoms and their related influencing factors in patients with Parkinson's disease (PD).Methods:Thirty-six PD patients accepted bilateral STN-DBS in our hospital from January 2017 to April 2019 were chosen in our study. Two weeks before STN-DBS and one year after STN-DBS, Unified Parkinson's Disease Rating Scale part III (UPDRS III), Mini-Mental State Examination (MMSE), Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), non-motion complications 30 questions questionnaire (NMS), 39 quality of life questionnaire for Parkinson's disease (PDQ39) and Parkinson's disease sleep rating scale (PDSS) were performed on these patients, and the levodopa equivalent dose (LED) of drugs and LED of levodopa receptor agonist were calculated. The improvement rate of each scale before and after STN-DBS were compared, and the correlations of improvement of sleep symptom with improvement rates of scores of each scale were analyzed.Results:The scores of UPDRS III ( "off"episodes), HAMA, HAMD, NMS, PDQ39 in patients one year after STN-DBS were significantly lower as compared with those before STN-DBS ( P<0.05). The total LED and LED of levodopa receptor agonist in patients one year after STN-DBS were significantly decreased as compared with those before STN-DBS ( P<0.05). The total scores of PDSS and sub-scale scores except for PDSS-6 and PDSS-15 scores one year after STN-DBS were significantly higher as compared with those before STN-DBS ( P<0.05). The improvement rates of PDSS total scores and sub-scale scores had correlations with improvement rates of UPDRSIII, HAMA and PDQ39 scores, and total LED deceased rate. Conclusion:Bilateral STN-DBS can obviously improve the night sleep quality of patients, which is partly benefited from improvement of exercise symptoms and anxiety relief.

Objective: To investigate the feasibility and safety of endoscopic trans-gastric gallbladder-preserving cholecystolithotomy (ETGC) for gallstones. Methods: The clinical data of 84 cholecystolithiasis patients, who received ETGC at Endoscopic Center of Zhongshan Hospital from March 2017 to May 2019 were analyzed retrospectively. The operation completion rate, operation time, complications and recurrence of calculus were summarized. Results: In the 84 cases of cholecystolithiasis, there were 19 cases (22.6%) of single stone, 53 cases (63.1%) of multiple stones, and 12 cases (14.3%) of gallstones with gallbladder polyps. A total of 82 patients (97.6%) successfully completed ETGC with median operation time of 88 min. Ten patients (12.2%) suffered from abdominal pain after operation, of which 6 patients relieved after conservative treatments. The other 4 cases, including 2 cases of hemoperitoneum, 1 case of biliary fistula, and 1 case of choledocholithiasis with obstructive jaundice, were recovered after corresponding interventions. As of June 14, 2019, 5 cases were lost to follow-up (follow-up rate was 93.9%, 77/82). Residual stones were found in 2 cases (2.6%, 2/77). Stone recurrence was discovered in 4 cases (5.2%, 4/7), and 2 cases (2.6%, 2/77) had cholesterol crystallization in gallbladder. Conclusion ETGC is minimally invasive, feasible and safe in treatment of cholecystolithiasis, and can retain the function of gallbladder. However, how to completely remove the stones and avoid residue by ETGC still needs further exploration, and its long-term efficacy still needs further observation.

A matrix solid phase dispersion ( MSPD) method was developed for the simultaneous preparation of samples of 15 mycotoxin biomarkers including deoxynivalenol, aflatoxins and zearalenone from eggs, which were subsequently determined by liquid chromatography-electrospray ionization tandem mass spectrometry ( LC-ESI-MS/MS) under the multiple reaction monitoring ( MRM) mode. For the analysis, the samples were first mixed with C18 particles and loaded into an empty column, then 20 mL of acetonitrile/methanol (1:1, V/V) containing 1 mmol/L ammonium formate was used to elute the sample. The eluent was then dried with nitrogen flow and redissolved into the mobile phase. After filtration, samples were brought into vials and used for analysis. Different from other methods, no extra complicated purification and centrifugation steps were required in the procedure of MSPD. This method had good linearity in the range of 0. 2-100 ng/mL, with the correlation coefficient (r2) greater than 0. 9931. The limits of detection (LODs, S/N=3) and limits of quantification ( LOQs, S/N=3 ) of this method were 0. 05-2 μg/kg and 0. 2-4 μg/kg respectively. Comprehensive extraction recoveries of the 15 compounds ranged from 61% to 90%.

Adipocytes ; cytology ; Humans ; Stem Cell Transplantation ; methods ; Stroke ; therapy

BACKGROUND:Young patients with cruciate ligament injury and high activity levels are prone to grade III medial colateral ligament injury in knee joint. Conventional construction methods such as direct restoration of injured ligaments and muscle-tendon transposition may induce the loosening of medial colateral ligament complex. OBJECTIVE:To explore the clinical effect of autologous tendon transplantation for grade III medial colateral ligament injury of the knee joint. METHODS: Forty-seven patients with grade III medial colateral ligament rupture were treated by operative repair and reconstruction. After repairing the anatomical structure of medial colateral ligaments, we liberated organic semitendinous tendon, bone-patela tendon-bone, and hamstring tendon, to reconstruct superficial medial colateral ligament. RESULTS AND CONCLUSION:Thirty-seven patients were folowed up for 48 months. Preoperative Lysholm score, IKDC score, Tegner score at the final folow-up, and the widened medial joint space on valgus stress X-Ray films were significantly improved compared with before reconstruction (P < 0.05). According to clinical efficacy scores, 12 cases achieved excelent reconstruction, 18 cases achieved good reconstruction, 4 cases achieved moderate reconstruction, and 3 cases achieved poor reconstruction. The excelent and good rate was 82%. Medial colateral ligament reconstruction based on repairing the anatomical structure is effective and satisfactory. Autologous bone-patela tendon-bone or semitendinous tendon is a good choice for medial colateral ligament reconstruction.

It remains a common problem that the evaluation model of course learning for stu-dents is so simple in the higher education of China. Moreover, the teachers are usually used to evalu-ating student's course learning by summative appraisal and ignore process appraisal, so that the stu-dents are usually lack of learning enthusiasm for self study. Besides, the course learning evaluation of students generally lacks the uniform and detail standard in the country. To resolve these problems, a comprehensive evaluation model of course learning based on the principle of talent evaluation has been practiced and improved since 2007 in some basic medical courses at our university. This model is composed of four parts:the evaluation of mastering basic knowledge, the evaluation of the ability to resolve problems through applied knowledge, the evaluation of practical study and the evaluation of learning initiatives. The model has showed in the practice the characteristics of powerful operability, pluralistic evaluating indicators, combining summative appraisal and process one, reflecting objectively the mastering degree of expertise of students and promoting the self-study of students.