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

Objective To compare and analyze the tilt and decentration of the intraocular lens in patients receiving four-point and two-point suspension fixation,as well as their relationship with visual prognosis.Methods A total of 80 patients(80 eyes)who underwent intraocular lens suspension fixation at the Ophthalmology Department of Baoding No.1 Central Hospital from June 2021 to April 2022 were selected as the subjects.These patients were randomly divided into the experimental group(41 patients,41 eyes,underwent four-point suspension fixation)and the control group(39 patients,39 eyes,underwent traditional two-point suspension fixation).They were followed up for at least 6 months after surgery to re-cord their uncorrected visual acuity(UCVA)and best corrected visual acuity(BCVA)before surgery and at the last follow-up.The tilt angle and decentration distance of the intraocular lens of patients in the two groups were measured after surger-y by a panoramic ultrasound biomicroscope.The preoperative and last follow-up UCVA and BCVA of patients in the two groups,as well as tilt angle and decentration distance of the intraocular lens after surgery,were compared,and the corre-lation between tilt angle,decentration distance and postoperative UCVA,BCVA was analyzed by Person correlation analy-sis.Results The UCVA and BCVA at the last follow-up in the experimental group and control group were better than those before surgery(all P＜0.05).The difference in postoperative UCVA between the experimental group and the control group was statistically significant(t=-6.20,P=0.00),and the experimental group had better postoperative UCVA than the control group.There was no statistically significant difference in postoperative BCVA between the experimental group and the control group(t=-1.43,P=0.16).The postoperative horizontal and vertical tilt angles of the intraocular lens in the experimental group were 0.70°±0.24° and 0.60°±0.16°,respectively;while those in the control group were 2.66°± 1.40° and 3.76°±0.67°,respectively.The differences between the two groups were statistically significant(t=-8.51 and-29.42,P=0.00 and 0.00).The postoperative horizontal and vertical decentration distances of the intraocular lens in the experimental group were(0.24±0.10)mm and(0.25±0.10)mm,respectively,while those in the control group were(0.85±0.77)mm and(2.14±0.50)mm,respectively.The differences between the two groups were statistically signifi-cant(t=-4.82 and-21.68,P=0.00 and 0.00).In the experimental group,neither the horizontal and vertical tilt angles of intraocular lenses nor the horizontal and vertical decentration distances were correlated with postoperative UCVA and BCVA(all P＞0.05).In the control group,the horizontal tilt angle of intraocular lenses was positively correlated with post-operative UCVA and BCVA(both P＜0.05),while the vertical tilt angle was not correlated with postoperative UCVA and BCVA(both P＞0.05);the horizontal decentration distance was positively correlated with postoperative UCVA and BCVA(both P＜0.05),but the vertical decentration distance was not correlated with postoperative UCVA and BCVA(both P＞0.05).Conclusion Both four-point suspension fixation and traditional two-point suspension fixation can effectively im-prove postoperative vision of patients,while the tilt and decentration of the intraocular lens are smaller after four-point sus-pension fixation.

Pulmonary hypertension(PH)is a progressive disease characterized by pulmonary vascular remodeling.Current treatments for PH remain suboptimal,and there is an urgent need to better decipher the underlying pathomechanisms to identify new therapeutic targets.MicroRNA(miRNA)are key components in the post-transcriptional machinery that mediates cellular functions and mainly act by regulating the expression of downstream target genes.Numerous in vivo and in vitro studies have demonstrated the involvement of miRNA and their regulators in PH development.However,there is no unified model for the mechanism of miRNA's regulation of pulmonary vascular remodeling.Therefore,this article provides a review on the mechanisms of miRNA in PH characterized in recent years.

OBJECTIVE: To determine the feasibility of conducting a full-scale randomized controlled trial (RCT) and investigate the basic information and safety of acupuncture for patients with chronic spontaneous urticaria (CSU). METHODS: A total of 80 participants with CSU from July 2018 to July 2019 were randomly assigned to receive active acupuncture (n=41) on a fixed prescription of acupoints or sham acupuncture (n=39) with superficial acupuncture on non-acupuncture points through the completely randomized design. Patients in both groups received 5 sessions per week for 2 weeks, and participants were followed for a further 2 weeks. Feasibility was assessed by recruitment and randomization rates, retention of participants, treatment protocol adherence, and the incidence of adverse events (AEs). The clinical primary outcome was the changes from baseline weekly urticaria activity scores (UAS7) after treatment at 2 weeks. Secondary outcomes included the Visual Analogue Scale (VAS) score of itching intensity, Dermatology Life Quality Index (DLQI), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA). RESULTS: A total of 80 participants were enrolled. The recruitment rate of 24.02%, randomization rate of 100%, a loss rate of 6.25%, and no obvious AEs were observed in either group. The decrease from baseline in the mean UAS7 total score at week 2 in the active acupuncture group was -8.63 (95%CI, -11.78 to -5.49) and -6.21 (95%CI, -9.43 to -2.98) in the sham acupuncture group for a between-group difference of -2.42 (95% CI, -6.93 to 2.07). The change in the DLQI, VAS of itching intensity, HAMA, and HAMD were a slightly better improvement trend in the active acupuncture group than the sham acupuncture group, but the between-group difference was not significant. CONCLUSIONS Active acupuncture had a better improvement trend in alleviating symptoms, improving quality of life and regulating the mood of anxiety and depression in patients with CSU than sham acupuncture. (Registration Nos. AMCTR-ICR-18000190 and ChiCTR2100054776).

Objective To explore the possible role of thrombospondin-1(THBS1)in the excessive fibrosis of vaginal wall induced by estrogen deficiency in rats,the morphological structure of collagen fibers and the expression of THBS1 in the vaginal wall were detected in the estrogen deficiency model of rats.Methods Twenty-four SD rats aged 3 months without delivery were randomly divided into sham operation group and experimental group,with 12 rats in each group.After 12 weeks of modeling,the rats were killed and the vaginal walls were taken for analysis.Masson staining was used to observe the morphological and structural changes of collagen fibers in vaginal wall of rats.Immunohistochemical staining and Western blotting were used to detect the expression level of THBS1 protein.Results After 12 weeks of modeling,the uterine atrophy of experimental group was obvious,the increase of body mass was significantly higher than that of sham operation group,and the level of estradiol was significantly lower than that of sham operation group(P<0.01).Compared with the sham operation group,the upper cortex of vaginal wall of experimental group was significantly atrophy,the smooth muscle bundles were thinner,the muscle gap was wider,the collagen fiber deposition in lamina propria and muscle layer was increased,and the arrangement and distribution were disordered and fragmented.THBS1 expression in vaginal wall of experimental group was significantly higher than that of sham operation group(P<0.05).Conclusion Estrogen deficiency may mediate excessive fibrosis of vaginal wall by upregulating THBS1 expression,thereby damaging the biomechanical properties of vaginal wall and leading to an increased susceptibility to pelvic organ prolapse development.

Objective:To explore the methods of standardized residency training for internal medicine residents in the post-epidemic era, and to provide theoretical basis for improving and optimizing the standardized residency training.Methods:A total of 228 resident physicians from Batch 2017 to Batch 2019 were recruited, and a questionnaire survey was conducted to investigate their basic information, their attitudes and actions in facing the epidemic and the epidemic impact on the occupational planning and rotation plan. Original data of this study were exported through the questionnaire platform "Questionnaire Network", sorted out by Microsoft Excel, and plotted and analyzed by Origin software.Results:Residents of our hospital, socialized medical residents, other unit sponsor residents and combined professional masters willing to go to Hubei for medical support accounted for 100% (30 people), 86% (6 people), 84% (80 people) and 77% (72 people) respectively. Almost all of the residents were willing to learn the knowledge of COVID-19 and to educate the public (99%-100%). Eighty percent (24 people) of the residents of our hospital participated in anti-epidemic, while the proportion of other unit sponsor residents, socialized medical residents and combined professional masters were 46% (44 people), 14% (1 people) and 12% (11 people), respectively. Additionally, 97% (29 people) of our hospital residents, 89% (85 people) of other unit sponsor residents, 86% (6 people) of the socialized medical residents, and 82% (76 people) of the combined professional masters would still like to engage in the clinical work in the future. What's more, the resident physicians who thought that phylaxiology, epidemiology, general practice medicine, traditional Chinese medicine and critical care medicine should be strengthened to train accounted for 98% (221 people), 98% (221 people), 90% (203 people), 70% (158 people) and 60% (135 people) respectively.Conclusion:Most resident physicians have strong awareness and active actions in fighting against the epidemic. In the future, the standardized residency training of physicians should further strengthen the training of phylaxiology, epidemiology, general practice medicine, traditional Chinese medicine and critical care medicine.

Objective:To explore the effect of visual processing patterns on emotional face processing in patients with Alzheimer's disease (AD).Methods:From June 2020 to August 2021, twenty-two AD patients (AD group) who met the conditions of this study were selected from the memory impairment clinic of the First Affiliated Hospital of Anhui Medical University, and demographically matched twenty-one elderly healthy people (control group) were selected from the patients' family members and community residents. The two groups of subjects performed emotional face visual scanning and facial recognition experiments after completing the evaluation of the cognitive scale and eye movement data were recorded in the emotional face visual scanning task. Statistical analysis of the obtained results was performed using SPSS 23.0 Windows version software. The data that conformed to the normal distribution were tested by independent samples t-test and variance analysis, and the data that did not conform to the normal distribution were tested by nonparametric test. Results:(1)In the emotional face recognition task, the total accuracy of facial emotion recognition of AD patients(0.52(0.42, 0.59)) was lower than that of the normal control group(0.67(0.64, 0.69)), and the difference was statistically significant( Z=-4.023, P<0.01), which was mainly manifested in recognizing complex facial emotion. (2) In the emotional face visual processing task, the saccade count ((1.96±0.97), (2.50±0.44)), fixation count ((3.93±2.58), (6.37±2.08))and fixation time ((1 205.89±727.32)s, (1 761.38±525.54)s)of AD patients were lower than those of the control group( t=-2.314, -3.402, -2.880, all P<0.05), and the surrounding facial fixation time (384.95 (276.51, 587.78)s, 276.06 (190.03, 384.55)s) was higher than that of the control group( Z=-2.478, P=0.013). Patients with AD had a lower fixation count than that in the control group on the eye area of surprise ((3.76±2.90), (6.25±2.19)), anger ((4.48±2.72), (7.06±2.55)) and disgust ((4.10±2.45), (6.67±2.45)), and the differences were statistically significant ( t=-3.164, -3.207, -3.436, all P<0.05). Patients with AD had a lower fixation time than those of the control group on the eye area of surprise ((1 150.26±753.22)s, (1 779.91±551.66)s), angry ((1 430.85±869.52)s, (1 944.51±612.63)s) and disgust ((1 266.14±765.67)s, (1 898.33±676.02)s), and the differences were statistically significant ( t=-3.115, -2.247, -2.865, all P<0.05). (3) Spearman correlation analysis showed that the accuracy of overall emotional face recognition was positively correlated with the fixation time in the eye area in AD patients ( r=0.429, P<0.05). Conclusion:The impaired visual processing of AD patients causes emotional face recognition disorders. Therefore, AD patients have different visual processing patterns in emotional face processing than age-matched normal controls, mainly manifested as the decreased fixation on the eye area.

Objective:To investigate the blood pressure change in patients with acute ischemic stroke (AIS) and hypertension treated with cinepazide maleate injection.Methods:This was a subgroup analysis of post-marketing clinical confirmation study of cinepazide maleate injection for acute ischemic stroke: a randomized, double-blinded, multicenter, placebo-parallel controlled trial, which conducted in China from August 2016 to February 2019. Eligible patients fulfilled the inclusive criteria of acute anterior circulation ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores of 7-25. The primary endpoints were mean blood pressure of AIS patients treated with cinepazide maleate or control, which were assessed during the treatment period (14 days), and the proportion of the patients with normal blood pressure was analyzed after the treatment period. Furthermore, a subgroup analysis was performed to investigate a possible effect of the history of hypertension on outcomes.Results:This analysis included 809 patients with hypertension. There was no significant difference in patients blood pressure and the proportion of patients with normal blood pressure (60.5% vs. 59.0%, P>0.05) between cinepazide maleate group and control group. Conclusion:Administration of cinepazide maleate injection does not affect the management of clinical blood pressure in patients with AIS.

Objective:To investigate the significance of 12 inflammatory cytokines in early detection and treatment guidance of hematologic malignant patients with Cytokine release syndrome (CRS) after Chimeric antigen receptor (CAR)-T cell immunotherapy.Methods:A total of 12 patients, including 6 males and 6 females, aged 53.0 (49.8, 62.5) years old, were treated with CAR-T cell immunotherapy in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2020. Cytometric bead array was used to detect the serum levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, IFN-α, IFN-γ, and TNF-α at different time points after cell infusion in all patients receiving CAR-T cell immunotherapy. C-reactive protein (CRP), D-dimer (D-D), serum ferritin (SF), and lactate dehydrogenase (LDH) were measured at the corresponding period. CRS was classified into four grades according to the diagnostic criteria, from 0 to 3. The differences of the above mentioned parameters between the four groups were compared. The Speedman correlation coefficient was used to analyze the correlation between inflammatory cytokine expression levels and CRS grades. Plot the subject′s receiver operating characterist (ROC) curve to determine the sensitivity and specificity of inflammatory cytokines to predict CRS.Results:CRS grading was performed on day 1, 4, 7, and 11 after CAR-T cell infusion in 12 patients. There are 48 cases in total, including 25 cases of CRS grade 0, 6 cases of CRS grade 1, 9 cases of CRS grade 2, and 8 cases of CRS grade 3. The correlation analysis of 48 cases showed that the expression levels of IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-1β, and IL-8 were positively correlated with CRS grade ( P<0.05). The correlation coefficients were 0.384, 0.730, 0.632, 0.341, 0.681, 0.319, and 0.622, respectively. 7 inflammatory cytokines (IL-6, IL-10, IFN-γ, IL-8, IL-2, TNF-α, and IFN-α) were elevated in 12 patients, and the average time to start the rise was 3.4, 5.3, 6.1, 2.9, 4.3, 6.0 and 5.8 days, respectively. The time for CRP, D-D, SF, and LDH to begin to rise were 6.6, 7.6, 8.3 and 7.6 days, which were higher than that of the 7 inflammatory cytokines. After effective treatment, except for IL-6, the remaining 6 inflammatory cytokines (IL-10, IFN-γ, IL-8, IL-2, TNF-α and IFN-α) had their recovery times as 7.8, 3.9, 5.1, 8.0, 6.0, and 2.5 day,respectively, which were lower than that of CRP, D-D, SF, and LDH(9.7, 9.2, 13.7, and 13.8 days, respectively). The ROC showed that IL-6, IL-10, IFN-γ, and IL-8 can serve as biomarkers for diagnosis of CRS with high sensitivity and specificity. Conclusion:The monitoring of 12 inflammatory cytokines play an important role in CRS grading after CAR-T cell immunotherapy, which contributes to the early diagnosis of CRS and the prediction of clinical outcome.

BACKGROUND: Functional constipation (FC) is one of the most prevalent functional gastrointestinal disorders. Dissatisfaction with medications prescribed to treat FC may lead patients to seek alternative treatments. Numerous systematic reviews (SRs) examining the use of acupuncture to treat FC have reported inconsistent results, and the quality of these studies has not been fully evaluated. OBJECTIVE: In this overview, we evaluated and summarized clinical evidence on the effectiveness and safety of acupuncture for treating FC and evaluated the quality and bias of the SRs we reviewed. SEARCH STRATEGY: The search strategy was structured by medical subject headings and search terms such as "acupuncture therapy" and "functional constipation." Electronic searches were conducted in eight databases from their inception to September 2020. INCLUSION CRITERIA: SRs that investigated the effectiveness and safety of acupuncture for managing FC were included. DATA EXTRACTION AND ANALYSIS: Two authors independently extracted information and appraised the methodology, reporting accuracy, quality of evidence, and risk of bias using the following critical appraisal tools: (1) A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2); (2) Risk of Bias in Systematic Reviews (ROBIS); (3) Preferred Reporting Items for Systematic Reviews and Meta-analyses for Acupuncture (PRISMA-A); and (4) the Grading of Recommendations, Assessment, Development and Evaluations (GRADE). A κ index was used to score the level of agreement between the 2 reviewers. RESULTS: Thirteen SRs that examined the clinical utility of acupuncture for treating FC were identified. Using the AMSTAR 2 tool, we rated 92.3% (12/13) of the SRs as "critically low" confidence and one study as "low" confidence. Using the ROBIS criteria, 38.5% (5/13) of the SRs were considered to have "low risk" of bias. Based on PRISMA-A, 76.9% (10/13) of the SRs had over 70% compliance with reporting standards. The inter-rater agreement was good for AMSTAR 2, ROBIS, and PRISMA-A. Using the GRADE tool, we classified 22.5% (9/40) of the measured outcomes as "moderate" quality, 57.5% (23/40) as "low" quality, and 20.0% (8/40) as "very low" quality. The inter-rater agreement was moderate when using GRADE. Descriptive analyses indicated that acupuncture was more efficacious than sham acupuncture for improving weekly complete spontaneous bowel movements (CSBMs) and for raising the Bristol Stool Form Scale (BSFS) score. Acupuncture appeared to be superior to anti-constipation drugs for improving weekly spontaneous bowel movements, the total effective rate, and the Patient Assessment of Constipation Quality of Life score. Although ten SRs mentioned the occurrence of adverse events, serious adverse events were not associated with acupuncture treatment. CONCLUSION: Acupuncture may be more efficacious than sham acupuncture for improving CSBMs and BSFS scores and may be superior to anti-constipation drugs for improving bowel movement frequency, as well as quality of life. Limitations to current studies and inconsistent evidence suggest a need for more rigorous and methodologically sound SRs to draw definitive conclusions. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020189173.
Acupuncture Therapy ; Constipation/therapy* ; Humans ; Quality of Life ; Systematic Reviews as Topic