OBJECTIVES: To investigate the role of the calcium/calmodulin (CaM)-mediated activation of calcineurin (CN)-nuclear factor of activated T cells (NFAT) signaling pathway in mediating the regulatory effect of hyperforin (HY) on stress-induced depression-like disorder (DP) in mice. METHODS: C57BL/6J mice were randomly divided into control group, DP model group, and hyperforin treatment group (n=15). Behavioral changes of the mice were assessed using open field test (OFT), sucrose preference test (SPT), tail suspension test (TST), light/dark box test (LDB), and novel object suppression test (NSFT). Immunohistochemistry was used to detect tyrosine hydroxylase (TH) expression in the CA1 region of the hippocampus, and serum serotonin (5-HT) and norepinephrine (NA) levels were detected with ELISA. Western blotting was used to analyze the expressions of TNF-α, IL-1β, IL-2, and CN-NFAT pathway proteins. In cultured BV-2 microglial cells with lipopolysaccharide (LPS) stimulation, the effects of hyperforin and CN inhibitor (CNIS) on expressions of ionized calcium-binding adapter molecule 1 (IBA-1), 5-HT, NA, inflammatory cytokines and CN-NFAT pathway proteins were examined using immunofluorescence assay, ELISA or Western blotting. RESULTS: Compared with the control mice, the mice in DP group showed significantly reduced activity in OFT, decreased sucrose consumption in SPT, reduced shuttle crossing in LDB, and lowered food intake in NSFT with significantly increased immobility in TST. The mice with DP showed significantly decreased TH-positive neurons, lowered 5-HT and NA levels, and increased expressions of TNF-α, IL-1β, IL-2 and CaM-CN-NFAT pathway proteins. In cultured BV-2 cells, LPS stimulation strongly increased cellular IBA-1 expression, decreased the levels of neurotransmitters (5-HT and NA), and increased the levels of inflammatory cytokines and CN-NFAT signaling, and these changes were effectively reversed by treatment with hyperforin or CNIS. CONCLUSIONS Hyperforin improves stress-induced depression-like behaviors in mice and activated BV-2 cells by targeting the CN-NFAT signaling pathway.
Animals ; Mice, Inbred C57BL ; Mice ; Microglia/drug effects* ; Depression/etiology* ; Perylene/pharmacology* ; Calcineurin/metabolism* ; NFATC Transcription Factors/metabolism* ; Calcium Signaling/drug effects* ; Stress, Psychological ; Phloroglucinol/pharmacology* ; Signal Transduction ; Male ; Behavior, Animal/drug effects* ; Terpenes

BACKGROUND:Talus cartilage injury is a common motor system disease.This type of injury will affect the patient's daily life and work ability,and may worsen the condition if left untreated.Surgical treatment is commonly used,but the selection of surgical methods and the evaluation of medium-and long-term follow-up results have always been difficult clinical problems. OBJECTIVE:To explore the influence of T1ρ technique on the range of quantitative evaluation of talus osteochondral injury on the choice of surgical method and the results of medium-and long-term follow-up. METHODS:A total of 154 patients with osteochondral injury of talus admitted to The Second Hospital of Tangshan from January 2019 to August 2022 were retrospectively selected as the study subjects.The lesion site of talus was examined by MRI before operation,and the T1ρ and T2 values of different types were compared.Different surgical methods were selected according to the different T1ρ values.Group A(n=73)was treated with microfracture surgery with T1ρ<45 ms;group B(n=81)was treated with autogenous bone and cartilage transplantation with T1ρ≥45 ms.The general clinical characteristics and curative effects of patients under different surgical methods were compared;the important factors of postoperative recurrence were analyzed by multivariate Logistic regression,and the relationship between T1ρ value and postoperative recurrence was analyzed by restricted cubic spline graph,y=1-1/(1+e-z)regression equation to build a prediction model.The stability of the model was verified by cross-checking method. RESULTS AND CONCLUSION:(1)Classification of talus osteochondral injury in 154 patients(type Ⅰ:36 cases;type Ⅱ:37 cases;type Ⅲ:40 cases;type Ⅳ:41 cases),T1ρ and T2 values of the four groups were statistically significant(P<0.05);pairwise comparison was also statistically significant(all P<0.05).(2)After treatment of 154 patients,7 cases(4.6％)had local swelling,3 cases(2.0％)had pain aggravation,and 5 cases(3.3％)had wound infection.There were 2 cases(1.3％)with poor cartilage healing.(3)After treatment,there were statistically significant differences between groups A and B in terms of American Orthopaedic Foot&Ankle Society score,visual analog scale score,plantar flexor motion range,dorsoextension motion range,subchondral bone marrow edema volume,interleukin-6,interleukin-8,C-reactive protein,procalcitonin,platelet-derived growth factor,transforming growth factor-β1,and efficacy(P<0.05).The total effective rate of group B(90％)was higher than that of group A(85％)(P<0.05).(4)Age(OR=1.589,95％CI:0.305-1.252,P=0.036),interleukin-6(OR=1.737,95％CI:0.974-5.254,P=0.049),interleukin-8(OR=1.385,95％CI:1.066-4.355,P=0.034),C-reactive protein(OR=1.957,95％CI:1.323-2.178,P=0.035),transforming growth factor-β1(OR=1.459,95％CI:0.897-2.455,P=0.038),T1-ρ(OR=1.687,95％CI:0.854-3.321,P=0.026),T2(OR=1.843,95％CI:0.657-2.454,P=0.036),complications(OR=1.719,95％CI:0.654-3.464,P=0.019),and classification of osteochondral injury of talus(OR=3.789,95％CI:1.023-5.897,P=0.028)were independent risk factors for postoperative recurrence.Microfracture surgery(OR=0.751,95％CI:0.321-1.264,P=0.012)and autogenous bone and cartilage grafting(OR=0.649,95％CI:0.246-1.356,P=0.023)were independent protective factors for recurrence after medium-and long-term follow-up.(5)When T1ρ value≤35 ms,the risk of postoperative recurrence decreased rapidly,and when T1ρ value>35 ms,the risk of postoperative recurrence increased rapidly.(6)Further stepwise regression analysis showed that these nine risk factors were most closely associated with postoperative recurrence,and the formula for postoperative recurrence was obtained.The probability of postoperative recurrence was calculated using the regression equation.When P=0.75,the maximum value of Jorden index was 77.728,indicating that the model has a better prediction effect.(7)It is indicated that the quantitative evaluation of T1ρ before operation can effectively guide the selection of surgical methods,improve the success rate of surgery and the quality of life of patients.

Objective Non-compliance of active treatments occurred in clinical trials is usually unavoidable,and improper use of standard approaches may lead to biased results,especially for non-inferiority trials.Thus,for three-arm non-inferiority clinical trials,we established a Bayes causal model to estimate causal effects in the presence of non-compliance.Methods Based on the framework of principal stratification,population was stratified according to types of compliance,and the issue was transformed into mixed-distribution identification.Bayes causal model was constructed and data augmentation(DA)algorithm were employed to calculate the posterior distribution of parameters of interest and complete statistical inference.Through simulation,we evaluated performances of our approach,compared with traditional methods including ITT,PP and AT.Results The method of ITT,PP,and AT all had a significant bias when the type of compliance associated with outcomes.The method proposed in this study both had a good performance whether the type of compliance associated with outcomes or not.Conclusion For non-inferiority trials with a high proportion of non-compliance,the method in this article has a better control of the bias.

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.
Humans ; Mycophenolic Acid/adverse effects* ; Azathioprine/adverse effects* ; Tacrolimus/therapeutic use* ; Lupus Nephritis/complications* ; Immunosuppressive Agents ; Treatment Outcome ; Recurrence

Objective:To investigate the effects of rituximab on lymphocytes and immunoglobulin in the treatment of focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD).Methods:The subjects were FSGS and MCD patients admitted to Ruijin Hospital affiliated to Shanghai Jiaotong University on July 1, 2014 and July 1, 2019. All the enrolled patients were confirmed by clinical examination and renal biopsy, and received rituximab treatment (4 infusions of 375 mg/m 2 with the interval of 7-14 d). The levels of immunoglobulin IgA, IgG, IgM, and lymphocytes of CD19 +, CD20 +, CD3 +, CD3 +CD4 +, CD3 +CD8 + and natural killer cells (CD56 +CD16 +) were compared between baseline and the third month, the sixth month, the ninth month and the twelfth month after treatment. Results:Ninety-six patients with FSGS or MCD were enrolled in this study. The midian age was 28 years old (14-77 years old). The ratio of men to woman was 1.8∶1. There were 65 cases of MCD and 31 cases of FSGS. After rituximab treatment, the 24 h-proteinuria was significantly lower than that before treatment, and the serum albumin level was increased (both P<0.05). After rituximab treatment of 3 months, 6 months, 9 months and 12 months, CD19 + and CD20 + lymphocyte counts were significantly decreased (all P<0.01), and gradually recovered after 6 months. Compared with baseline, at 3, 6, 9, 12 months after rituximab treatment, the level of blood IgG was significantly increased ( P=0.004,<0.001,<0.001,<0.001, respectively), and the level of blood IgM was significantly decreased ( P<0.001, =0.008, =0.005,<0.001, respectively) but the median level still within the normal range (400-3 450 mg/L). The level of blood IgA was not significantly changed (all P<0.05). T lymphocytes (CD3 +, CD3 +CD4 + and CD3 +CD8 +) and natural killer cells (CD56 +CD16 +) showed no significant difference from baseline (all P>0.05). Conclusions:Rituximab can effectively eliminate CD19 + and CD20 + lymphocytes, and has little influence on peripheral blood lymphocyte count and immunoglobulin level except CD19 + and CD20 + lymphocytes. The standard administration of rituximab is safe for patients with FSGS and MCD.

Objective    To compare the 5-year survival rates between two different follow-up patterns of postoperative stage Ⅰ-ⅢA non-small cell lung cancer (NSCLC) patients. Methods    Pathological stage Ⅰ-ⅢA NSCLC 11 958 patients who underwent surgical resection and received follow-up within 6 months after initial diagnosis through telephone follow-up system were included in nine hospitals from July 2014 to July 2020. The patients were divided into two groups including a proactive follow-up group (n=3 825) and a passive follow-up group (n=8 133) according to the way of following-up. There were 6 939 males and 5 019 females aged 59.8±9.5 years. The Kaplan-Meier and Cox proportional hazards regression model were used. Results    The median follow-up frequency was 8.0 times in the proactive follow-up group and 7.0 times in the passive follow-up group. The median call duration was 3.77 minutes in the proactive follow-up group and 3.58 minutes in the passive follow-up group. The 5-year survival rate was 81.8% and 74.2% (HR=0.60, 95CI 0.53-0.67, P<0.001) in the proactive follow-up group and the passive follow-up group, respectively. Multivariate analysis showed that follow-up pattern, age, gender and operation mode were independent prognostic factors, and the results were consistent in all subgroups stratified by clinical stages. Conclusion    The proactive follow-up leads to better overall survival for resected stage Ⅰ-ⅢA NSCLC patients, especially in the stage ⅢA.

Objective To evaluate the diagnostic value of one-stop cardiac CT (stress dynamic CT-MPI combining with CTA) in CAD. Methods Thirty patients underwent CCTA combined with stress dynamic CT-MPI and stress SPECT-MPI including 16 patients underwent ICA were retrospectively enrolled. All procedures were performed within 2 weeks without related treatment. CT-MPI and SPECT-MPI were evaluated visually and MBF was quantified according to dynamic CT-MPI which was compared through paired t test. The diagnostic value of CT-MPI for myocardial ischemia was evaluated with SPECT-MPI as the reference standard. The consistency between the two techniques was determined by Kappa test. With SPECT combined with ICA as the reference standard, we evaluated the value of CT-MPI and its combination with CCTA in the diagnosis of CAD with hemodynamic stenosis. Results On stress CT-MPI, 19 of 30 patients and 52 segments were evaluated with myocardial perfusion defects. There was a significant difference in MBF values between normal[(117.61±29.82)ml·100 ml-1·min-1] and hypoperfused [(80.60±22.15)ml·100 ml - 1 · min - 1] segments (t=15.764,P<0.001). With SPECT as reference standard, the sensitivity, specificity were 94.12% (32/34), 95.80% (456/476) on the vessel basis. The Kappa value of the two examinations was 0.772(P<0.001). As for the 16 patients who also underwent ICA, 15 patients with 22 vessel-areas had hemodynamic stenosis on CT-MPI. Compared with SPECT combined with ICA, the sensitivity, specificity for detecting hemodynamic stenosis were 92.31% (12/13), 71.43% (25/35) for CT-MPI;100%(13/13), 51.43%(18/35) for CTA and 92.31%(12/13), 82.86%(29/35) for CT-MPI combined with CTA, respectively. Moderate correlation was observed between the combination of CT-MPI and CCTA and reference standard (r=0.690,P<0.001). Conclusion Stress dynamic CT-MPI can detect myocardial perfusion defects and hemodynamic changes and improves the diagnostic ability of functional stenosis of CAD combined with CTA, which can finally achieve the one-stop mode of cardiac CT in CAD.

Objective To analyze the clinicopathological characteristics of renal lesions in type 2 diabetic patients and to differentiate diabetic nephropathy (DN) from non-diabetic renal diseases (NDRD).Methods Type 2 diabetic patients who received renal biopsy in Ruijin Hospital from January 2011 to December 2015 were recruited in this study. Clinical history, laboratory results and pathological data were retrospectively collected. According to the pathological findings, the patients were divided into 3 groups: DN, NDRD, DN+NDRD. Logistic model was applied to explore the independent clinical predictive factors in differentiating DN from NDRD. Results A total of 207 type 2 diabetic patients received renal biopsy, accounting for 6.82% of all biopsy population. Fifty-one patients were diagnosed with DN, 142 with NDRD and 14 with both DN and NDRD. In NDRD, membranous nephropathy(MN) (34.5%) was the most common finding, followed by IgA nephropathy(19.7%).By contrast, NDRD patients manifested a shorter diabetic course, a higher baseline hemoglobin level, a lower baseline serum creatinine, a higher prevalence of hematuria, a lower prevalence of hypertension and diabetic retinopathy, a better control of blood glucose, better compliance of monitoring blood glucose and less family history of diabetes. In multivariate logistic model, diabetic family history(OR=4.68, P=0.04) and long history of diabetes(OR=1.01, P=0.02) were risk factors of DN. Conclusion There is a high prevalence of NDRD in diabetic patients with renal lesions. Family history of diabetes and duration of diabetes are independent predictors of DN.

Establishment of quality management system (QMS) plays a critical role in the clinical data management (CDM). The objectives of CDM are to ensure the quality and integrity of the trial data. Thus, every stage or element that may impact the quality outcomes of clinical studies should be in the controlled manner, which is referred to the full life cycle of CDM associated with the data collection, handling and statistical analysis of trial data. Based on the QMS, this paper provides consensus on how to develop a compliant clinical data management plan (CDMP). According to the essential requirements of the CDM, the CDMP should encompass each process of data collection, data capture and cleaning, medical coding, data verification and reconciliation, database monitoring and management, external data transmission and integration, data documentation and data quality assurance and so on. Creating and following up data management plan in each designed data management steps, dynamically record systems used, actions taken, parties involved will build and confirm regulated data management processes, standard operational procedures and effective quality metrics in all data management activities. CDMP is one of most important data management documents that is the solid foundation for clinical data quality.

This paper is prepared to discuss the common issues in data management, such as building and training of data management team, standard operation procedure, document management, execution and communication, strategies to correct and prevent mistakes, and measures to improve the quality and efficiency of clinical trials and data management.