ObjectiveTo investigate the recurrence of ischemic stroke (IS) and to analyze the association between four indices of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) and the risk of IS recurrence by analyzing the follow-up data related to IS in the community-based natural population of Songjiang District, Shanghai, so as to provide a scientific basis for improving the prognosis of stroke patients in the community and controlling IS recurrence. MethodsA prospective follow-up study was conducted among the IS patients in the community-based cohort population, collecting data about patient’s age, gender, disease history, biochemical indicators, and etc. Cox regression model and restricted cubic spline model were used to analyze the relationship between different levels of plasma lipids and the recurrence of IS in these patients. ResultsA total of 1 368 patients with IS were included. The total follow-up duration was 7 171.46 person-years, with a median follow-up time of 6.24 years. There were 420 cases of IS recurrence, resulting in a cumulative recurrence rate of 30.70%. The results of multivariate Cox regression analysis showed that the recurrence risk of IS was reduced when the baseline TC and LDL-C levels of IS patients were in the ranges of 4.65‒5.67 mmol·L^-1 and 2.52‒3.46 mmol·L^-1, respectively. The results of restricted cubic spline analysis showed a U-shaped relationship between baseline TC and LDL-C levels and the recurrence risk in IS patients. ConclusionThe cumulative recurrence rate of patients with IS in the community of Songjiang District in Shanghai is high, and the levels of TC and LDL-C at baseline survey are correlated with the recurrence of IS in these patients. It is suggested to pay more attention to the levels of LDL-C and TC in patients with IS, so as to improve the prognosis.

BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To study the anti-osteoporotic effect of different concentrations of hesperidin on ovariectomized rat model of osteoporosis(Ovariectomy,OVX)by reducing inflammatory molecules and oxidative stress response mechanism and the relationship between hesperidin and dose.Methods SD female rats were randomly divided into OVX group and Sham group,and OVX operation and sham operation were performed respectively.OVX group was randomly divided into 5 groups with 6 rats in each group,and 6 rats in Sham group were randomly selected as normal control group.They were Sham group(Sham rats+1%CMC suspension),control group(OVX rats+1%CMC suspension),HP1 group(OVX rats+5 mg·kg-1 HP),HP2 group(OVX rats+10 mg·kg-1 HP),HP3 group(OVX rats+20 mg·kg-1 HP)and AN group(OVX rats+2.5 mg·kg-1 AN).After 4 weeks of ovariectomized or sham operation,the drug was given by oral administration every morning for 10 weeks.After 10 weeks of administration,the change of body weight of rats was measured.Before the rats were killed,the serum of abdominal aorta was obtained and placed in the specimen cabinet at-20℃,the levels of Ca2+ and P5+,the levels of inflammatory factors TNF-α,IL-6 and IL-1β,and the levels of periosseous transition markers ALP,ACP,β-CTx and OC were also measured.After the rats were killed,the left femur was also placed in the specimen cabinet at-20℃.After treatment,the levels of oxidative stress factor TRARS and antioxidant enzymes GSH,GST,GR,GPx and CAT in the left femur were measured,and the bone mineral density,Young's modulus,maximum load,energy absorption and maximum stress in the middle part of the left femur were measured,and the expression level of SIRT1 gene was obtained.Results Compared with the control group,after 10 weeks of treatment with different concentrations of HP,the weight gain was significantly reduced(P<0.001),the levels of Ca2+ and P5+ in OVX rats were significantly decreased(P<0.001),and the levels of periosseous transition markers ALP,ACP,β-CTx and OC were significantly decreased(P<0.001).It significantly increased bone mineral density,Young's modulus,maximum load,energy absorption,maximum stress and stiffness(P<0.001),significantly decreased the level of OVX-induced thiobarbituric acid reactive substances and increased the levels of antioxidant enzymes GSH,GST,GR,GPx and CAT(P<0.001),and significantly decreased the levels of inflammatory molecules TNF-α,IL-6 and IL-1β(P<0.001).The expression level of SIRT1 gene was significantly decreased(P<0.001).Compared with the control group,the above parameters in the high concentration HP group were significantly different from those in the control group(P<0.001).Conclusion It is suggested that hesperidin can inhibit osteoporosis by reducing pro-inflammatory cytokines and oxidative stress in ovariectomized rats in a concentration-dependent manner.

Objective: : Ischemia and hemorrhage of pituitary adenomas (PA) caused important clinical syndrome. However, the differences on clinical characteristics and surgical outcomes between these two kinds apoplexy were less reported. Methods: : A retrospective analysis was made of patients with pituitary apoplexy between January 2013 and June 2018. Baseline and clinical characteristics before surgery were reviewed. All patients underwent transsphenoidal surgery and were followed up at least 1 year. Results: : Total 67 cases (5.8%) among 1147 pituitary tumor patients were enrolled, which consisted of 28 (~2.4%) ischemic PA and 39 (~3.4%) hemorrhagic PA. There were more male patients in the ischemic group compared with hemorrhagic group (78.6% vs 53.8%, p=0.043). However, the mean age, tumor size and functional tumor ratio were significant higher in the hemorrhagic group. Headache was more common in ischemic PA (82.1%) than that of hemorrhagic PA (51.3%, p=0.011). Magnetic resonance imaging findings found that mucosal thickening and enhancement of the sphenoid sinus was observed in 15 ischemic PA patients (n=27, 55.6%), but none in patients with hemorrhagic PA (n=38, p<0.0001). It was worth noting that the rate of pre-surgical hypopituitarism in ischemic PA patients were seemed higher than that in hemorrhagic PA patients, but not significant. The two groups got a total tumor resection rate at 94.1% and 92.9%, independently. No significant difference on the operative time, blood loss in operation and complications in perioperative period was observed in two groups. After operation, cranial nerve symptoms recovered to normal at 81.8% of ischemic PA patients and 82.6% of hemorrhagic PA patients. Importantly, the incidence of postoperative hypopituitarism partially decreased in both groups, among which the rate of hypothyroidism in ischemic PA patients significantly decreased from 46.4% to 18.5% (p=0.044). Conclusion : Patients with ischemic PA presented different clinical characteristics to the hemorrhagic ones. Transsphenoidal surgery should be considered for the patients with neuro-ophthalmic deficits and might benefit for pituitary function recovery of the apoplectic adenoma patients, especially pituitary thyroid axis in ischemic PA patients.

Objective:To detect the abnormal changes of myocardial blood perfusion in patients with hypertrophic cardiomyopathy (HCM) by myocardial contrast echocardiography(MCE) combined with exercise stress test.Methods:Twenty-seven patients with clinically diagnozed of asymmetric HCM in Fuwai Central China Cardiovascular Hospital from May 2020 to April 2021 were selected as the HCM group, and 29 healthy subjects during the same period were selected as the control group. All patients underwent routine echocardiography, resting and exercise stress MCE. The myocardial perfusion parameters of each segment of interventricular septum in the 2 groups were quantitatively analyzed: the peak plateau intensity (A value), ascending slope of the curve(β value) and value of A×β. According to the end-diastolic myocardial thickness, the interventricular septum of the HCM group was divided into hypertrophic and non-hypertrophic segments, and the myocardial contrast parameters of the interventricular septum of the study group were compared with those of the control group. The myocardial blood flow reserve value of the two groups were calculated, and the correlation of myocardial blood flow reserve value with left ventricular mass index (LVMI) and left ventricular remodeling index (LVRI) were analyzed.Results:No matter at rest or under stress, the A value, β value and A×β value of ventricular septal hypertrophic and non-hypertrophic segments in the hypertrophic cardiomyopathy group were lower than those in the control group, and the differences were statistically significant (all P<0.05). Under stress, the A value, β value and A×β value of interventricular septal hypertrophic segments were lower than those in non-hypertrophic segments in the HCM group, and the differences were statistically significant (all P<0.05). The myocardial blood flow reserve in the HCM group was negatively correlated with LVMI and LVRI( r=-0.899, -0.676; all P<0.001). Conclusions:In patients with HCM under resting and exercise stress, microcirculation disorders were found in both hypertrophic and non-hypertrophic segments of the ventricular wall, and the myocardial blood flow reserve was negatively correlated with LVMI and LVRI.

Objective: Chronic graft-versus-host disease (cGVHD) is a major long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . It is important to study the changes of serum biomarkers expression in patients for early diagnosis and treatment. Methods: The expression levels of five serum protein markers (IL-1b, IL-16, CXCL9, CCL19, CCL17) in patients with or without cGVHD after allo-HSCT were detected by liquid suspension microarray. Results: Compared with the control group without cGVHD, the expression levels of CXCL9 and CCL17 in serum of patients with cGVHD were significantly increased (P<0.05) . CCL17 was correlated with the severity of cGVHD (P<0.001) . CXCL9 was significantly increased in the serum of patients with skin lesion (P<0.01) , and CCL17 was significantly expressed in cGVHD patients with liver as the target organ (P<0.01) . Conclusion: The combination of CXCL9 and CCL17 can be used as serum biomarkers of cGVHD, which has certain reference value in assisting the diagnosis and evaluation of cGVHD severity.
Biomarkers ; Chronic Disease ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Transplantation, Homologous

Objective: Chronic graft-versus-host disease (cGVHD) is a major long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . It is important to study the changes of serum biomarkers expression in patients for early diagnosis and treatment. Methods: The expression levels of five serum protein markers (IL-1b, IL-16, CXCL9, CCL19, CCL17) in patients with or without cGVHD after allo-HSCT were detected by liquid suspension microarray. Results: Compared with the control group without cGVHD, the expression levels of CXCL9 and CCL17 in serum of patients with cGVHD were significantly increased (P<0.05) . CCL17 was correlated with the severity of cGVHD (P<0.001) . CXCL9 was significantly increased in the serum of patients with skin lesion (P<0.01) , and CCL17 was significantly expressed in cGVHD patients with liver as the target organ (P<0.01) . Conclusion The combination of CXCL9 and CCL17 can be used as serum biomarkers of cGVHD, which has certain reference value in assisting the diagnosis and evaluation of cGVHD severity.

Objective: To understand the seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China. Methods: This was a retrospective study which involved patients hospitalized for asthma exacerbation in 29 hospitals throughout 7 geographic areas in the mainland of China (northeast, north, central, east, south, northwest and southwest). The numbers of asthmatic patients and total inpatients of the respiratory department of each hospital were recorded. The monthly ratio of asthmatic patients to the total inpatients in every area was calculated and compared. Results: During the study period, 6 480 patients were admitted for asthma exacerbation, accounting for 3.14% of all the 206 135 patients admitted to the respiratory departments in the 29 hospitals. The ratio of asthmatic patients to total inpatients in the northeast area (5.61%) was highest, and the ratio in east area was lowest (1.97%). Statistical analysis showed that the difference among different areas was significant (P<0.000 1). In most areas, both the number and proportion of hospitalized asthmatic patients peaked in spring (February-April) and autumn (September-October). In the northeast area, east area and south area, the peaks in spring were more obvious, while in the north area and southwest area, the peaks in autumn were more obvious. In the northwest area the peaks occurred in winter (December-January) and summer (June-August), respectively. The differences in hospitalization due to asthma among different months were significant in the northeast, north, and southwest areas (P<0.005). Conclusion: The number of patients hospitalized for asthma exacerbation fluctuated with season in different areas in China. In most areas, more asthmatic patients were admitted to hospitals in spring and autumn.
Asthma ; China/epidemiology* ; Hospitalization/statistics & numerical data* ; Humans ; Retrospective Studies ; Seasons

Objective    To compare the effects of transthoracic device closure and surgical closure on ventricular septal defect systemically. Methods    A systematic literature search was conducted using the PubMed, EMbase, The Cochrane Library, VIP, CNKI, CBM, Chinese Clinical Trial Register, ClinicalTrials. gov and Wanfang Database up to July 31, 2016. Quality was assessed and data of included articles were extracted. The meta-analysis was conducted using RevMan 5.0 and Stata 14.0 software. Results    Eleven studies were identified, including 5 RCTs and 6 cohort studies involving 2 504 patients. For success rate, there was no statistical difference between the transthoracic closure group and the surgical closure group in RCT (RR=0.99, 95%CI 0.96 to 1.03, P=0.70); the success rate in the transthoracic closure group was lower than that in the surgical closure group in the cohort study (OR=0.21, 95%CI 0.08 to 0.55, P=0.002). Both  results of RCTs and cohort studies showed that compared with surgical closure, transthoracic device closure reduced duration of the operation (RCT MD=–79.38, 95%CI –95.00 to –63.76, P<0.000 01; cohort study MD=–66.26, 95%CI –71.20 to –61.31, P<0.000 01) and hospital stay (RCT MD=–2.10, 95%CI –2.65 to –1.55, P<0.000 01; cohort study MD=–3.99, 95%CI –6.03 to –1.94, P=0.000 1), and the patients with blood transfusion (RCT RR= 0.04, 95%CI 0.01 to 0.11, P<0.000 01; cohort study OR=0.01, 95%CI 0.00 to 0.13, P=0.001). In the transthoracic closure group the risk of postoperative arrhythmia reduced (RCT RR=0.20, 95%CI 0.13 to 0.32, P<0.000 01; cohort study OR=0.46, 95%CI 0.31 to 0.67, P<0.000 1). In the transthoracic closure group a higher postoperative valvular regurgitation risk in RCT induced (RR=1.45, 95%CI 1.07 to 1.96, P=0.02) and the rate of postoperative valvular regurgitation in cohort study reduced (OR=0.43, 95%CI 0.20 to 0.92, P=0.03). However, there was no statistical difference in postoperative residual shunt (RCT RR=0.96, 95%CI 0.57 to 1.62, P=0.89; cohort study OR=0.52, 95%CI 0.12 to 2.25, P=0.38). Conclusion    Transthoracic device closure can shorten duration of the operation, hospital stay and reduce the patients with blood transfusion and post- and intraoperative arrhythmia risk. Therefore, transthoracic device closure may be a better approach for some ventricular septal defect patients.