2018年 · 第131卷第17期

Background: There was still conflict on the antithrombotic advantage of ticagrelor versus clopidogrel among East Asian population with acute coronary syndrome (ACS). We considered that the baseline bleeding risk might be an undetected key factor that significantly affected the efficacy of ticagrelor. Methods: A total of 20,816 serial patients who underwent percutaneous coronary intervention (PCI) from October 2011 to August 2014 in the General Hospital of Shenyang Military Region were enrolled in the present study. Patients receiving ticagrelor or clopidogrel were further subdivided according to basic bleeding risk. The primary outcome was net adverse clinical events (NACEs) defined as major adverse cardiac or cerebral events (MACCE, including all-cause death, myocardial infarction, ischemia-driven target vessel revascularization, or stroke) and any bleeding during 1-year follow-up. Comparison between ticagrelor and clopidogrel was adjusted by propensity score matching (PSM). Results: Among the 20,816 eligible PCI patients who were included in this study, there were 1578 and 779 patients in the clopidogrel and ticagrelor groups, respectively, after PSM, their clinical parameters were well matched. Patients receiving ticagrelor showed comparable NACE risk compared with those treated by clopidogrel (5.3% vs. 5.1%, P = 0.842). Furthermore, ticagrelor might reduce the MACCE risk in patients with low bleeding risk but increase MACCE in patients with moderate-to-high bleeding potential (ticagrelor vs. clopidogrel, low bleeding risk: 2.5% vs. 4.9%, P = 0.022; moderate-to-high bleeding risk: 4.8% vs. 3.0%, P = 0.225; interaction P = 0.021), with vast differences in all bleeding (low bleeding risk: 1.5% vs. 0.8%, P = 0.210; moderate-to-high bleeding risk: 4.8% vs. 3.0%, P = 0.002; interaction P = 0.296). Conclusion: Among real-world Chinese patients with ACS treated by PCI, ticagrelor only showed superior efficacy in patients with low bleeding risk but lost its advantage in patients with moderate-to-high bleeding potential.

Background: Coronary calcification is a major determinant of stent underexpansion and subsequent adverse events. This study aimed to evaluate the acute- and long-term outcomes of rotational atherectomy (RA) followed by cutting balloon (CB) versus plain balloon before drug-eluting stent implantation for calcified coronary lesions. Methods: From June April 2013 to March 2016, a total of 127 patients with moderately or severely calcified coronary lesions were treated with RA. Patients were divided into two groups according to the balloon type after RA: RA+CB group (n = 75) and RA+plain balloon group (n = 52). Minimal lumen diameter and acute lumen gain were analyzed by quantitative coronary angiography. In-hospital and long-term (>1 year) outcomes were recorded. Multivariate Cox regression analysis was performed to determine the independent predictors of in-stent restenosis. Results: The mean age of the patients was 65.5 years, and 76.4% were men. Total lesion length and minimal lumen diameter at baseline were similar in the two groups. After RA and balloon dilation, the lumen diameter was significantly larger in the RA+CB group than in the RA+plain balloon group (1.57 ± 0.46 mm vs. 1.10 ± 0.40 mm, t = 4.123, P < 0.001). The final lumen diameter was also larger in the RA+CB group compared to that in the RA group (2.81 ± 0.41 mm vs. 2.60 ± 0.25 mm, t = 2.111, P = 0.039). Moreover, patients receiving RA and CB tended to have larger final lumen gain (2.15 ± 0.48 mm vs. 1.95 ± 0.47 mm, t = 1.542, P = 0.132). Multivariate Cox regression analysis indicated that the strategy of RA+CB was a significant protective factor against long-term (>1 year) in-stent restenosis (hazard ratio: 0.136, 95% confidence interval: 0.020–0.936, P = 0.043). Conclusions: In patients with moderately or severely calcified lesions, a strategy of RA followed by CB before stent implantation can increase lumen diameter and acute lumen gain. This strategy is safe with lower risk of long-term in-stent restenosis.

Background: The impact of fasting plasma glucose (FPG) on survival outcomes in patients with acute heart failure (HF) is unclear, and the relationship between intensity of glycemic control of FPG in diabetes mellitus (DM) patients and HF prognosis remains uncertain. This retrospective study aimed to evaluate the prognostic impact of FPG in patients with acute HF. Methods: A total of 624 patients hospitalized with acute HF from October 2000 to April 2014 were enrolled in this study. All patients were stratified by three groups according to their admission FPG levels (i.e., DM, impaired fasting glucose [IFG], and non-DM). All-cause and cardiovascular mortality was the primary end point, and HF re-hospitalization was the secondary end point during follow-up period. Results: A total of 587 patients were included in final analysis. The all-cause mortality rates of patients with DM, IFG, and non-DM were 55.5%, 40.3%, and 39.2%, with significant difference (P = 0.001). Moreover, compared with those with IFG (34.3%) and non-DM (32.6%), patients with DM had significantly higher rate of cardiovascular mortality (45.1%). Multiple Cox regression analysis showed that DM as well as IFG was related to all-cause mortality (DM: hazard ratio [HR] = 1.936, P < 0.001; IFG: HR = 1.672, P = 0.019) and cardiovascular mortality (DM: HR = 1.739, P < 0.001; IFG: HR = 1.817, P = 0.013). However, they were both unrelated to HF re-hospitalization. DM patients with strictly controlled blood glucose (FPG <3.9 mmol/L) had higher all-cause mortality than patients with non-DM, IFG, and DM patients with moderately controlled glucose (3.9 mmol/L≤ FPG <7.0 mmol/L). Likewise, both the primary end point and secondary end point were found to be worse in DM patients with poorly controlled blood glucose (FPG ≥7.0 mmol/L). Conclusions: IFG and DM were associated with higher all-cause mortality and cardiovascular mortality in patients with acute HF. The association between mortality and admission FPG in DM patients with acute HF appeared U-shaped.

Background: Mounts of studies have shown that low estimated glomerular filtration rate (eGFR) is associated with increased risk of adverse outcomes in patients with coronary artery disease. However, high level of eGFR was less reported. In the study, we aimed to explore the relationship between the baseline eGFR, especially the high level, and contrast-induced acute kidney injury (CI-AKI) in a Chinese population who underwent an emergency percutaneous coronary intervention (PCI). Methods: Patients who underwent an emergency PCI from 2013 to 2015 were enrolled and divided into five groups as eGFR decreasing. Baseline characteristics were collected and analyzed. The rates of CI-AKI and the composite endpoint (including nonfatal myocardial infarction, revascularization, stroke, and all-cause death) at 6- and 12-month follow-up were compared. Logistic analysis for CI-AKI was performed. Results: A total of 1061 patients were included and the overall CI-AKI rate was 22.7% (241/1061). The separate rates were 77.8% (7/9) in Group 1 (eGFR ≥120 ml·min−1·1.73 m−2), 26.0% (118/454) in Group 2 (120 ml·min−1·1.73 m−2> eGFR ≥90 ml·min−1·1.73m−2), 18.3% (86/469) in Group 3 (90 ml·min−1·1.73 m−2> eGFR ≥60 ml·min−1·1.73 m−2), 21.8% (26/119) in Group 4 (60 ml·min−1·1.73 m−2> eGFR ≥30 ml·min−1·1.73 m−2), and 40.0% (4/10) in Group 5 (eGFR <30 ml·min−1·1.73 m−2), with statistical significance (χ2 = 25.19, P < 0.001). The rates of CI-AKI in five groups were 77.8%, 26.0%, 18.3%, 21.8%, and 40.0%, respectively, showing a U-typed curve as eGFR decreasing (the higher the level of eGFR, the higher the CI-AKI occurrence in case of eGFR ≥60 ml·min−1·1.73 m−2). The composite endpoint rates in five groups were 0, 0.9%, 2.1%, 6.7%, and 0 at 6-month follow-up, respectively, and 0, 3.3%, 3.4%, 16.0%, and 30.0% at 12-month follow-up, respectively, both with significant differences (χ2 = 16.26, P = 0.009 at 6-month follow-up, and χ2 = 49.05, P < 0.001 at 12-month follow-up). The logistic analysis confirmed that eGFR was one of independent risk factors of CI-AKI in emergency PCI patients. Conclusions: High level of eGFR might be associated with increased risk of CI-AKI in patients with emergency PCI, implying for future studies and risk stratification in clinical practice.

Background: Wheat-dependent, exercise-induced anaphylaxis (WDEIA) is an allergic reaction induced by intense exercise combined with wheat ingestion. The gold standard for diagnosis of WDEIA is a food exercise challenge; however, this test is unacceptable for Chinese WDEIA patients and unable to be approved by the Ethics Committee of Chinese hospitals due to substantial risk. There are no diagnostic criteria for Chinese WDEIA patients. The aim of present study was to propose new practical diagnosis criteria for Chinese WDEIA patients. Methods: We prospectively included 283 clinically diagnosed WDEIA patients from January 1, 2010 to June 30, 2014, and in the meanwhile, three groups were enrolled which included 133 patients with the history of anaphylaxis induced by food other than wheat, 186 recurrent urticaria patients, and 94 healthy participants. Clinical comprehensive evaluation by allergists used as the reference gold standard, receiver operator characteristic (ROC) curves were plotted, areas under curve (AUC) for specific immunoglobin E (sIgE) were compared to evaluate the diagnostic value of IgE specific to wheat, gluten, and ω-5 gliadin. Patients were followed up by telephone questionnaire 1 year after diagnosis. Results: We reviewed 567 anaphylactic reactions in 283 WDEIA patients. Of these anaphylactic reactions, 415 (73.3%) reactions were potentially life-threatening anaphylaxis. Among the 567 anaphylactic reactions, 75% (425/567) occurred during exercise. The highest AUC (0.910) was observed for sIgE for gluten, followed by omega-5 gliadin (AUC 0.879). Combined gluten- and ω-5 gliadin-specific IgE testing provided sensitivity and specificity of 73.1% and 99.0%, respectively. During the 1-year follow-up period, repeat anaphylaxis was rare when patients observed strict avoidance of wheat products combined with exercise or other triggering agents. Conclusions: In this study, we proposed diagnostic criteria and management of WDEIA patients in China. Our present study suggested that confirmed anaphylactic reactions triggered by wheat with positive sIgE to gluten and omega-5-gliadin may provide supportive evidence for clinicians to make WDEIA diagnosis without performing a food exercise challenge.

Background: The pathogenicity of cleft lip (CL) is pretty complicated since it is influenced by the interaction of environment and genetic factors. The purpose of this study was to conduct a genome-wide screening of aberrant methylation loci in partial lesion tissues of patients with nonsyndromic CL (NSCL) and preliminarily validate candidate dysmethylated genes associated with NSCL. Methods: Fifteen healthy and sixteen NSCL fetal lip tissue samples were collected. The Infinium HumanMethylation450 BeadChip was used to screen aberrant methylation loci in three NSCL and three healthy lip tissues. The differential methylation sites and functions of the annotated genes between NSCL and healthy lip tissues were analyzed using minfi package of R software, cluster analysis, Gene Ontology (GO) annotation, and metabolic pathway annotation. Gene expression was assessed in nine differentially methylated genes by real-time polymerase chain reaction (PCR). The transcriptions mRNA levels of three out of nine candidate genes were downregulated remarkably in NSCL lip tissues, and these three genes’ abnormal methylation loci were validated by pyrosequencing in 16 NSCL cases and 15 healthy cases. Results: In total, 4879 sites in the genes of NSCL odinopoeia fetuses showed aberrant methylation when compared with normal lip tissue genome. Among these, 3661 sites were hypermethylated and 1218 sites were hypomethylated as compared to methylation levels in healthy specimens. These aberrant methylation sites involved 2849 genes and were widely distributed among the chromosomes. Most differentially methylated sites were located in cytosine-phosphoric acid-guanine islands. Based on GO analysis, aberrantly methylated genes were involved in 11 cellular components, 13 molecular functions, and a variety of biological processes. Notably, the transcription of DAB1, REELIN, and FYN was significantly downregulated in lesion tissues of NSCL fetus (P < 0.05). Pyrosequencing results validated that there were two loci in DAB1 with high methylation status in patient tissues (P < 0.05). Conclusions: We detected numerous aberrantly methylated loci in lesion tissues of NSCL fetus. Aberrant gene expression in the REELIN signaling pathway might be related with NSCL. Decreased transcription of DAB1, a member of REELIN signal pathway, resulted from its abnormal high methylation, which might be one of the factors underlying the occurrence of NSCL.

Background: Accumulating documents have demonstrated that long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis. As an lncRNA, nuclear-enriched abundant transcript 1 (NEAT1) has been identified to be involved in the progression of many types of cancers. However, the biological function of NEAT1 in cervical cancer is not fully investigated. The aim of this study was to disclose the specific biological function of lncRNA NEAT1 in cervical cancer progression. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to identify the expression of lncRNA NEAT1 in the cervical cancer tissues and cell lines. All cervical cancer samples used in this study were collected from the Affiliated Suzhou Hospital of Nanjing Medical University between September 2012 and September 2017. The correlation between NEAT1 expression and the overall survival rate of cervical cancer patients was analyzed by Kaplan-Meier analysis. The effects of NEAT1 knockdown or overexpression on cell proliferation were tested by performing MTT assays and colony formation assays. Transwell assays were conducted to detect the migratory ability of cervical cancer cells, in which NEAT1 was silenced or overexpressed. Western blotting was utilized to validate whether NEAT1 promotes cervical cancer progression through activating PI3K-Akt signaling pathway. Results: High expression of NEAT1 predicted poor prognosis of cervical cancer patients (χ2 = 0.735, P = 0.005). Knockdown of NEAT1 decreased the number of colonies in CaSki cell from 136.667 ± 13.503 to 71.667 ± 7.506 (t= −18.76, P = 0.003) and decreased the number of colonies in HeLa cell from 128.667 ± 13.317 to 65.667 ± 7.024 (t = −5.54, P = 0.031). However, overexpression of NEAT1 increased the number of colonies in SiHa cell from 84.667 ± 12.014 to 150.667 ± 18.037 (t = 7.27, P = 0.018). Knockdown of NEAT1 decreased the migratory number of CaSki cell from 100.333 ± 9.866 to 58.333 ± 5.859 (t = −8.08, P = 0.015) and reduced the migratory number in HeLa cell from 123.667 ± 12.097 to 67.667 ± 7.095 (t = −6.03, P = 0.026). Overexpression of NEAT1 increased the migratory number of SiHa cell from 127.333 ± 16.042 to 231.333 ± 31.786 (t = 4.92, P = 0.039). Conclusion: NEAT1 may exert oncogenic function in cervical cancer and serve as a novel therapeutic target for cervical cancer.

Background: Immune disorder is an important feature of patients with out-of-hospital cardiac arrest (OHCA) after the return of spontaneous circulation (ROSC). We investigated the expression of circulatory T helper type (Th) 1, Th2, and Th17 cells to explore the early immune alteration in OHCA patients after ROSC. Methods: During July–September 2016 and March–September 2017, 65 consecutive OHCA patients with ROSC >12 h and 30 healthy individuals were enrolled in this study. Clinical and 28-day survival data were collected. Peripheral blood samples were analyzed to evaluate the expression of Th1/Th2/Th17 cells by flow cytometry from OHCA patients after ROSC on days 1 and 3 and from healthy individuals. Results: Compared with healthy individuals, T lymphocyte counts and Th1 cell counts decreased on days 1 and 3 after ROSC (1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118]/μl, χ2 = 30.342, P < 0.001; 154 [90, 246] vs. 39 [19, 78] vs. 24 [12, 53]/μl, χ2 = 42.880, P < 0.001), and Th2 and Th17 cell counts decreased on day 3 (17.0 [10.8, 24.0] vs. 9.0 [3.0, 15.5]/μl, Z= –3.228, P = 0.001; 4.7 [2.7, 9.1] vs. 2.7 [1.0, 6.5]/μl, Z = –2.294, P = 0.022). No change in CD4+/CD3+ lymphocyte ratio was seen on day 1 or day 3 (57.9 [49.4, 63.0] vs. 55.4 [46.5, 66.5] vs. 55.4 [50.2, 67.0]%, χ2 = 0.171, P = 0.918). Th1/CD4+ lymphocyte ratio decreased on days 1 and 3 (19.0 [14.0, 24.9] vs. 9.3 [4.6, 13.9] vs. 9.5 [4.9, 13.6]%, χ2 = 25.754, P < 0.001), and Th2/CD4+ lymphocyte ratio increased on day 1 and decreased on day 3 (1.9 [1.2, 2.5] vs. 2.5 [1.6, 4.0] vs. 1.9 [1.6, 3.8]%, χ2 = 6.913, P = 0.032). Th1/Th2 cell ratio also decreased on both days (9.4 [7.3, 13.5] vs. 3.1 [1.9, 5.6] vs. 4.2 [2.8, 5.9], χ2 = 44.262, P < 0.001). Despite an upward trend in the median of Th17/CD4+ lymphocyte ratio in OHCA patients, there was no significant difference compared with healthy individuals (0.9 [0.4, 1.2] vs. 0.7 [0.4, 1.2] vs. 0.6 [0.3, 1.0]%, χ2 = 2.620, P = 0.270). The dynamic expression of Th1/Th2/Th17 cells on days 1 and 3 were simultaneously analyzed in 28/53 OHCA patients who survived >3 days; patients were divided into survivors (n = 10) and nonsurvivors (n = 18) based on 28-day survival. No significant differences in Th1/Th2/Th17 cell counts, ratios in CD4+ lymphocytes, and Th1/Th2 cell ratio were seen between survivors and nonsurvivors on both days (all P > 0.05). There was no difference over time in both survivors and nonsurvivors (all P > 0.05). Conclusion: Downregulated T lymphocyte counts, including Th1/Th2/Th17 subsets and Th1/Th2 cell ratio imbalance, occur in the early period after ROSC, that may be involved in immune dysfunction in OHCA patients.

Background: Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway. Methods: VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay. Results: VPA could induce CHD (P < 0.001) and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression (all P < 0.05). In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression (P < 0.01), while knockdown of Hdac1/2 had no influence (P > 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P < 0.01), while overexpression of Hdac3 could rescue the VPA-induced inhibition (P > 0.05). Conclusion: VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.

Background: Fibroblasts were the main seed cells in the studies of tissue engineering of the pelvic floor ligament. Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) were widely studied but at various concentrations. This study aimed to optimize the concentrations of combined bFGF and EGF by evaluating their effects on proliferation and collagen secretion of fibroblasts. Methods: Fibroblasts were differentiated from rat adipose mesenchymal stem cells (ADSCs). Flow cytometry and immunohistochemistry were used for cell identification. The growth factors were applied at concentrations of 0, 1, 10, and 100 ng/ml as three groups: (1) bFGF alone, (2) EGF alone, and (3) bFGF mixed with EGF. Cell proliferation was evaluated by Cell Counting Kit-8 assays. Expression of Type I and III collagen (Col-I and Col-III) mRNAs was evaluated by real-time quantitative reverse transcription-polymerase chain reaction. Statistical analysis was performed with SPSS software and GraphPad Prism using one-way analysis of variance and multiple t-test. Results: ADSCs were successfully isolated from rat adipose tissue as identified by expression of typical surface markers CD29, CD44, CD90, and CD45 in flow cytometry. Fibroblasts induced from ADSC, compared with ADSCs, were with higher mRNA expression levels of Col I and Col III (F = 1.29, P = 0.0390). bFGF, EGF, and the mixture of bFGF with EGF can enhanced fibroblasts proliferation, and the concentration of 10 ng/ml of the mixture of bFGF with EGF displayed most effectively (all P < 0.05). The expression levels of Col-I and Col-III mRNAs in fibroblasts displayed significant increases in the 10 ng/ml bFGF combined with EGF group (all P < 0.05). Conclusions: The optimal concentration of both bFGF and EGF to promote cell proliferation and collagen expression in fibroblasts was 10 ng/ml at which fibroblasts grew faster and secreted more Type I and III collagens into the extracellular matrix, which might contribute to the stability of the pelvic floor microenvironment.

Objective: Peripheral T-cell lymphomas (PTCLs) confer dismal prognosis and no consensus has been established on the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to its rarity and heterogeneity. The purpose was to review key points of allo-HSCT for PTCLs, including indication, times of transplantation, conditioning regimen, graft versus host disease prophylaxis, and treatment of relapse. Data Sources: A comprehensive search in PubMed and Cochrane up to February 28, 2018, with the keywords "Peripheral" , "T" , "Lymphoma" , and "Transplantation" was done. Study Selection: Relevant articles including HSCT for PTCLs were carefully reviewed. Results: Promising data have been reported from advances in transplant technology and more and more PTCLs patients with poor prognosis could benefit from allo-HSCT. Conclusion: Allo-HSCT is a useful choice for patients with refractory/relapsed PTCLs or high-risk new diagnosed PTCLs.