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Aims Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. Methods and results The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. Conclusion Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. Clinical trial registration Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300 [ABSTRACT FROM AUTHOR]

Abstract Background p8 is a stress-induced protein with multiple functions and biochemically related to the architectural factor HMG-I/Y. We analyzed the expression and function of p8 in pancreatic cancer-derived cells. Methods Expression of p8 was silenced in the human pancreatic cancer cell lines Panc-1 and BxPc-3 by infection with a retrovirus expressing p8 RNA in the antisense orientation. Cell growth was measured in control and p8-silenced cells. Influence on p8 expression of the induction of intracellular pathways promoting cellular growth or growth arrest was monitored. Results p8-silenced cells grew more rapidly than control cells transfected with the empty retrovirus. Activation of the Ras→Raf→MEK→ERK and JNK intracellular pathways down-regulated p8 expression. In addition, the MEK1/2 inhibitor U0126 and the JNK inhibitor SP600125 up-regulates expression of p8. Conversely, p38 or TGFβ-1 induced p8 expression whereas the specific p38 inhibitor SB203580 down-regulated p8 expression. Finally, TGFβ-1 induction was in part mediated through p38. Conclusions p8 inhibits the growth of human pancreatic cancer cells. p8 expression is induced through pathways involved in growth inhibition and repressed by factors that promote cell growth. These results suggest that p8 belongs to a pathway regulating the growth of pancreatic cancer cells.

Molecular biology can diagnose and quantify vaginal flora anomalies. High vaginal loads of Atopobium vaginae and Gardnerella vaginalis are associated with preterm birth and shorter pregnancies. A. vaginae may be a useful target in preventing preterm birth.Background. Bacterial vaginosis is a risk factor for preterm birth. The various conventional methods for its diagnosis are laborious and not easily reproducible. Molecular quantification methods have been reported recently, but the specific risk factors they might identify remain unclear.Methods. A prospective multicenter national study included pregnant women at risk of preterm birth. A quantitative molecular tool using a specific real-time polymerase chain reaction assay and serial dilutions of a plasmid suspension quantified Atopobium vaginae, Gardnerella vaginalis, lactobacilli, Mycoplasma hominis, and the human albumin gene (for quality control).Results. In 813 pregnancies, high vaginal loads of either or both of A. vaginae and G. vaginalis were associated with preterm birth (hazard ratio [HR], 3.9; 95% confidence interval {CI}, 1.1–14.1; P = .031). A high vaginal load of A. vaginae was significantly associated with shortened time to delivery and therefore pregnancy length. These times were, respectively, 152.2 and 188.2 days (HR, 5.6; 95% CI, 1.5–21.3; P < .001) before 22 weeks, 149.0 and 183.2 days (HR, 2.8; 95% CI, 1.1–8.2; P = .048) before 28 weeks, and 132.6 and 170.4 days (HR, 2.2; 95% CI, 1.1–4.6; P = .033) before 32 weeks. After multivariate analysis, A. vaginae levels ≥108 copies/mL remained significantly associated with delivery before 22 weeks of gestation (adjusted HR, 4.7; 95% CI, .2–17.6; P = .014).Conclusions. High vaginal loads of A. vaginae and G. vaginalis are associated with late miscarriage and prematurity in high-risk pregnancies. A high vaginal load of A. vaginae (DNA level ≥108 copies/mL) identifies a population at high risk of preterm birth. Further studies that both screen for and then treat A. vaginae are needed.Clinical Trials Registration. NCT00484653. [ABSTRACT FROM PUBLISHER]

Antibodies against Saccharomyces cerevisiae (ASCA) and Escherichia coli outer membrane porin C (anti-OmpC) are known to be detectable in the serum of patients with Crohn’s disease (CD) but display a very poor sensitivity for the disease especially in forms with isolated colonic involvement. In this study we aimed at evaluating performances of these markers in supernatant of cultured colonic biopsies. Patients with colonic CD (n =  67), ulcerative colitis (UC) (n = 35) and control individuals (n = 37) were prospectively recruited for colonoscopy pinch biopsies and blood sampling. Serum and supernatant of culture tissues were analyzed for ASCA and anti-OmpC. Direct immunofluorescence was also performed on colonic tissues for total IgA detection. We detected for the first time ASCA IgA/IgG and anti-OmpC IgA in cultured colonic tissue supernatants. For both markers, sensitivities for diagnosing CD were better in supernatants (ASCA: 53.7%, anti-OmpC: 28.4%) than in serum (ASCA: 31.3%, anti-OmpC: 22.4%). Combination of results from a panel of these tests gave the greatest sensitivity ever described for CD diagnosis in colonic forms (70.2%). In this study, we described, for the first time, ASCA in supernatant of colonic tissue cultures. This assaying approach in CD diagnosis should be taken into consideration in the future especially in CD forms with isolated colonic involvement. [ABSTRACT FROM AUTHOR]

Background: p8 is a stress-induced protein with multiple functions and biochemically related to the architectural factor HMG-I/Y. We analyzed the expression and function of p8 in pancreatic cancer-derived cells. Methods: Expression of p8 was silenced in the human pancreatic cancer cell lines Panc-1 and BxPc- 3 by infection with a retrovirus expressing p8 RNA in the antisense orientation. Cell growth was measured in control and p8-silenced cells. Influence on p8 expression of the induction of intracellular pathways promoting cellular growth or growth arrest was monitored. Results: p8-silenced cells grew more rapidly than control cells transfected with the empty retrovirus. Activation of the Ras→Raf→MEK→ERK and JNK intracellular pathways down-regulated p8 expression. In addition, the MEK1/2 inhibitor U0126 and the JNK inhibitor SP600125 up-regulates expression of p8. Conversely, p38 or TGFβ-1 induced p8 expression whereas the specific p38 inhibitor SB203580 down-regulated p8 expression. Finally, TGFβ-1 induction was in part mediated through p38. Conclusions: p8 inhibits the growth of human pancreatic cancer cells. p8 expression is induced through pathways involved in growth inhibition and repressed by factors that promote cell growth. These results suggest that p8 belongs to a pathway regulating the growth of pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate whether clopidogrel-induced inhibition of platelet reactivity could reduce the level of circulating endothelial cells (CEC), reflecting the endothelial injury induced by percutaneous coronary intervention (PCI). Background: Clopidogrel loading dose before percutaneous coronary angioplasty (PCI) reduces platelet activation through a selective and irreversible blockade of the adenosine diphosphate (ADP) receptor P2Y12. The impact of clopidogrel on endothelial cells has been scarcely studied. Methods: A total of 149 patients undergoing PCI for stable angina were enrolled. Levels of CEC were measured at baseline (H0) and 6 (H6) and 24 (H24) h after the procedure using a CD146-based immunomagnetic separation assay. The CEC delta-change (CEC at H6 − CEC at H0) was analyzed according to ADP receptor P2Y12 blockade, assessed by a vasodilator-stimulated phosphoprotein (VASP) assay after a 600-mg loading dose of clopidogrel. Results: The PCI induced a significant rise in CEC levels 6 h after the procedure. The CEC peak value was significantly higher in patients with high on-treatment platelet reactivity (VASP index ≥50%: 59.6 ± 27.5 cells/ml) as compared with good responders (VASP index <50%: 27 ± 22 cells/ml; p = 0.04). The endothelial injury, assessed by CEC delta-change between H6 and H0, was significantly higher in the high on-treatment platelet reactivity group compared with the good responders group (52.6 ± 25.6 vs. 18.6 ± 23.5, respectively; p < 0.001) and correlated with the VASP index (r = 0.59; p < 0.001). In multivariate analysis, VASP group, the number of diseased vessels, and the number of implanted stents independently predicted the endothelial injury (p < 0.001). Conclusions: Optimal ADP receptor P2Y12 blockade reduces the endothelial injury during PCI. This protective effect of clopidogrel on endothelial cells could add to the clinical benefit associated with this drug. [Copyright &y& Elsevier]