Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS

Background: Oxytocin is used therapeutically in psychiatric patients. Many of these also receive anti-depressant or anti-psychotic drugs causing acquired long-QT-syndrome (LQTS) by blocking HERG/IKr. We previously identified an oxytocin-induced QT-prolongation in LQT2 rabbits, indicating potential harmful effects of combined therapy. We thus aimed to analyze the effects of dual therapy with oxytocin and fluoxetine/risperidone on cardiac repolarization. Methods: Effects of risperidone, fluoxetine and oxytocin on QT/QTc, short-term variability (STV) of QT, and APD were assessed in rabbits using in vivo ECG and ex vivo monophasic AP recordings in Langendorff-perfused hearts. Underlying mechanisms were assessed using patch clamp in isolated cardiomyocytes. Results: Oxytocin, fluoxetine and risperidone prolonged QTc and APD in whole hearts. The combination of fluoxetine + oxytocin resulted in further QTc- and APD-prolongation, risperidone + oxytocin tended to increase QTc and APD compared to monotherapy. Temporal QT instability, STVQTc was increased by oxytocin, fluoxetine / fluoxetine + oxytocin and risperidone / risperidone + oxytocin. Similar APD-prolonging effects were confirmed in isolated cardiomyocytes due to differential effects of the compounds on repolarizing ion currents: Oxytocin reduced IKs, fluoxetine and risperidone reduced IKr, resulting in additive effects on IKtotal-tail. In addition, oxytocin reduced IK1, further reducing the repolarization reserve. Conclusion: Oxytocin, risperidone and fluoxetine prolong QTc / APD. Combined treatment further prolongs QTc/APD due to differential effects on IKs and IK1 (block by oxytocin) and IKr (block by risperidone and fluoxetine), leading to pronounced impairment of repolarization reserve. Oxytocin should be used with caution in patients in the context of acquired LQTS. © 2022 The Author

Characterization of Chromosomal Instability in Murine Colitis-Associated Colorectal Cancer

Patients suffering from ulcerative colitis (UC) bear an increased risk for colorectal cancer. Due to the sparsity of colitis-associated cancer (CAC) and the long duration between UC initiation and overt carcinoma, elucidating mechanisms of inflammation-associated carcinogenesis in the gut is particularly challenging. Adequate murine models are thus highly desirable. For human CACs a high frequency of chromosomal instability (CIN) reflected by aneuploidy could be shown, exceeding that of sporadic carcinomas. The aim of this study was to analyze mouse models of CAC with regard to CIN. Additionally, protein expression of p53, beta-catenin and Ki67 was measured to further characterize murine tumor development in comparison to UC-associated carcinogenesis in men.The AOM/DSS model (n = 23) and IL-10(-/-) mice (n = 8) were applied to monitor malignancy development via endoscopy and to analyze premalignant and malignant stages of CACs. CIN was assessed using DNA-image cytometry. Protein expression of p53, beta-catenin and Ki67 was evaluated by immunohistochemistry. The degree of inflammation was analyzed by histology and paralleled to local interferon-γ release.CIN was detected in 81.25% of all murine CACs induced by AOM/DSS, while all carcinomas that arose in IL-10(-/-) mice were chromosomally stable. Beta-catenin expression was strongly membranous in IL-10(-/-) mice, while 87.50% of AOM/DSS-induced tumors showed cytoplasmatic and/or nuclear translocation of beta-catenin. p53 expression was high in both models and Ki67 staining revealed higher proliferation of IL-10(-/-)-induced CACs.AOM/DSS-colitis, but not IL-10(-/-) mice, could provide a powerful murine model to mechanistically investigate CIN in colitis-associated carcinogenesis

Late Carboniferous foreland basin formation and Early Carboniferous stretching in Northwestern Europe: inferences from quantitative subsidence analyses

The large thickness of Upper Carboniferous strata found in the Netherlands suggests that the area was subject to long-term subsidence. However, the mechanisms responsible for subsidence are not quantified and are poorly known. In the area north of the London Brabant Massif, onshore United Kingdom, subsidence during the Namurian-Westphalian B has been explained by Dinantian rifting, followed by thermal subsidence. In contrast, south and east of the Netherlands, along the southern margin of the Northwest European Carboniferous Basin, flexural subsidence caused the development of a foreland basin. It has been proposed that foreland flexure due to Variscan orogenic loading was also responsible for Late Carboniferous subsidence in the Netherlands. In the first part of this paper, we present a series of modelling results in which the geometry and location of the Variscan foreland basin was calculated on the basis of kinematic reconstructions of the Variscan thrust system. Although several uncertainties exist, it is concluded that most subsidence calculated from well data in the Netherlands cannot be explained by flexural subsidence alone. Therefore, we investigated whether a Dinantian rifting event could adequately explain the observed subsidence by inverse modelling. The results show that if only a Dinantian rifting event is assumed, such as is found in the United Kingdom, a very high palaeowater depth at the end of the Dinantian is required to accommodate the Namurian-Westphalian B sedimentary sequence. To better explain the observed subsidence curves, we propose (1) an additional stretching event during the Namurian and (2) a model incorporating an extra dynamic component, which might well explain the very high wavelength of the observed subsidence compared with the wavelength of the predicted flexural foreland basin. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd