Valproate, thalidomide and ethyl alcohol alter the migration of HTR-8/SVneo cells

BACKGROUND: Valproate, thalidomide and alcohol (ethanol) exposure during the first trimester of pregnancy is known to cause several developmental disorders. All these teratogens are known to pass the placental barrier and interfere directly with the normal development of the fetus. However, these teratogens also alter the formation and function of the placenta itself which may in turn affect the proper nourishment and development of the fetus. Optimum development of the placenta requires adequate invasion of trophoblast into the maternal uterine tissues. Changes in the migratory behavior of trophoblast by maternal exposure to these teratogens during placentogenesis may therefore alter the structure and function of the placenta. METHODS: In the present study, the effects of sodium valproate, thalidomide and alcohol on the migration of human first trimester trophoblast cell line (HTR-8/SVneo) were examined in vitro. Cells were cultured in the wells of 48-well culture plates as mono or multilayers. Circular patches of cells were removed from the center of the wells by suction, and the migration of cells into the wound was studied using microscopy. Effects of low and high concentrations of valproate, thalidomide and alcohol were examined on the healing of wounds and on the migration rate of cells by determining the wound areas at 0, 3, 6, 12, 24 and 48 h. Effects of drugs and alcohol on the proliferation and the expression levels of integrin subunits beta1 and alpha5 in cells were examined. RESULTS: The migration rates of trophoblast differed between wounds created in mono and multilayers of cells. Exposure to teratogens altered the migration of trophoblast into mono and multilayer wounds. The effects of valproate, thalidomide and alcohol on the proliferation of cells during the rapid migratory phase were mild. Drug exposure caused significant changes in the expression levels of beta1 and alpha5 integrin subunits. CONCLUSION: Results suggest that exposure to valproate, thalidomide or alcohol during the first trimester of pregnancy may change the ultrastructure of the placenta by altering the migration of trophoblast cells and this effect may be mediated by drug- or alcohol-induced changes in the expression levels of beta1 and alpha5 integrin subunits

Bleeding-related admissions in patients with atrial fibrillation receiving antithrombotic therapy: results from the Tasmanian Atrial Fibrillation

Purpose: Limited data are available from the Australian settingregarding bleeding in patients with atrial fibrillation (AF)receiving antithrombotic therapy. We aimed to investigate theincidence of hospital admissions due to bleeding and factorsassociated with bleeding in patients with AF who receivedantithrombotic therapy.Methods: A retrospective cohort study was conducted involvingall patients with AF admitted to the Royal HobartHospital, Tasmania, Australia, between January 2011 andJuly 2015. Bleeding rates were calculated per 100 patientyears(PY) of follow-up, and multivariable modelling wasused to identify predictors of bleeding.Results: Of 2202 patients receiving antithrombotic therapy,113 presented to the hospital with a major or minor bleedingevent. These patients were older, had higher stroke and bleedingrisk scores and were more often treated with warfarin andmultiple antithrombotic therapies than patients who did notexperience bleeding. The combined incidence of major andminor bleeding was significantly higher in warfarin- versusdirect-acting oral anticoagulants (DOAC)- and antiplatelettreatedpatients (4.1 vs 3.0 vs 1.2 per 100 PY, respectively;p = 0.002). Similarly, the rate of major bleeding was higher inpatients who received warfarin than in the DOAC and antiplateletcohorts (2.4 vs 0.4 vs 0.6 per 100 PY, respectively;p = 0.001). In multivariate analysis, increasing age, priorbleeding, warfarin and multiple antithrombotic therapies wereindependently associated with bleeding.Conclusion: The overall rate of bleeding in this cohort waslow relative to similar observational studies. The rate of majorbleeding was higher in patients prescribed warfarin comparedto DOACs, with a similar rate of major bleeding for DOACsand antiplatelet agents. Our findings suggest potential to strategiesto reduce bleeding include using DOACs in preferenceto warfarin, and avoiding multiple antithrombotic therapies inpatients with AF