Description: Normal placentation and a successful pregnancy depend on appropriate trophoblast cell migration and invasion. Inadequate trophoblast invasion and impaired spiral artery remodeling may lead to pregnancy-related disorders, such as preeclampsia. RPS4Y1 (ribosomal protein S4, Y-linked 1) is a member of the S4E family of ribosomal proteins. In this study, we found that RPS4Y1 levels were upregulated in placental samples collected from preeclamptic patients, when compared with the normotensive pregnant women. In vitro, inhibition of RPS4Y1 induced trophoblast cell invasion, promoted placental explant outgrowth, and increased STAT3 (signal transducer and activator of transcription 3) phosphorylation along with elevated expression of N-cadherin and vimentin. Conversely, overexpression of RPS4Y1 results in reduced trophoblast cell invasion and decreased STAT3 phosphorylation. In addition, the suppression of RPS4Y1 promotes trophoblast cell invasion, which could be abolished by the STAT3 knockdown. Meanwhile, we observed reductions of STAT3 phosphorylation expression in preeclampsia patients. Collectively, these results demonstrate that the level of RPS4Y1 expression may be associated with preeclampsia by affecting trophoblast cell migration and invasion via the STAT3/epithelial–mesenchymal transition pathway.

Description: Background:Stroke prevention with oral anticoagulants (OACs) is the cornerstone for the management of atrial fibrillation (AF). However, data about the use of OACs among patients ≥90 years of age are limited. We aimed to investigate the risk of ischemic stroke and intracranial hemorrhage (ICH) and the net clinical benefit of OAC treatment for very elderly patients with AF (≥90 years of age).Methods:This study used the National Health Insurance Research Database in Taiwan. Risks of ischemic stroke and ICH were compared between 11 064 and 14 658 patients with and without AF ≥90 years of age without antithrombotic therapy from 1996 to 2011. Patients with AF (n=15 756) were divided into 3 groups (no treatment, antiplatelet agents, and warfarin), and the risks of stroke and ICH were analyzed. The risks of ischemic stroke and ICH were further compared between patients treated with warfarin and nonvitamin K antagonist OACs (NOACs) from 2012 to 2015 when NOACs were available in Taiwan.Results:Compared with patients without AF, patients with AF had an increased risk of ischemic stroke (event number/patient number, incidence = 742/11 064, 5.75%/y versus 1399/14 658, 3.00%/y; hazard ratio, 1.93; 95% confidence interval, 1.74–2.14) and similar risk of ICH (131/11 064, 0.97%/y versus 206/14 658, 0.54%/y; hazard ratio, 0.85; 95% confidence interval, 0.66–1.09) in competing risk analysis for mortality. Among patients with AF, warfarin use was associated with a lower stroke risk (39/617, 3.83%/y versus 742/11 064, 5.75%/y; hazard ratio, 0.69; 95% confidence interval, 0.49–0.96 in a competing risk model), with no difference in ICH risk compared with nontreatment. When compared with no antithrombotic therapy or antiplatelet drugs, warfarin was associated with a positive net clinical benefit. These findings persisted in propensity-matched analyses. Compared with warfarin, NOACs were associated with a lower risk of ICH (4/978, 0.42%/y versus 19/768, 1.63%/y; hazard ratio, 0.32; 95% confidence interval, 0.10–0.97 in a competing risk model), with no difference in risk of ischemic stroke.Conclusions:Among patients with AF ≥90 years of age, warfarin was associated with a lower risk of ischemic stroke and positive net clinical benefit. Compared with warfarin, NOACs were associated with a lower risk of ICH. Thus, OACs may still be considered as thromboprophylaxis for elderly patients, with NOACs being the more favorable choice.

Description: Objective—ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13) is primarily synthesized in liver. The biosynthesis of ADAMTS13 and its physiological role in placenta are not known.Approach and Results—We used real-time polymerase chain reaction, immunohistochemistry, and Western blotting analyses, as well as proteolytic cleavage of FRETS (fluorescent resonance energy transfers)-VWF73, to determine ADAMTS13 expression in placenta and trophoblasts obtained from individuals with normal pregnancy and patients with severe preeclampsia. We also determined the role of ADAMTS13 in extravillous trophoblasts using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound scratch assay, transwell migration assay, tube formation assay, and tissue outgrowth assays. We showed that full-length and proteolytically active ADAMTS13 was expressed in normal human placenta, primarily in the trophoblasts and villous core fetal vessel endothelium during pregnancy. Placental expression of ADAMTS13 mRNA, protein, and proteolytic activity was at the highest levels during the first trimester and significantly reduced at the term of gestation. Additionally, significantly reduced levels of placental ADAMTS13 expression was detected under hypoxic conditions and in patients with preeclampsia. In addition, recombinant ADAMTS13 protease stimulated proliferation, migration, invasion, and network formation of trophoblastic cells in culture. Finally, knockdown of ADAMTS13 expression attenuated the ability of tube formation in trophoblast (HTR-8/SVNEO) cells and the extravillous trophoblast outgrowth in placental explants.Conclusions—Our results demonstrate for the first time the expression of ADAMTS13 mRNA and protein in normal and abnormal placental tissues and its role in promoting angiogenesis and trophoblastic cell development. The findings support the potential role of the ADAMTS13–von Willebrand factor pathway in normal pregnancy and pathogenesis of preeclampsia.

Description: Background and Purpose—The risk of stroke in patients with short-run atrial tachyarrhythmia (AT) remains unclear. This study aimed to investigate the relationship between short-run AT and the stroke and the use of the CHA2DS2-VASc score for the risk stratification.Methods—From the registry of 24-hour Holter monitoring, 5342 subjects without known atrial fibrillation or stroke were enrolled. Short-run AT was defined as episodes of supraventricular ectopic beats 25 beats/d) independently predicted the risk of stroke. In subgroup analyses, short-run AT patients were divided into 3 groups based on their CHA2DS2-VASc scores: low score (score of 0 [men] or 1 [women]; n=324), intermediate score (score of 1 [men] or 2 [women]; n=275), and high score (score of ≥2 [men] or ≥3 [women]; n=996). When compared with low score, intermediate and high scores were independent predictors for stroke (hazard ratio, 6.165; P