Investigation of Association between PFO Complicated by Cryptogenic Stroke and a Common Variant of the Cardiac Transcription Factor GATA4

Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke

The endogenous retrovirus ENS-1 provides active binding sites for transcription factors in embryonic stem cells that specify extra embryonic tissue

<p>Abstract</p> <p>Background</p> <p>Long terminal repeats (LTR) from endogenous retroviruses (ERV) are source of binding sites for transcription factors which affect the host regulatory networks in different cell types, including pluripotent cells. The embryonic epiblast is made of pluripotent cells that are subjected to opposite transcriptional regulatory networks to give rise to distinct embryonic and extraembryonic lineages. To assess the transcriptional contribution of ERV to early developmental processes, we have characterized <it>in vitro </it>and <it>in vivo </it>the regulation of ENS-1, a host adopted and developmentally regulated ERV that is expressed in chick embryonic stem cells.</p> <p>Results</p> <p>We show that <it>Ens-1 </it>LTR activity is controlled by two transcriptional pathways that drive pluripotent cells to alternative developmental fates. Indeed, both Nanog that maintains pluripotency and Gata4 that induces differentiation toward extraembryonic endoderm independently activate the LTR. Ets coactivators are required to support Gata factors' activity thus preventing inappropriate activation before epigenetic silencing occurs during differentiation. Consistent with their expression patterns during chick embryonic development, Gata4, Nanog and Ets1 are recruited on the LTR in embryonic stem cells; in the epiblast the complementary expression of Nanog and Gata/Ets correlates with the <it>Ens-1 </it>gene expression pattern; and Ens-1 transcripts are also detected in the hypoblast, an extraembryonic tissue expressing Gata4 and Ets2, but not Nanog. Accordingly, over expression of Gata4 in embryos induces an ectopic expression of <it>Ens-1</it>.</p> <p>Conclusion</p> <p>Our results show that <it>Ens-1 </it>LTR have co-opted conditions required for the emergence of extraembryonic tissues from pluripotent epiblasts cells. By providing pluripotent cells with intact binding sites for Gata, Nanog, or both, <it>Ens-1 </it>LTR may promote distinct transcriptional networks in embryonic stem cells subpopulations and prime the separation between embryonic and extraembryonic fates.</p

Decidual-Secreted Factors Alter Invasive Trophoblast Membrane and Secreted Proteins Implying a Role for Decidual Cell Regulation of Placentation

Inadequate or inappropriate implantation and placentation during the establishment of human pregnancy is thought to lead to first trimester miscarriage, placental insufficiency and other obstetric complications. To create the placental blood supply, specialized cells, the ‘extravillous trophoblast’ (EVT) invade through the differentiated uterine endometrium (the decidua) to engraft and remodel uterine spiral arteries. We hypothesized that decidual factors would regulate EVT function by altering the production of EVT membrane and secreted factors. We used a proteomics approach to identify EVT membrane and secreted proteins regulated by decidual cell factors. Human endometrial stromal cells were decidualized in vitro by treatment with estradiol (10−8 M), medroxyprogesterone acetate (10−7 M) and cAMP (0.5 mM) for 14 days. Conditioned media (CM) was collected on day 2 (non-decidualized CM) and 14 (decidualized CM) of treatment. Isolated primary EVT cultured on Matrigel™ were treated with media control, non-decidualized or decidualized CM for 16 h. EVT CM was fractionated for proteins <30 kDa using size-exclusion affinity nanoparticles (SEAN) before trypsin digestion and HPLC-MS/MS. 43 proteins produced by EVT were identified; 14 not previously known to be expressed in the placenta and 12 which had previously been associated with diseases of pregnancy including preeclampsia. Profilin 1, lysosome associated membrane glycoprotein 1 (LAMP1), dipeptidyl peptidase 1 (DPP1/cathepsin C) and annexin A2 expression by interstitial EVT in vivo was validated by immunhistochemistry. Decidual CM regulation in vitro was validated by western blotting: decidualized CM upregulated profilin 1 in EVT CM and non-decidualized CM upregulated annexin A2 in EVT CM and pro-DPP1 in EVT cell lysate. Here, non-decidualized factors induced protease expression by EVT suggesting that non-decidualized factors may induce a pro-inflammatory cascade. Preeclampsia is a pro-inflammatory condition. Overall, we have demonstrated the potential of a proteomics approach to identify novel proteins expressed by EVT and to uncover the mechanisms leading to disease states

Performance of a lead-glass detector for high-energy gamma -rays

An array of 84 lead-glass blocks covering 1.8 m/sup 2/ has been used in a series of experiments in a short-lived neutral beam at the CERN PS. The photon energy is measured with a fwhm of Delta E=0.11* square root E(GeV) for photon energies between 0.5 and 5.0 GeV. The energy calibration has been monitored continuously during the course of the experiments using electrons which originated mainly from K/sub e3//sup 0/ decays, the momenta being measured in a magnetic spectrometer. (14 refs)

Sedation versus General Anesthesia for Tracheal Intubation in Children with Difficult Airways: A Cohort Study from the Pediatric Difficult Intubation Registry

Background: Sedated and awake tracheal intubation approaches are considered safest in adults with difficult airways, but little is known about the outcomes of sedated intubations in children. The primary aim of this study was to compare the first-attempt success rate of tracheal intubation during sedated tracheal intubation versus tracheal intubation under general anesthesia. The hypothesis was that sedated intubation would be associated with a lower first-attempt success rate and more complications than general anesthesia. Methods: This study used data from an international observational registry, the Pediatric Difficult Intubation Registry, which prospectively collects data about tracheal intubation in children with difficult airways. The use of sedation versus general anesthesia for tracheal intubation were compared. The primary outcome was the first-attempt success of tracheal intubation. Secondary outcomes included the number of intubation attempts and nonsevere and severe complications. Propensity score matching was used with a matching ratio up to 1:15 to reduce bias due to measured confounders. Results: Between 2017 and 2020, 34 hospitals submitted 1,839 anticipated difficult airway cases that met inclusion criteria for the study. Of these, 75 patients received sedation, and 1,764 patients received general anesthesia. Propensity score matching resulted in 58 patients in the sedation group and 522 patients in the general anesthesia group. The rate of first-attempt success of tracheal intubation was 28 of 58 (48.3%) in the sedation group and 250 of 522 (47.9%) in the general anesthesia group (odds ratio, 1.06; 95% CI, 0.60 to 1.87; P = 0.846). The median number of intubations attempts was 2 (interquartile range, 1 to 3) in the sedation group and 2 (interquartile range, 1, 2) in the general anesthesia group. The general anesthesia group had 6 of 522 (1.1%) intubation failures versus 0 of 58 in the sedation group. However, 16 of 58 (27.6%) sedation cases had to be converted to general anesthesia for successful tracheal intubation. Complications were similar between the groups, and the rate of severe complications was low. Conclusions: Sedation and general anesthesia had a similar rate of first-attempt success of tracheal intubation in children with difficult airways; however, 27.6% of the sedation cases needed to be converted to general anesthesia to complete tracheal intubation. Complications overall were similar between the groups, and the rate of severe complications was low

The NA48 LKr calorimeter digitizer electronics chain

The 13500 channels of the NA48 liquid-krypton electromagnetic calorimeter readout electronics were put into operation in 1997. The digitizer electronics employs a new gain switching technique that expands the dynamic range of a standard 10-bit ADC to 14 bits at 40 MHz sampling rate employing a custom-developed integrated circuit (KRYPTON). The KRYPTON has been fabricated in 1.2 mu m BiCMOS technology and was successfully developed together with industry on a short timescale. The performance and the experience from the first year of the operation of the liquid-krypton calorimeter electronics will also be briefly discussed. (C) 1998 Elsevier Science B.V. All rights reserved

A 40 MHz pipelined trigger for K-0 -&gt; 2 pi(0) decays for the CERN NA48 experiment

A first level trigger system based on a 40 MHz digital pipeline has been developed for the CERN NA48 [1] experiment, aiming at measuring CP violation in K-0 --&gt; 2 pi decays.The outputs of the 13340 cells of the 10 m(3) liquid krypton calorimeter are summed into 64 X and 64 Y projection strips and continuously digitised with 40 MHz FADCs.This information is used to reconstruct at each clock cycle and for the two calorimeter projections, the number of clusters, the impact time of each of them (with a precision of about 3 ns), their total energy and the first and second moments of the energy distribution.Based on the quantities listed above, a programmable look-up table system subsequently computes online the longitudinal position of the kaon decay vertex and performs an event selection.The system is described