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  • FGF ERK signaling has been implicated in epithelial mesenchy


    FGF/ERK signaling has been implicated in epithelial-mesenchymal interactions in a wide range of tissues (Huh et al., 2015, Klein et al., 2006, Rice et al., 2004, Zhang et al., 2006, El Ramy et al., 2005, Volckaert and Langhe, 2015). During embryonic organogenesis and in adult organs, we often observed Spry4 expression localized to mesenchyme immediately underlying an adjacent epithelial layer, for example in the limb bud, cephalic, olfactory, genital tubercle and uterine mesenchyme (Fig. 10, Fig. S9). This is consistent with the hypothesis that the epithelial or mesenchymal –restricted expression of distinct Sprouty family members within adjacent BX-912 australia can mediate the cell type specific regulation of RTK signaling (Klein et al., 2006). Hence, the reporter may be useful to reveal novel interactions between different adjacent cell types in vivo. FGF/ERK signaling also plays a central role in limb bud formation and FGF ligands and receptors are expressed both within the limb bud epithelium and mesenchyme (Ornitz and Itoh, 2015). At E12.5 we observed nuclear-localized Venus at high levels within the mesenchyme and at low levels within the epithelium, including the AER (Fig. 9E). The difference in Venus levels between the epithelium and mesenchyme of the limb bud may indicate a differential regulation of FGF/ERK signaling within these adjacent cell types, as described in other contexts (Klein et al., 2006). In summary, this mouse line reports Spry4 expression throughout embryonic development and in adult organs, potentially uncovering new aspects of FGF signaling regulation. Furthermore, in combination with an Fgf reporter, this could be used to map autocrine and paracrine FGF signaling activities in tissues and organisms.
    Acknowledgements We thank the Wellcome Trust-Medical Research Council Centre for Stem Cell Research Transgenics Facility, Cambridge, UK for generating germline transmitting chimeras; members of the Hadjantonakis lab for critical discussions of the reporter and comments on the manuscript; Lenka Filipkova, Sung Ly, Michelle Protzek and Daniel Stephen for technical assistance and Sho Fujisawa of from MSKCC's Molecular Cytology Core Facility for assistance with quantification of time-lapse data. This work was supported by grants from the NIH (R01HD094868, R01DK084391 and P30CA00874 - AKH), the Max-Planck Society (CS and DR). The work of AMA, JN and CS is supported by a BBSRC Project grant (BB/M023370/1). SMM is supported by a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (110151/Z/15/Z). NS was supported by a Starr Foundation Tri-Institutional Stem Cell Initiative postdoctoral fellowship for part of this work.
    Introduction Syncope is a rather frequent condition, responsible for 1–1.5% of Emergency Department (ED) visits [1]. The incidence in the general population is, however, much higher (up to 50 times) [2]. Despite guidelines (GL), hospitalization rate is still very high (up to 50%), especially compared with the incidence of short-term adverse events, which is globally 11%, but decreases to 4% when events already diagnosed in ED are excluded [1]. Although syncope is usually associated with a favourable prognosis, the incidence of adverse events in patients considered at low risk and thus discharged from the ED is not meaningless, either in the short or long term [3,4]. The 2018 European Society of Cardiology (ESC) GL for the diagnosis and management of syncope [5] focus on decreasing inappropriate admissions and tests, while maintaining the safety of the patient. This article analyzes the main innovations introduced by the ESC GL in ED management of syncope and highlights some critical aspects which may deserve further improvement.
    ED management of syncopal patients, according to ESC guidelines Evaluation of syncope in the ED should be carried out with the following steps: i) differentiation between syncope and non-syncopal transient loss of consciousness (TLOC); ii) initial evaluation, consisting in history, physical examination (including supine and standing blood pressure) and electrocardiogram, with any additional examinations, aimed achieving an aetiological diagnosis; iii) management of patients according to the final diagnosis; iv) risk stratification of patients with undetermined syncope [5].