Wnt3a encodes a signal that is expressed in the primitive streak of the gastrulating mouse embryo and is required for paraxial mesoderm development. In its absence cells adopt ectopic neural fates. Embryos lacking the T-boxcontaining transcription factors, Brachyury or Tbx6, also lack paraxial mesoderm. Here we show that Brachyury is specifically down-regulated in Wnt3a mutants in cells fated to form paraxial mesoderm. Transgenic analysis of the T promoter identifies T (Brachyury) as a direct transcriptional target of the Wnt signaling pathway. Our results suggest that Wnt3a, signaling via Brachyury, modulates a balance between mesodermal and neural cell fates during gastrulation. Received September 13, 1999; revised version accepted October 13, 1999. The embryonic mesoderm of the mammalian embryo is formed by a series of inductive interactions first in the primitive streak, which gives rise to head and trunk mesoderm, and later in the tailbud, which generates the most posterior mesoderm of the tail. As development progresses, successively posterior structures are generated, leading to a posterior extension of the body axis. Previous studies have established that Wnt3a, which encodes a member of the Wnt family of secreted signaling molecules (for review, see Cadigan and Nusse 1997;Moon et al. 1997), is expressed in pluripotent ectoderm cells of the primitive streak during gastrulation (Takada et al. 1994). At early somite stages [8.0-8.5 days postcoitum (dpc)], the Wnt3a expression domain correlates with a domain of cells in the anterior primitive streak fated to give rise to paraxial mesoderm (for review, see Tam and Trainor 1994;Wilson and Beddington 1996). Moreover, the anterior and lateral limits of the Wnt3a expression domain lie between cells fated to give rise to paraxial mesoderm and cells that will give rise to neural ectoderm.A requirement for Wnt3a in the specification of trunk and tail paraxial somitic mesoderm fates has been demonstrated by mutant analyses. Wnt3a homozygous null mutant embryos lack all but the anterior-most seven to nine somites (Takada et al. 1994;Greco et al. 1996;Yoshikawa et al. 1997). As a consequence, only the most rostral cervical vertebrae are formed. Histological and molecular analyses demonstrate that ectopic neural structures form in place of posterior paraxial mesoderm (Yoshikawa et al. 1997 Mesoderm specification is thought to be regulated, at least in part, by members of the T-box gene family of DNA-binding transcription factors (Smith 1999). Two of these, T and Tbx6, are coexpressed with Wnt3a in the primitive streak during gastrulation (Takada et al. 1994;Chapman et al. 1996). Mutations in either gene lead to a loss of trunk and tail mesoderm (Chesley 1935;Chapman and Papaioannou 1998). Ectopic neural tubes form in place of paraxial mesoderm in the Tbx6 mutants, but it is not clear how similar the neural tube abnormalities noted in the T homozygotes are to the Wnt3a phenotype. Given the similarities between the Wnt3a and T-box mutant phenotypes, we have investiga...

Wnt-3a mutant embryos show defects caudal to the forelimb level; somites are absent, the notochord is disrupted, and the central nervous system has a pronounced dysmorphology. Previous studies revealed that the primary defects of the mutant embryos are likely to be in the process of paraxial mesoderm formation. In this study, we analyzed the phenotype of Wnt-3a mutant embryos at early somite stages (8.0 days post coitum), when somite formation is initiated. In Wnt-3a mutants, cells which have ingressed through the primitive streak do not migrate laterally but remain under the streak and form an ectopic tubular structure. Several neural-specific molecular markers, but no paraxial mesoderm markers, are expressed in this structure, suggesting that the ectopic tube is an additional neural tube. In normal embryos, Wnt-3a is expressed in the primitive ectoderm, including the cells which are fated to give rise to the paraxial mesoderm and neurectoderm, but expression is absent in migrating mesoderm cells. These results suggest that Wnt-3a signaling may play a role in regulating paraxial mesodermal fates, at the expense of neurectodermal fates, within the primitive ectoderm of the gastrulating mouse embryo.

This novel trauma workflow, comprising immediate CT diagnosis and rapid bleeding control without patient transfer, as realized in the Hybrid ER, may improve mortality in severe trauma.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

BackgroundLittle evidence supports anticoagulant therapy as effective adjuvant therapy to reduce mortality overall in sepsis. However, several studies suggest that anticoagulant therapy may reduce mortality in specific patients. This study aimed to identify a subset of patients with high benefit profiles for anticoagulant therapy against sepsis.MethodsThis post hoc subgroup analysis of a nationwide multicentre retrospective registry was conducted in 42 intensive care units in Japan. Consecutive adult patients with sepsis were included. Treatment effects of anticoagulants, e.g. antithrombin, recombinant thrombomodulin, heparin, and protease inhibitors, were evaluated by stratifying patients according to disseminated intravascular coagulation (DIC) and Sequential Organ Failure Assessment (SOFA) score. Intervention effects of anticoagulant therapy on in-hospital mortality and bleeding complications were analysed using Cox regression analysis stratified by propensity scores.ResultsParticipants comprised 2663 consecutive patients with sepsis; 1247 patients received anticoagulants and 1416 received none. After adjustment for imbalances, anticoagulant administration was significantly associated with reduced mortality only in subsets of patients diagnosed with DIC, whereas similar mortality rates were observed in non-DIC subsets with anticoagulant therapy. Favourable associations between anticoagulant therapy and mortality were observed only in the high-risk subset (SOFA score 13–17; adjusted hazard ratio 0.601; 95 % confidence interval 0.451, 0.800) but not in the subsets of patients with sepsis with low to moderate risk. Although the differences were not statistically significant, there was a consistent tendency towards an increase in bleeding-related transfusions in all SOFA score subsets.ConclusionsThe analysis of this large database indicates anticoagulant therapy may be associated with a survival benefit in patients with sepsis-induced coagulopathy and/or very severe disease.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012543). Registered on 10 December 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1415-1) contains supplementary material, which is available to authorized users.