Evidence is presented for a new pathway participating in anterior neural development. It was found that IGF binding protein 5 (IGFBP-5), as well as three IGFs expressed in early embryos, promoted anterior development by increasing the head region at the expense of the trunk in mRNA-injected Xenopus embryos. A secreted dominant-negative type I IGF receptor (DN-IGFR) had the opposite effect. IGF mRNAs led to the induction of ectopic eyes and ectopic head-like structures containing brain tissue. In ectodermal explants, IGF signals induced anterior neural markers in the absence of mesoderm formation and DN-IGFR inhibited neural induction by the BMP antagonist Chordin. Thus, active IGF signals appear to be both required and sufficient for anterior neural induction in Xenopus.

Patterning of the central nervous system is regulated by a signaling center located at the midbrain-hindbrain boundary (MHB), or isthmus organizer. Fibroblast growth factors secreted from the MHB are required and sufficient to direct the ordered growth and regionalization of the midbrain and anterior hindbrain. In an unbiased secretion cloning screen of Xenopus gastrula embryos we identified a novel gene, which we designated as Isthmin (xIsm) due to its prominent expression at the MHB. xIsm encodes a secreted protein of 449 amino acids containing one copy of the thrombospondin type 1 repeat (TSR). We also found orthologous Isthmin genes in human (hIsm) and mouse (mIsm), as well as a gene encoding an Isthmin-like human unknown protein (hIsm-l). The conservation of a unique carboxy-terminal region between hIsm and hIsm-l suggests that Isthmin is the founding member of a new family of secreted proteins. xIsm was strongly expressed maternally in the Xenopus egg and showed zygotic expression in the ventral blastopore lip, notochord, and MHB. Additional expression domains were detected in neural crest, ear vesicle, and developing blood islands. Interestingly, xIsm was co-expressed with Fibroblast growth factor-8 (xFgf-8) at multiple sites including the MHB, indicating that these two genes are part of a synexpression group which also includes sprouty and sef homologs.

Purpose: The purpose of this study was to investigate the effect of integrated evaluation of resting static computed tomography perfusion (CTP) and coronary computed tomography angiography (CCTA)–derived fractional flow reserve (FFRCT) on therapeutic decision-making and predicting major adverse cardiovascular events (MACEs) in patients with suspected coronary artery disease. Materials and Methods: In this post hoc analysis of a prospective trial of CCTA in patients assigned to either CCTA or CCTA plus FFRCT arms, 500 patients in the CCTA plus FFRCT arm were analyzed. Both resting static CTP and FFRCT were evaluated by using the conventional CCTA. Perfusion defects in the myocardial segments with ≥50% degree of stenosis in the supplying vessels were defined as resting static CTP positive, and any vessel with an FFRCT value of ≤0.80 was considered positive. Patients were divided into 3 groups: (1) negative CTP-FFRCT match group (resting static CTP-negative and FFRCT-negative group); (2) mismatch CTP-FFRCT group (resting static CTP-positive and FFRCT-negative or resting static CTP-negative and FFRCT-positive group); and (3) positive CTP-FFRCT match group (resting static CTP-positive and FFRCT-positive group). We compared the revascularization-to-invasive coronary angiography ratio and the MACE rate among 3 subgroups at 1- and 3-year follow-ups. The adjusted Cox hazard proportional model was used to assess the prognostic value of FFRCT and resting static CTP to determine patients at risk of MACE. Results: Patients in the positive CTP-FFRCT match group were more likely to undergo revascularization at the time of invasive coronary angiography compared with those in the mismatch CTP-FFRCT group (81.4% vs 57.7%, P=0.033) and the negative CTP-FFRCT match group (81.4% vs 33.3%, P=0.001). At 1- and 3-year follow-ups, patients in the positive CTP-FFRCT match group were more likely to have MACE than those in the mismatch CTP-FFRCT group (10.5% vs 4.2%, P=0.046; 35.6% vs 9.4%, P<0.001) and the negative CTP-FFRCT match group (10.5% vs 0.9%, P<0.001; 35.6% vs 5.4%, P<0.001). A positive CTP-FFRCT match was strongly related to MACE at 1-year (hazard ratio=8.06, P=0.003) and 3-year (hazard ratio=6.23, P<0.001) follow-ups. Conclusion: In patients with suspected coronary artery disease, the combination of FFRCT with resting static CTP could guide therapeutic decisions and have a better prognosis with fewer MACE in a real-world scenario.