Should neonatal-perinatal medicine move to two-year fellowships?

The duration of the majority of fellowships in pediatrics has been three-years. With increasing shortages of some outpatient-based pediatric subspecialists, shorter two-year fellowships are being considered for clinically oriented trainees not interested in a career based on research. Shortening the duration of fellowship may have some financial merits such as achieving a higher salary earlier after shorter training. However, we feel that continuing with a three-year duration for neonatology is more pragmatic at this time due to reductions in intensive care rotations during residency, time required to  achieve procedural excellence, the need for exposure to quality assurance methodology, proficiency in novel techniques such as bedside ultrasound, and to maintain the physician-scientist pipeline. The demand for neonatal fellowship continues to be high. Ongoing evaluation of the job market, training needs and fellowship curriculum is needed to determine if the duration of fellowship should be altered in the future.

Teaching culturally competent healthcare in neonatal-perinatal medicine.

Disparities in maternal and infant health care and outcomes exist despite advances in prenatal, perinatal, and neonatal care. In this article, the graduate medical educational goals to ensure that trainees in Neonatal-Perinatal Medicine have the knowledge, skills, and attitudes required for practicing culturally competent care are described. A framework for curriculum development, teaching, and learner evaluation for cultural competence will also be discussed. Included in this discussion are the educational objectives of preparing specialists in Neonatal-Perinatal Medicine to provide appropriate medical management to neonates, identify existing disparities in perinatal and neonatal care, and develop quality improvement initiatives to achieve equity in delivery of care.

Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation.

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation.

Endothelial cell migration during murine yolk sac vascular remodeling occurs by means of a Rac1 and FAK activation pathway in vivo.

The molecular mechanism(s) controlling cell migration during vascular morphogenesis in vivo remain largely undefined. To address this within a physiological context, we used retinaldehyde dehydrogenase-2 (Raldh2) null mouse embryos and demonstrate that retinoic acid (RA) deficiency results in abnormal yolk sac vascular remodeling due to decreased Rac1 activation, increased RhoA activation, and increased focal adhesions. Vinculin was increased in Raldh2-/- yolk sacs, and molecular events important for focal adhesion turnover, FAK phosphorylation (Tyr397) and FAK-paxillin association, were decreased. RA-rescue of vascular remodeling down-regulated vinculin and restored FAK phosphorylation (Tyr397) and FAK-paxillin association. Furthermore, vascular rescue with vascular endothelial growth factor-A, Indian hedgehog, and basic fibroblast growth factor restored FAK phosphorylation (Tyr397) in the endothelium of Raldh2-/- yolk sacs. Our results provide new insights into the regulation of endothelial cell migration during vascular remodeling in vivo by adding the Rac1 and FAK activation pathway as a critical mediator of focal adhesion formation and turnover during vascular remodeling.

Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2.

Atrioventricular (AV) septal defects resulting from aberrant endocardial cushion (EC) formation are observed at increased rates in infants of diabetic mothers. EC formation occurs via an epithelial-mesenchymal transformation (EMT), involving transformation of endocardial cells into mesenchymal cells, migration, and invasion into extracellular matrix. Here, we report that elevated glucose inhibits EMT by reducing myocardial vascular endothelial growth factor A (VEGF-A). This effect is reversed with exogenous recombinant mouse VEGF-A165, whereas addition of soluble VEGF receptor-1 blocks EMT. We show that disruption of EMT is associated with persistence of platelet endothelial cell adhesion molecule-1 (PECAM-1) and decreased matrix metalloproteinase-2 (MMP-2) expression. These findings correlate with retention of a nontransformed endocardial sheet and lack of invasion. The MMP inhibitor GM6001 blocks invasion, whereas explants from PECAM-1 deficient mice exhibit MMP-2 induction and normal EMT in high glucose. PECAM-1-negative endothelial cells are highly motile and express more MMP-2 than do PECAM-1-positive endothelial cells. During EMT, loss of PECAM-1 similarly promotes single cell motility and MMP-2 expression. Our findings suggest that high glucose-induced inhibition of AV cushion morphogenesis results from decreased myocardial VEGF-A expression and is, in part, mediated by persistent endocardial cell PECAM-1 expression and failure to up-regulate MMP-2 expression.