Noninvasive Assessment of Antenatal Hydronephrosis in Mice Reveals a Critical Role for Robo2 in Maintaining Anti-Reflux Mechanism

Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR

A manifestly covariant framework for causal set dynamics

We propose a manifestly covariant framework for causal set dynamics. The framework is based on a structure, dubbed covtree, which is a partial order on certain sets of finite, unlabeled causal sets. We show that every infinite path in covtree corresponds to at least one infinite, unlabeled causal set. We show that transition probabilities for a classical random walk on covtree induce a classical measure on the -algebra generated by the stem sets

Quantitative Evaluation of the Fetal Cerebellar Vermis Using the Median View on Two-Dimensional Ultrasound

BACKGROUND: Evaluation of the cerebellum and vermis is one of the integral parts of the fetal cranial anomaly screening. OBJECTIVES: The aim of this study was to create a nomogram for fetal vermis measurements between 17 and 30 gestational weeks. PATIENTS AND METHODS: This prospective study was conducted on 171 volunteer pregnant women between March 2013 and December 2014. Measurements of the fetal cerebellar vermis diameters in the sagittal plane were performed by two-dimensional transabdominal ultrasonography. RESULTS: Optimal median planes were obtained in 117 of the cases. Vermian diameters as a function of gestational age were expressed by regression equations and the correlation coefficients were found to be highly statistically significant (P < 0.001). The normal mean (± standard deviation) for each gestational week was also defined. CONCLUSION: This study presents the normal range of the two-dimensional fetal vermian measurements between 17 and 30 gestational weeks. In the absence of a three-dimensional ultrasonography, two-dimensional ultrasonography could also be used confidently with more time and effort