Villification in the mouse: Bmp signals control intestinal villus patterning.

In the intestine, finger-like villi provide abundant surface area for nutrient absorption. During murine villus development, epithelial Hedgehog (Hh) signals promote aggregation of subepithelial mesenchymal clusters that drive villus emergence. Clusters arise first dorsally and proximally and spread over the entire intestine within 24 h, but the mechanism driving this pattern in the murine intestine is unknown. In chick, the driver of cluster pattern is tensile force from developing smooth muscle, which generates deep longitudinal epithelial folds that locally concentrate the Hh signal, promoting localized expression of cluster genes. By contrast, we show that in mouse, muscle-induced epithelial folding does not occur and artificial deformation of the epithelium does not determine the pattern of clusters or villi. In intestinal explants, modulation of Bmp signaling alters the spatial distribution of clusters and changes the pattern of emerging villi. Increasing Bmp signaling abolishes cluster formation, whereas inhibiting Bmp signaling leads to merged clusters. These dynamic changes in cluster pattern are faithfully simulated by a mathematical model of a Turing field in which an inhibitor of Bmp signaling acts as the Turing activator. In vivo, genetic interruption of Bmp signal reception in either epithelium or mesenchyme reveals that Bmp signaling in Hh-responsive mesenchymal cells controls cluster pattern. Thus, unlike in chick, the murine villus patterning system is independent of muscle-induced epithelial deformation. Rather, a complex cocktail of Bmps and Bmp signal modulators secreted from mesenchymal clusters determines the pattern of villi in a manner that mimics the spread of a self-organizing Turing field.

Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi.

In the adult intestine, an organized array of finger-like projections, called villi, provide an enormous epithelial surface area for absorptive function. Villi first emerge at embryonic day (E) 14.5 from a previously flat luminal surface. Here, we analyze the cell biology of villus formation and examine the role of paracrine epithelial Hedgehog (Hh) signals in this process. We find that, before villus emergence, tight clusters of Hh-responsive mesenchymal cells form just beneath the epithelium. Cluster formation is dynamic; clusters first form dorsally and anteriorly and spread circumferentially and posteriorly. Statistical analysis of cluster distribution reveals a patterned array; with time, new clusters form in spaces between existing clusters, promoting approximately four rounds of villus emergence by E18.5. Cells within mesenchymal clusters express Patched1 and Gli1, as well as Pdgfrα, a receptor previously shown to participate in villus development. BrdU-labeling experiments show that clusters form by migration and aggregation of Hh-responsive cells. Inhibition of Hh signaling prevents cluster formation and villus development, but does not prevent emergence of villi in areas where clusters have already formed. Conversely, increasing Hh signaling increases the size of villus clusters and results in exceptionally wide villi. We conclude that Hh signals dictate the initial aspects of the formation of each villus by controlling mesenchymal cluster aggregation and regulating cluster size.

Impact of hands-on care on infant sleep in the neonatal intensive care unit.

STUDY OBJECTIVES: Sleep disruption is increasingly recognized in hospitalized patients. Impaired sleep is associated with measureable alterations in neurodevelopment. The neonatal intensive care unit (NICU) environment has the potential to affect sleep quality and quantity. We aimed: (i) to determine the frequency and duration of hands-on care, and its impact on sleep, for NICU patients; and (ii) to assess the incidence of respiratory events associated with handling for a cohort of sick neonates. METHODS: Term and near-term neonates admitted to the NICU and at risk for cerebral dysfunction due to severity of illness or clinical suspicion for seizures underwent attended, bedside polysomnography. Continuous polysomnogram segments were analyzed and data on handling, infant behavioral state, and associated respiratory events were recorded. RESULTS: Video and polysomnography data were evaluated for 25 infants (gestational age 39.4 ± 1.6 weeks). The maximum duration between handling episodes for each infant was 50.9 ± 26.2 min, with a median of 2.3 min between contacts. Handling occurred across all behavioral states (active sleep 29.5%; quiet sleep 23.1%; awake 29.9%; indeterminate 17.4%; P = 0.99). Arousals or awakenings occurred in 57% of contacts with a sleeping infant. Hypopnea, apnea, and oxygen desaturation occurred with 16%, 8%, and 19.5% of contacts, respectively. Hypopnea was most likely to occur following contact with infants in active sleep (28%; P < 0.001). CONCLUSIONS: Infants in the NICU experience frequent hands-on care, associated with disturbances of sleep and respiration. The potential health and developmental impact of these disturbances merits study, as strategies to monitor sleep and minimize sleep-disordered breathing might then improve NICU outcomes. Pediatr Pulmonol. 2017;52:84-90 © 2016 Wiley Periodicals, Inc.

An Evaluation of Cerebral and Systemic Predictors of 18-Month Outcomes for Neonates With Hypoxic Ischemic Encephalopathy.

Amplitude-integrated EEG (aEEG) is a commonly used predictor of outcome after hypoxic ischemic encephalopathy. Cerebral and systemic near-infrared spectroscopy and acute kidney injury might also have prognostic value. The authors monitored neonates with aEEG, cerebral and systemic near-infrared spectroscopy during therapeutic hypothermia, assigned an acute kidney injury stage, and measured neurodevelopmental outcome. For 18 infants, cerebral near-infrared spectroscopy variables did not differentiate between those with favorable (n = 13) versus adverse (death or moderate-severe disability; n = 5) 18-month outcomes. However, systemic rSO2 variability was higher during hours 48-72 of cooling among those with favorable outcomes (.02 < P < .03). Mean aEEG amplitude during hours 24 to 48 of cooling was higher among those with good outcomes (.027 < P < .032). The aEEG lower margin was also higher during hours 12 to 48 for those with good outcomes (.014 < P < .035). Acute kidney injury did not predict outcome (P > .05). aEEG is a useful prognostic tool for outcomes after neonatal hypoxic ischemic encephalopathy, but the role of near-infrared spectroscopy in the hypothermia-treated population remains uncertain.