An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome.

The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.

Bolus versus continuous feeding regimens post gastrostomy tube placement in children.

BACKGROUND/PURPOSE: Owing to the frequency of gastrostomy tube placement in children and the numerous regimens used to start feeds after placement we attempted to see if it matters if the initial feeds after a gastrostomy tube placement are provided in a bolus or continuous manner. METHODS: Using a prospective randomized trial, children were randomized to initial bolus or continuous chimney feeding after gastrostomy tube placement. Feeding tolerance and complications related to the gastrostomy tube were collected for 4 weeks after placement. RESULTS: Demographics were similar in the two groups. Times to goal feeds were similar in both groups, but in the first two weeks more feeding modifications were required in the bolus group. Other than the rate of leakage during the second week after placement which occurred more in the bolus group, all other clinical outcomes were similar in the two groups. CONCLUSIONS: Other than minor, clinically insignificant differences noted above, the method of initial feeding after a gastrostomy tube placement does not affect feeding tolerance or gastrostomy tube complication in the first month after placement. LEVEL OF EVIDENCE: Therapeutic, level II.

Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia.

BACKGROUND: Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders, yet the consequences of an abnormal ECM on cellular communication remains less well understood METHODS: Clinical and radiographic examinations defined the phenotype in this unappreciated bent bone skeletal disorder. Exome analysis identified the genetic alteration, confirmed by Sanger sequencing. Quantitative PCR, western blot analyses, immunohistochemistry, luciferase assay for WNT signaling were employed to determine RNA, proteins levels and localization, and dissect out the underlying cell signaling abnormalities.  Migration and wound healing assays examined cell migration properties. FINDINGS: This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin-mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered ß1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling. INTERPRETATION: This newly described mechanism revealed a LAMA5-ß1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. FUNDING: Supported by NIH awards R01 AR066124, R01 DE019567, R01 HD070394, and U54HG006493, and Czech Republic grants INTER-ACTION LTAUSA19030, V18-08-00567 and GA19-20123S.

Nationwide trends of clinical characteristics and economic burden of emergency department visits due to acute ischemic stroke.

We aimed to provide estimates of the volume and associated charges of acute ischemic stroke (AIS) visits in the US, as well as to assess predictors of patient disposition following an emergency department (ED) visit for AIS. Our study was conducted using the 2010-2013 data from the Nationwide Emergency Department Sample. We identified adult visits with AIS as the primary diagnosis. A generalized linear model was used to calculate mean charges per visit after adjusting for covariates. Multinomial logistic regression was used to assess predictors of patient disposition following an ED visit for AIS. The national incidence did not appreciably change over time, increasing from 26.4 to 27.0 visits per 10,000 adults. Adjusted mean charges per event were highest in the West, increasing from $3,761 in 2010 to $4,575 in 2013. Multinomial logistic regression showed that older age was associated with increased likelihood of both hospital admission and mortality in the ED, while male sex was associated with lower odds of mortality in the ED. Despite improvements in primary and secondary prevention of cardiovascular disease, AIS remains a significant burden on the health care system with a high volume of ED visits and increasing charges for care.