Rationale: Animal models have been highly informative for understanding the characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR 2/2 rat has revealed insights into the airway mucus defect characteristic of CF but does not replicate a human-relevant CFTR (cystic fibrosis transmembrane conductance regulator) variant.Objectives: We hypothesized that a rat expressing a humanized version of CFTR and harboring the ivacaftor-sensitive variant G551D could be used to test the impact of CFTR modulators on pathophysiologic development and correction.Methods: In this study, we describe a humanized-CFTR rat expressing the G551D variant obtained by zinc finger nuclease editing of a human complementary DNA superexon, spanning exon 2-27, with a 59 insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared with wildtype animals.Measurements and Main Results: The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity, were normalized after the administration of ivacaftor.Conclusions: This model is useful to understand the mechanisms of disease and the extent of pathology reversal with CFTR modulators.
An outbreak of enteritis occurred amongst babies in a nursery unit. 25 babies were affected and 5 required intravenous therapy; there were not fatalities. From 24 of the 25 babies affected, an Escherichia coli with a previously undescribed O-antigen was isolated. An outbreak of diarrhoea had taken place in the same hospital a year before and re-examiniation of cultures of E. coli isolated at that time showed that 5 of the 15 babies affected had been excreting E. coli with the same O-antigen. Isolates from 10 of the babies were tested for enterotoxin production in the infant mouse model and 4 gave a positive response. The new O-antigen has been accepted into the international serotyping scheme and has been designated E. coli O159.
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