ObjectiveTo investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE).DesignAdults with active EoE (n=76) randomly received 14 days’ treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm2 hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation.ResultsHistological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients.ConclusionsBET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation.ClinicalTrials.gov numberNCT02280616; EudraCT number, 2009-016692-29.

Rodent inbred line crosses are widely used to map genetic loci associated with complex traits. This approach has proven to be powerful for detecting quantitative trait loci (QTL); however, the resolution of QTL locations, typically ‫02ف‬ cM, means that hundreds of genes are implicated as potential candidates. We describe analytical methods based on linear models to combine information available in two or more inbred line crosses. Our strategy is motivated by the hypothesis that common inbred strains of the laboratory mouse are derived from a limited ancestral gene pool and thus QTL detected in multiple crosses are likely to represent shared ancestral polymorphisms. We demonstrate that the combined-cross analysis can improve the power to detect weak QTL, can narrow support intervals for QTL regions, and can be used to separate multiple QTL that colocalize by chance. Moreover, combined-cross analysis can establish the allelic states of a QTL among a set of parental lines, thus providing critical information for narrowing QTL regions by haplotype analysis.

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The sterolin locus ( ABCG5/ABCG8 ) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [3H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ˜250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding single nucleotide polymorphisms. Subsequent mutation detection and genotyping yielded two disease-associated variants: ABCG5-R50C ( P = 4.94 × 10−9) and ABCG8-D19H ( P = 1.74 × 10−10) in high pairwise linkage disequilibrium ( r 2 = 0.95). [3H]-cholesterol export assays of allelic constructs harboring these genetic candidate variants demonstrated increased transport activity (3.2-fold, P = 0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German ( P = 0.018), Chilean ( P = 0.030), and Chinese ( P = 0.040) patient samples. Conclusion : This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation, thereby drawing a link between “postgenomic” and “pregenomic” pathophysiological knowledge about this common complex disorder.