Search

A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance:a loss-of-function variant in the CACNA1Agene and two missense variants in the RETand SLC20A2genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

OBJECTIVES:The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed.METHODS:This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included.RESULTS:A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn’s disease and ulcerative colitis patients, respectively. In both Crohn’s disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01–1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07–3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27–2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13–2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09–2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn’s disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51–0.87) and age (HR=0.98; 95% CI=0.97–0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe.CONCLUSIONS:The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Abstract BackgroundAfter multiple studies, including clinical trials, suggested some mild clinical benefits from the use of rhDNase by patients with cystic fibrosis, a widespread acceptance of the drug has followed. However, long term effects, specifically on lung disease progression, have not been demonstrated. Experience with the use of this drug in a single cystic fibrosis centre is presented and compared with the trends seen in the patient population of the centre before the introduction of the drug. MethodsPatients with cystic fibrosis routinely followed at the University of Minnesota Cystic Fibrosis Center and prescribed rhDNase for at least two years were included in this retrospective study. Data on spirometric parameters (FEV ₁ and FEV ₁/FVC), allometric index, and admissions to hospital were retrieved from the centre's database for the two years preceding the prescription of rhDNase and the two years that followed. Trends in pulmonary function and allometric index were analysed by mixed linear modelling, and hospital admission rates for both periods were calculated and compared. Results One hundred and ninety patients met the inclusion criteria for the study. In the two years preceding the prescription of rhDNase the trends noted were those of a mild decline in FEV ₁, a stable FEV ₁/FVC, and a mild improvement in allometric index. In the two years that followed the prescription of rhDNase a mild decline in all these parameters occurred which was a significant change from the previous period (all p <0.009). There was no difference between females and males in the trends experienced after the start of rhDNase. By logistic regression analysis only the presence of malnutrition at the time of prescription was associated with a positive trend after the introduction of rhDNase. No significant change in the hospital admission rates occurred, with rates of 0.52 (0.16) and 0.56 (0.21) admissions/patient/year for the periods before and after the prescription of rhDNase, respectively. Conclusions The introduction of rhDNase to the regimen of patients with cystic fibrosis cared for at this centre has not been followed by a positive trend in lung function and nutritional parameters. There are some differences between this patient population and those who participated in previous studies which may help to explain the contrasting findings of this study. However, it is also possible that factors other than mucus clearance need to be improved to achieve a favourable response in disease progression. Patients on this treatment should be followed closely and the benefit judged on an individual basis. More studies are needed to define better the specific indications and use of this form of treatment.

Mycotoxins are the toxic secondary metabolite produced by fungi which can evoke a toxic response when introduced in low concentration. Several commercial laboratories have developed tests to measure mycotoxin exposure, but the methodologies underlying these tests are not well known.