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Background: Childhood celiac disease in Sweden is presently seen at an incidence of around 1/250 and is thus one of the commonest chronic diseases in children. It has recently been shown that children with untreated celiac disease have increased levels of nitrate/nitrite in the urine, most likely reflecting an increased production of nitric oxide in the inflamed mucosa. Nitric oxide is produced from L-arginine by an inducible or a constitutive nitric oxide synthase. The inducible nitric oxide synthase (iNOS) can be stimulated in various cells by, for instance, inflammatory mediators. The present study has been done to find a possible source of nitric oxide in the small intestine that could result in the increased levels of nitrate/nitrite in the urine in children with active celiac disease. Methods: Small-intestinal biopsy specimens from children with active celiac disease were labeled with rabbit-anti-human antibodies to iNOS and visualized with fluorescent pig anti-rabbit antibodies. The specimens were then analyzed with confocal microscopy to assess the labeling pattern. Results: In all of seven specimens from children with increased levels of nitrate/nitrite in the urine, we detected antibodies to iNOS, whereas in five of six control specimens-that is, from children with normal nitrate/nitrite levels-we could not detect any iNOS. Conclusions: Children with active celiac disease have a gluten-induced nitric oxide production in the small intestine reflected by increased urine levels of nitrate/nitrite and iNOS expression in the intestine. We conclude that the increased production of nitric oxide could presumably, directly or indirectly, result in injury of the small-intestinal tissue. [ABSTRACT FROM AUTHOR]

Background: The bladder exstrophy-epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases., Methods: We performed array comparative genomic hybridization (array-CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies., Results: We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10 -4 ). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1 wt and Lztr1 mut , indicating a potential functional effect of the LZTR1 mut ., Conclusion: Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)