ABSTRACT
Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies.
Subject(s)
Autoantigens/genetics , Collagen Type IV/genetics , Hematuria/genetics , Mutation , Nephritis, Hereditary/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , DNA Mutational Analysis , Exome , Female , Genetic Association Studies , Hematuria/diagnosis , Hematuria/metabolism , Humans , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/metabolism , Male , Middle Aged , Nephritis, Hereditary/diagnosis , Nephritis, Hereditary/metabolism , Portugal , Young AdultABSTRACT
BACKGROUND/OBJECTIVES: Adequate nutrition is considered important for learning, but there is little robust research on the association between diet and learning in school-aged children in industrialized countries. This study investigated the effect of tailored modifications to the food and dining experience in secondary schools on learning-related behaviours. SUBJECTS/METHODS: In 2008, 12 co-educational secondary schools in England were recruited. Schools were randomly allocated to receive a tailored action plan and support to modify their food provision and dining environment over a 15-week period (intervention or to control). Learning-related behaviours were systematically observed during post-lunchtime classes at all schools. Observations were made by trained observers using a validated protocol to determine whether pupils were 'on-task' (concentrating and alert) or 'off-task' (disruptive or disengaged). RESULTS: In total, 156 pupils were observed (control n = 58, intervention n = 98) at baseline (12,210 and 20,560 observations, control and intervention, respectively) and at follow-up (16,846 and 23,462, respectively). On-task and off-task behaviours were similar across treatment groups at baseline. At follow-up, intervention group pupils were 18% more likely to be on-task (odds ratio (OR) 1.18, 95% confidence interval ((95% CI) 1.05-1.33) and 14% less likely to be off-task (OR 0.86, 95% CI 0.75-0.98) compared with control group pupils. CONCLUSIONS: This study suggests that modifying food provision and the dining environment can improve learning-related behaviours of secondary school pupils in the post-lunch period. This finding supports ongoing investment and interventions by local authorities across the United Kingdom to improve school food and lunchtime dining facilities.
Subject(s)
Child Behavior , Diet/psychology , Feeding Behavior , Learning , Schools , Child , England , Environment , Follow-Up Studies , Food , Food Services , Humans , Logistic Models , Random AllocationABSTRACT
OBJECTIVE: The aim of this study was to examine the effects of recombinant human Fgf18 on chondrocyte proliferation and matrix production in vivo and in vitro. In addition, the expressions of Fgf18 and Fgf receptors (Fgfr) in adult human articular cartilage were examined. METHODS: Adenovirus-mediated transfer of Fgf18 into murine pinnae and addition of FGF18 to primary cultures of adult articular chondrocytes were used to assess the effects of FGF18 on chondrocytes. In situ hybridization was used to examine the expression of Fgf18 and Fgfr s in adult human articular cartilage. RESULTS: Expression of Fgf18 by adenovirus-mediated gene transfer in murine pinnae resulted in a significant increase in chondrocyte number. Chondrocytes were identified by staining with toluidine blue and a monoclonal antibody directed against type II collagen. Fgf18, Fgfr 2-(IIIc), Fgfr 3-(IIIc), and Fgfr 4 mRNAs were detected within these cells by in situ hybridization. The nuclei of the chondrocytes stained with antibodies to PCNA and FGF receptor (FGFR) 2. Addition of FGF18 to the culture media of primary articular chondrocytes increased the proliferation of these cells and increased their production of extracellular matrix. To assess the receptor selectivity of FGF18, BaF3 cells stably expressing the genes for the major splice variants of Fgfr1-3 were used. Proliferation of cells expressing Fgfr 3-(IIIc) or Fgfr 2-(IIIc) was increased by incubation with FGF18. Using FGFR-Fc fusion proteins and BaF3 cells expressing Fgfr 3-(IIIc), only FGFR 3-(IIIc)-Fc, FGFR 2-(IIIc)-Fc or FGFR 4-Fc reduced FGF18-mediated cell proliferation. Expression of Fgf18, Fgfr 3-(IIIc) and Fgfr 2-(IIIc) mRNAs was localized to chondrocytes of human articular cartilage by in situ hybridization. CONCLUSION: These data demonstrate that Fgf18 can act as a trophic factor for elastic chondrocytes and their progenitors in vivo and articular chondrocytes cultured in vitro. Expression of Fgf18 and the genes for two of its receptors in chondrocytes suggests that Fgf18 may play an autocrine role in the biology of normal articular cartilage.
Subject(s)
Chondrocytes/metabolism , Fibroblast Growth Factors/genetics , Adult , Animals , Cartilage, Articular/chemistry , Cell Division/drug effects , Cell Movement/drug effects , Chondrocytes/cytology , Collagen Type II/metabolism , Ear, External , Female , Fibroblast Growth Factors/analysis , Gene Expression , Gene Transfer Techniques , Humans , Immunohistochemistry/methods , In Situ Hybridization/methods , Mice , Mice, Nude , Proteoglycans/metabolism , RNA, Messenger/analysis , Receptors, Fibroblast Growth Factor/analysis , Receptors, Fibroblast Growth Factor/genetics , Recombinant Proteins/pharmacology , SwineABSTRACT
IL-22 is an IL-10 homologue that binds to and signals through the class II cytokine receptor heterodimer IL-22RA1/CRF2-4. IL-22 is produced by T cells and induces the production of acute-phase reactants in vitro and in vivo, suggesting its involvement in inflammation. Here we report the identification of a class II cytokine receptor designated IL-22RA2 (IL-22 receptor-alpha 2) that appears to be a naturally expressed soluble receptor. IL-22RA2 shares amino acid sequence homology with IL-22RA1 (also known as IL-22R, zcytor11, and CRF2-9) and is physically adjacent to IL-20Ralpha and IFN-gammaR1 on chromosome 6q23.3-24.2. We demonstrate that IL-22RA2 binds specifically to IL-22 and neutralizes IL-22-induced proliferation of BaF3 cells expressing IL-22 receptor subunits. IL-22RA2 mRNA is highly expressed in placenta and spleen by Northern blotting. PCR analysis using RNA from various tissues and cell lines showed that IL-22RA2 was expressed in a range of tissues, including those in the digestive, female reproductive, and immune systems. In situ hybridization revealed the dominant cell types expressing IL-22RA2 were mononuclear cells and epithelium. Because IL-22 induces the expression of acute phase reactants, IL-22RA2 may play an important role as an IL-22 antagonist in the regulation of inflammatory responses.
