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Evaluation of Diagnostic Accuracy of Celiac Disease Screening Tests in Children

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Evaluation of Diagnostic Accuracy of Celiac Disease Screening Tests in Children Evaluation of Diagnostic Accuracy of Celiac Disease screening tests in children A. Polimeno, G. Frulio, A. Zambrotta, D. Palmieri, P. Carandente Giarrusso Celiac disease (CD) is an autoimmune-enteropathy caused by the ingestion of gluten-containing grains in genetically susceptible individuals. Small bowel biopsy is the gold standard for CD diagnosis (1) but serological tests are the first step in ascertaining a diagnosis of CD. Tests for CD in children include anti-tissue Transglutaminase IgA antibodies (anti-tTGA), anti-Endomysial IgA antibodies (EMA) and anti-Deamidated Gliadin Peptides IgA and IgG antibodies (a-DGP IgA/IgG) tested only in children younger than 2 years (2). In this context, it’s noteworthy that new ESPGHAN (European Society of Pediatric Gastroenterology Hepatology and Nutrition) Guidelines suggest exclusively anti-tTGA as initial approach to symptomatic subjects, also in children (3). So we compared the diagnostic accuracy of anti-tTGA and a-DGP IgA/IgG in children younger than 2 years. We selected 378 subjects (357 non CD subjects and 21 CD subjects diagnosed by duodenal biopsy) younger than 2 years from the Pediatric Clinic, University Hospital “Federico II” of Naples; for all subjects we performed anti-tTGA, a-DGP IgA and a-DGP IgG by Enzyme-Linked Immunosorbent Assay (ELISA). We determined the correlation between anti-tTGA and a-DGP IgA/IgG by Spearman’s correlation coefficient. Anti-tTGA significantly correlate with a-DGP IgA (ρ=0,383; p<0,0001) and a-DGP IgG (ρ=0,260; p<0,0001). Moreover, we evaluated the diagnostic accuracy of a-DGP IgA, a-DGP IgG and anti-tTGA tests by Receiver Operator Characteristic (ROC) curves. Anti-tTGA (sensitivity=100%; specificity=100%) are more sensitive and specific than a-DGP IgA (sensitivity=85%; specificity=99,4%) and a-DGP IgG (sensitivity=90%; specificity=95,5%). Our results suggest that anti-tTGA, because of high diagnostic accuracy, may be used as initial screening test for CD, also in children younger than 2 years, according to new ESPGHAN Guidelines. A-DGP IgA and a-DGP IgG could be used as additional screening tests in children younger than 2 years, negatives for anti-tTGA, but in whom the clinical symptoms give rise to a strong suspicion of CD. References: 1-Rubio-Tapia A., Murray J.A. Celiac Disease. Curr Opin Gastroenterol. 2010 March; 26(2):116- 122. 2-Panetta F., Torre G., Colistro F., Ferretti F., Daniele A., Diamanti A. Clinical accuracy of anti- tissue transglutaminase as screening test for celiac disease under 2 years. Acta Paediatr. 2011 May; 100(5)728-31. 3-Husby S., Koletzko S., Korponay-Szabó I.R., Mearin M.L., Phillips A., Shamir R., Troncone R., Giersiepen K., Branski D., Catassi C., Lelgeman M., Mäki M., Ribes-Koninckx C., Ventura A., Zimmer K.P.; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of celiac disease. J Pediatr Gastroenterol Nutr. 2012 Jan; 54(1):136-60. Role of the non-coding regions of the CFTR gene in cystic fibrosis Felice Amato, Ausilia Elce, Sonia Giordano, Manuela Scorza, Renato Liguori, Federica Zarrilli, Rossella Tomaiuolo, Giuseppe Castaldo Mutation epidemiology is crucial for cystic fibrosis (CF) diagnosis and counselling. About 6-7% of alleles from CF patients do not bear mutations in the coding regions of the Cystic Fibrosis Transmembrane Regulator (CFTR) disease gene; in these patients, mutations may be present in non-coding, regulatory regions of the gene as i) intronic regions (particularly in high conserved sequences); ii) the promoter region or iii) the area at the 3’ UTR of the gene, that is the target of microRNA regulation. We study these regions by gene sequencing in CF patients with one or both unidentified mutations after the analysis of CFTR coding regions, and in CF patients with a different clinical expression of the disease to evaluate if mutations in such regions may have a role in modulating CF clinical expression. Our analysis revealed so far: i) a dozen of mutations (most novel) in the large promoter area of 6000 bp at the 5’ of the gene; expression studies in four cell lines demonstrated that a half of such mutations may have a pathogenic effect; ii) a series of mutations in 52 conserved sequence tags (CSTs), i.e., intronic regions with a high homology between humans and mouse. Expression studies revealed the some of these mutations are able to increase or decrease the CFTR activity; iii) finally, we studied the 1500 bp region at the 3’ UTR of the gene, identifying three mutations. One of this has a pathogenic role, enhancing the interaction of CFTR with two inhibitory miRNAs. At our knowledge, this is the first example of such pathogenic mechanism in a monogenic disorder. To conclude: the sequencing of non coding regions may improve the detection rate of molecular analysis in cystic fibrosis, and may help to reveal novel pathogenic mechanisms of CF. References Castaldo G, Tomaiuolo R (2013) What is the role of the non-coding regions of the CFTR gene in cystic fibrosis? Expert Rev Respir Med 7: 327-329. Giordano S, Amato F, Elce A, Monti M, Iannone C, Pucci P,.Seia M,.Angioni A,.Zarrilli F,Castaldo G and Tomaiuolo, R. (2013).. Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. J Mol Diagn 15: 331-340. Amato F, Seia M, Giordano S, Elce A, Zarrilli F, Castaldo, G and Tomaiuolo, R.(2013). Gene mutation in microRNA target sites of CFTR gene: a novel pathogenetic mechanism in cystic fibrosis? PLoS One 8: e60448. Molecular approaches for the rapid diagnosis of bacterial and fungal infections De Gregorio E, Iula VD, Roscetto E, Pulcrano G, Catania MR. Respiratory and bloodstream infections represent severe and potentially fatal diseases demanding rapid diagnostic methods for detection of the responsible microorganisms. Classic microbiological diagnostics are time-consuming and characterized by a high rate of negative results, not only for fastidious, slow-growing, and/or nonculturable microorganisms but also for easy-to-culture pathogens. Culture-independent molecular methods improve the diagnostic outcome in terms of speed of analysis, sensibility and specificity and allow a prompt therapeutic treatment. Our research team is interested in studying molecular methods for rapid diagnosis of fungal and bacterial infections. A first approach concerns the direct identification of pathogens from biological samples by real time PCR. Primers and probes has been designed on: i) 16S and 23S rDNA and ITS region respectively; ii) repetitive coding sequences specific for different bacterial species (1). Another aspect of our research concerns the rapid identification of fungi and bacteria by MALDI- TOF mass spectrometry(MS) directly from blood cultures to greatly shorten laboratory times (2). Based on characteristic protein spectra obtained from intact cells, MALDI-TOF MS is characterized by low operational costs and allows a highly discriminatory identification of bacteria, yeasts and filamentous fungi starting from colonies. More recently MALDI-TOF MS is used to distinguish epidemiologically related isolates up to detect micro-evolutionary changes (3). MALDI-TOF MS in not only much easy and less time consuming than other typing methods, but it requires a limited amount of colonies, so representing a fast and reliable method for typing strains. MALDI-TOF MS is also used for detection of carbapenems and their degradation products from both Gram-negative isolates and directly from bloodstream cultures. These two applications will benefit patient care by optimizing antimicrobial therapies and defining outbreaks. 1) Di Nocera PP, De Gregorio E, Rocco F. (2013) GTAG- and CGTC-tagged palindromic DNA repeats in prokaryotes. BMC Genomics 31: 522. 2) Pulcrano G, Iula DV, Vollaro A, Tucci A, Cerullo M, Esposito M, Rossano F, Catania MR. (2013) Rapid and reliable MALDI-TOF mass spectrometry identification of Candida non-albicans isolates from bloodstream infections. J Microbiol Methods 94: 262-6. 3) Pulcrano G, Roscetto E, Iula VD, Panellis D, Rossano F, Catania MR. (2012) MALDI-TOF mass spectrometry and microsatellite markers to evaluate Candida parapsilosis transmission in neonatal intensive care units. Eur J Clin Microbiol Infect Dis 31: 2919-28. First and second generation Human Anti-tumor Immunoagents Chiara D’Avino, Gennaro Riccio, Rolando Paciello and Claudia De Lorenzo Immunotherapy is of great interest today as an effective strategy to fight cancer. An attractive target for immunotherapy is ErbB2, a tyrosine kinase receptor overexpressed on many carcinoma cells of different origin with a key role in the development of malignancy. Herceptin, a humanized anti-ErbB2 antibody, is effective in the therapy of breast carcinoma, but it engenders cardiotoxicity and many cancer patients are resistant to Herceptin-treatment. Novel human antitumor immunoconjugates were engineered in our laboratory by isolation through phage display technology of novel human antibody fragments, such as Erbicin, a human anti-ErbB2 scFv, and their fusion with either a human RNase or the Fc region of a human IgG1 (Erb-hcAb). Erbicin-Derived Immunoagents (EDIA) were found to be selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo. Furthermore, EDIA recognize an epitope different from that of Herceptin, are active on some Herceptin-resistant cancer cells both in vitro and in vivo, and are not cardiotoxic. Indeed, EDIA, differently from Herceptin, do not show toxic effects in vitro on rat and human cardiomyocytes, and do not impair cardiac function in vivo in a mouse model. Second generation EDIA were also obtained by the fusion of either Erb-hcAb with human pancreatic RNase (Erb-hcAb-RNase) or by the conjugation of Erbicin with a ribonuclease inhibitor-resistant variant of HP-RNase (Erb-HP-DDADD-RNase) .
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