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Showing results for tags 'mucosal'.
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Celiac.com 08/15/2019 - Does the cystic fibrosis transmembrane conductance regulator play a pathogenic role in celiac disease? Usually, when people consume dietary proteins, their guts prevent local inflammatory and immune responses, and encourage oral tolerance to the proteins. However, for about one out of a hundred people worldwide, gluten and related cereals trigger an HLA DQ2/8-restricted TH immune and antibody response, which develops into celiac disease, if untreated. Prior epithelial stress and innate immune activation are required to break oral tolerance to gliadin. How gliadin subverts host intestinal mucosal defenses remains elusive. Does the cystic fibrosis transmembrane conductance regulator play a pathogenic role in celiac disease? A team of researchers recently set out to shed some light on the way gliadin subverts host intestinal mucosal defenses. The research team included Valeria R Villella, Andrea Venerando, Giorgio Cozza, Speranza Esposito, Eleonora Ferrari, Romina Monzani, Mara C Spinella, Vasilis Oikonomou, Giorgia Renga, Antonella Tosco, Federica Rossin, Stefano Guido, Marco Silano, Enrico Garaci, Yu-Kai Chao , Christian Grimm, Alessandro Luciani, Luigina Romani, Mauro Piacentini, Valeria Raia, Guido Kroemer & Luigi Maiuri. Their team demonstrated that the a-gliadin-derived LGQQQPFPPQQPY peptide (P3–43) inhibits the function of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel pivotal for epithelial adaptation to cell-autonomous or environmental stress. P3–43 binds to, and reduces ATPase activity of, the nucleotide-binding domain- (NBD) of CFTR, thus impairing CFTR function. This creates epithelial stress, tissue transglutaminase and inflammasome activation, NF-jB nuclear translocation and IL-5 production, that all can be prevented by potentiators of CFTR channel gating. The CFTR potentiator VX-770 reduces gliadin-induced inflammation and promotes tolerance in gluten-sensitive mice and cells from patients with celiac disease. The team's results show that CFTR plays an early and crucial role in guiding gliadin activities, and reveals a new therapeutic possibility for treating celiac disease. Stay tuned for more developments on this and related stories. Read more at the EMBO Journal (209) 38: e000 The researchers are variously affiliated with the European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy; the Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy; the Department of Molecular Medicine, University of Padova, Padova, Italy; the Department of Health Sciences, University of Eastern Piedmont, Novara, Italy; the Department of Experimental Medicine, University of Perugia, Perugia, Italy; the Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University Naples, Naples, Italy; the Department of Biology, University of Rome “Tor Vergata”, Rome, Italy; Department of Chemical, Materials and Production Engineering, Federico II University Naples, Naples, Italy; the Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Roma, Italy; University San Raffaele and 21 IRCCS San Raffaele, Rome, Italy; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Munich (LMU), Munich, Germany; the Institute of Physiology CH, University of Zurich, Zurich, Switzerland; the National Institute for Infectious Diseases IRCCS “L. Spallanzani”, Rome, Italy; the Centre de Recherche des Cordeliers, Equipe11 labellisée Ligue Nationale Contrele Cancer, Paris, France; the Centre de Recherche des Cordeliers, INSERM U1138, Paris, France; the Université Paris Descartes, Paris, France; the Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; the Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; and the Department of Women’s and Children’s Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
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Celiac.com 10/26/2017 - Making an accurate count of intraepithelial lymphocytes (IEL) is important to making an accurate diagnosis of celiac disease, but so far, researchers have not been able to establish a definitive 'normal' IEL range. In a recent multi-center study, a team of researchers set out to do just that. The research team included Kamran Rostami, Michael N Marsh, Matt W Johnson, Hamid Mohaghegh, Calvin Heal, Geoffrey Holmes, Arzu Ensari, David Aldulaimi, Brigitte Bancel, Gabrio Bassotti, Adrian Bateman, Gabriel Becheanu, Anna Bozzola, Antonio Carroccio, Carlo Catassi, Carolina Ciacci, Alexandra Ciobanu, Mihai Danciu, Mohammad H Derakhshan, Luca Elli, Stefano Ferrero, Michelangelo Fiorentino, Marilena Fiorino, Azita Ganji, Kamran Ghaffarzadehgan, James J Going, Sauid Ishaq, Alessandra Mandolesi, Sherly Mathews, Roxana Maxim, Chris J Mulde, Andra Neefjes-Borst, Marie Robert, Ilaria Russo, Mohammad Rostami-Nejad, Angelo Sidoni, Masoud Sotoudeh, Vincenzo Villanacci, Umberto Volta, Mohammad R Zali, Amitabh Srivastava. They are variously affiliated with the twenty-eight institutions listed below. The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centers in eight countries on three continents, recruited 198 patients with Marsh III histology, and another 203 control subjects. They used a single agreed upon protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. They also collected demographic and serological data. The research team used receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off between normal and celiac disease (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. The average ages of celiac and control groups were 45.5 and 38.3 years, respectively. They found that mean IEL count was 54±18/100 enterocytes in celiac disease and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the sub-classification of the Marsh III lesion. Their ROC curve analyses show that a cut-off of 25 IEL/100 enterocytes for Marsh III lesions provides the best way to distinguish between normal control and celiac disease biopsies. They saw no differences in IEL counts between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental gluten antigenic influence. Source: GUT Affiliations: The team members for this study are affiliated with the Department of Gastroenterology and Pathology, Milton Keynes University Hospital, Milton Keynes, UK; the Department of Gastroenterology, Luton and Dunstable University Hospital, Luton, UK; the Wolfson College, University of Oxford, Oxford, UK; the Gastroenterology and Liver Diseases Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, The Islamic Republic of Iran; the Centre for Biostatistics, Faculty of Biology, Academic Health Science Centre, University of Manchester, Manchester, UK; the Department of Gastroenterology, Royal Derby Hospital, Derby, UK; the Department of Pathology, Ankara University Medical School, Ankara, Turkey; the Department of Gastroenterology, Warwick Hospital, Warwick, UK; the Service de Pathologie, Centre de Biologie et Pathologie Groupe Hospitalier du Nord, Hospices Civils de Lyon, Lyon, France; University of Perugia Medical School, Perugia, Italy; the Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Department of Pathology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Institute of Pathology Spedali Civili, Brescia, Italy; Internal Medicine and Pathology Unit, University of Palermo, Giovanni Paolo II Hospital, Sciacca, Italy; Department of Pediatrics and Surgical Pathology, Università Politecnica delle Marche, Ancona, Italy; Department of Medicine and Surgery, Scuola Medica Salernitana, University of Salerno, Salerno, Italy; Departments of Gastroenterology and Pathology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania; College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran; Center for Prevention and Diagnosis of Coeliac Disease and Pathology Unit, Fondazione IRCCS Ca' granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Medical and Surgical Sciences, University of Bologna and Diagnostic and Experimental, University of Bologna, Bologna, Italy; Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University 0f Medical Sciences, Mashhad, Iran; Pathology department, Razavi hospital, Mashhad, Iran; Department of Pathology, Southern General Hospital, Lanarkshire, UK; Department of Hepatogastroenterology and Pathology, Free University Medical Centre, Amsterdam, The Netherlands; Department of Pathology and Medicine, Yale University School of Medicine, New Haven, USA; Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran; Department of Pathology, Brigham & Women's Hospital, Boston, USA.
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Celiac.com 10/13/2017 - Tissue transglutaminase (tTG) immunoglobulin A (IgA) testing is a sensitive adjunct to the diagnosis of coeliac disease. The threshold for positivity was developed for diagnosis, with negative results reported as below the reference value (<4 U/mL). A team of researchers recently set out to investigate if an undetectable tissue transglutaminase IgA antibodies (tTG IgA<1.2 U/mL) is more predictive of healing compared to patients with negative but detectable serology (1.2-3.9 U/mL). The research team included H. Fang, K. S. King, J. J. Larson, M. R. Snyder, T. T. Wu, M. J. Gandhi, and J. A. Murray. They are variously affiliated with the Department of Medicine, the Division of Gastroenterology and Hepatology, the Division of Anatomic Pathology, the Division of Clinical Biochemistry and Immunology, the Division of Biomedical Statistics and Informatics, and the Division of Transfusion Medicine at the Mayo Clinic, Rochester, MN, USA. The research team conducted a retrospective study of 402 treated coeliac disease patients seen at the Mayo Clinic with negative tTG IgA values drawn within 1 month of duodenal biopsy between January 2009 and December 2015. The team used Corazza-Villanacci scores to assess mucosal healing, and logistic regression to assess the relationship of clinical variables with a normal biopsy. They also noted the presence of gastrointestinal symptoms. Their results showed that patients with undetectable test levels more frequently had normal duodenal histology, as compared with patients with detectable tTG IgA levels. Asymptomatic patients more often showed normal duodenal histology as compared to symptomatic patients. Patients with undetectable blood levels, and who followed a gluten-free diet for ≥2 years were more likely to have no villous atrophy, as compared to patients with detectable blood levels. Follow-up biopsies revealed that people recovering from celiac disease with negative tTG IgA serology showed that undetectable test levels are associated with normal histology. Source: AP&T
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Celiac.com 01/23/2017 - It makes some kind of sense that kids with celiac disease who follow a gluten-free diet will recover, their guts will normalize, and their levels of IgA tissue transglutaminase antibodies would drop to reflect this change; whereas high antibodies likely mean no recovery, right? But is that true? Is there really a correlation on any level? To test this idea, a team of researchers recently set out to document the rate of mucosal recovery in kids with celiac disease on a gluten-free diet. They also wanted to figure out whether IgA tissue transglutaminase (tTG) correlates with mucosal damage at the time of a repeat endoscopy with duodenal biopsy. The research team included Maureen M. Leonard, Dascha C. Weir, Maya DeGroote, Paul D. Mitchell, Prashant Singh, Jocelyn A. Silvester, Alan M. Leichtner, and Alessio Fasano. Their team conducted a retrospective chart review of one-hundred and three pediatric patients, under 21 years of age, with a diagnosis of celiac disease defined as Marsh 3 histology, and who underwent a repeat endoscopy with duodenal biopsy at least twelve months after initiating a gluten free diet. Their result showed that 19% of these pediatric patients treated with a gluten-free diet still had persistent enteropathy. At the time of the repeat biopsy, tTG was elevated in 43% of cases with persistent enteropathy, and in 32% of cases in which there was mucosal recovery. So, high tTG levels could be seen in both recovered patients, and non-recovered patients. The overall positive predictive value of the autoantibody tissue transglutaminase was 25%, and the negative predictive value was 83%, in patients on a gluten free diet for a average of 2.4 years. Nearly one in five children with celiac disease in this study population had persistent enteropathy, even with a gluten free diet. Also, IgA tTG was not an accurate marker of mucosal recovery. Neither the presence of symptoms, nor positive serology predicted a patient's histology at the time of repeat biopsy. These findings could help improve current monitoring and management criteria of celiac disease in children. Source: Journal of Pediatric Gastroenterology & Nutrition. doi: 10.1097/MPG.0000000000001460
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Celiac.com 04/20/2016 - People with celiac disease very often have reflux symptoms. A team of researchers recently set out to evaluate mucosal integrity and motility of the lower esophagus as possible contributors to reflux symptoms in patients with celiac disease. The research team included María Inés Pinto-Sánchez, Fabio D. Nachman, Claudia Fuxman, Guido Iantorno, Hui Jer Hwang, Andrés Ditaranto, Florencia Costa, Gabriela Longarini, Xuan Yu Wang, Xianxi Huang, Horacio Vázquez, María L. Moreno, Sonia Niveloni, Premysl Bercik, Edgardo Smecuol, Roberto Mazure, Claudio Bilder, Eduardo C. Mauriño, Elena F. Verdu, and Julio C. Bai. They are variously affiliated with the Farncombe Family Digestive Health Research Institute at McMaster University, in Hamilton, Ontario, Canada, the Department of Medicine, "Dr. Carlos Bonorino Udaondo" Gastroenterology Hospital in Buenos Aires, Argentina, Favaloro University Hospital in Buenos Aires, Argentina, Consejo de Investigación en Salud, MSAL, Gobierno de la Ciudad Autónoma de Buenos Aires, Argentina, and with the Gastroenterology Chair, Universidad del Salvador in Buenos Aires, Argentina. For their study, they enrolled newly diagnosed celiac disease patients with and without reflux symptoms, non-celiac patients with classical reflux disease (GERD), and control subjects, who had no reflux symptoms. Using both light microscopy and electron microscopy, they assessed endoscopic biopsies from the distal esophagus for dilated intercellular space (DIS). They used qRT-PC to determine tight junction (TJ) mRNA proteins expression for zonula occludens-1 (ZO-1) and claudin-2 and claudin-3 (CLDN-2; CLDN-3). Overall, patients with active celiac disease showed higher DIS scores than controls, and similar to GERD patients. They found altered DIS even in celiac disease patients without reflux symptoms, who had normalized after one year of a gluten-free diet. Celiac disease patients with and without reflux symptoms had lower expression of ZO-1 than controls. Celiac disease and GERD patients showed similar expression of CLDN-2 and CLDN-3. This study shows that patients with active celiac disease have altered esophageal mucosal integrity, independent of any reflux symptoms. Loss of TJ integrity in the esophageal mucosa may result from altered expression of ZO-1, which may contribute to the development of reflux symptoms. Source: Open Original Shared Link
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Celiac.com 07/15/2015 - Current celiac disease call for a follow-up biopsy taken 1 year after diagnosis to monitor gut recovery. Many celiac patients show incomplete gut recovery at that time, but there’s not much research to help doctors figure out how significant this might be. A team of researchers recently investigated associated factors and the significance of imperfect gut recovery in patients in whom the follow-up had been completed. The research team included Henna Pekki, Kalle Kurppa, Markku Mäki, Heini Huhtala, Harri Sievänen, Kaija Laurila, Pekka Collin and Katri Kaukinen. They are variously affiliated with the Medical School and the School of Health Sciences at the University of Tampere, the Tampere Center for Child Health Research at the University of Tampere and Tampere University Hospital in Tampere, Finland, the UKK Institute inTampere, Finland, the Department of Gastroenterology and Alimentary Tract Surgery, and the Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. For their study, the team split 263 biopsy-proven celiac patients into two groups: one with histological recovery, and the other with incomplete recovery, after one year on gluten-free diet. The team measured serology, laboratory values, bone mineral density, and various clinical variables at diagnosis and after one year. They used validated questionnaires to assess gastrointestinal symptoms and quality of life, and also gathered further long-term follow-up data on mortality, malignancies, and other severe complications. The results showed that the incomplete recovery group had more severe mucosal damage (P=0.003), higher antibody values (P=0.017), and more signs of malabsorption at diagnosis (P<0.001). The data showed no difference in gender, symptoms or quality of life, family history of celiac disease, or co-morbidities. Follow-up showed a difference in antibodies (P=0.018) and femoral T-scores (P=0.024). Histologically recovered patients showed better gluten-free dietary adherence, although both groups reported close adherence to a gluten-free diet (97% for recovered group, versus 87% for the incomplete group (P<0.001). Interestingly, there was no difference in long-term outcomes between groups. Although, patients with more severe celiac disease in terms of histology, serology, and signs of malabsorption were more likely to show histological non-response. Patients who closely follow a gluten-free diet, incomplete villous recovery after 1 year does not affect the clinical response or long-term prognosis. Source: The American Journal of Gastroenterology , (2 June 2015). doi:10.1038/ajg.2015.155
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Celiac.com 04/22/2014 - Blood tests are highly valuable for diagnosing celiac disease. However, their role in gauging mucosal healing in celiac children who have adopted gluten-free diets is unclear. A team of researchers recently set out to compare the performance of antibody tests in predicting small-intestinal mucosal status in diagnosis and follow-up of pediatric celiac disease. The research team included Edith Vécsei, Stephanie Steinwendner, Hubert Kogler, Albina Innerhofer, Karin Hammer, Oskar A Haas, Gabriele Amann, Andreas Chott, Harald Vogelsang, Regine Schoenlechner, Wolfgang Huf, and Andreas Vécsei. They are variously affiliated with the Clinical Department of Pathology and the Department of Internal Medicine III of the Division for Gastroenterology and Hepatology, the Center for Medical Physics and Biomedical Engineering, the Department of Pediatrics and Pediatric Gastroenterology of St. Anna Children's Hospital, all at Medical University Vienna, and with the Institute of Pathology and Microbiology, Wilhelminenspital in Vienna, and with the Department of Food Science and Technology, Institute of Food Technology, University of Natural Resources and Life Sciences in Vienna, Austria. The team conducted a prospective cohort study at a tertiary-care center, where 148 children received biopsies either for symptoms ± positive celiac disease antibodies (group A; n = 95) or following up celiac disease diagnosed ≥ 1 year before study enrollment (group B; n = 53). Using biopsy (Marsh ≥ 2) as the criterion standard, they calculated areas under ROC curves (AUCs) and likelihood-ratios to gauge the performance of antibody tests against tissue transglutaminase (TG2), deamidated gliadin peptide (DGP) and endomysium (EMA). They found that AUC values were higher when tests were used for celiac disease diagnosis compared with follow-up: 1 vs. 0.86 (P = 0.100) for TG2-IgA, 0.85 vs. 0.74 (P = 0.421) for TG2-IgG, 0.97 vs. 0.61 (P = 0.004) for DPG-IgA, and 0.99 vs. 0.88 (P = 0.053) for DPG-IgG, respectively. Empirical power was 85% for the DPG-IgA comparison, and on average 33% (range 13–43) for the non-significant comparisons. A total of 88.7% of group B children showed mucosal healing, at an average of 2.2 years after primary diagnosis. Only the negative likelihood-ratio of EMA was low enough (0.097) to effectively rule out persistent mucosal injury. However, out of 12 EMA-positive children with mucosal healing, 9 subsequently tested EMA-negative. Among the celiac disease antibodies examined, negative EMA most reliably predict mucosal healing. In general, however, antibody tests, especially DPG-IgA, are of limited value in predicting the mucosal status in the early years after celiac diagnosis, though they may do better over a longer time. Source: BMC Gastroenterology 2014, 14:28. doi:10.1186/1471-230X-14-28
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Celiac.com 09/25/2013 - People with celiac disease have higher rates of lymphoproliferative malignancy. Currently, doctors just don't know whether risk levels are affected by the results of follow-up intestinal biopsy, performed to document mucosal healing. A team of researchers recently tried to find out if overall risk for lymphoproliferative malignancy in people with celiac disease is connected with levels of mucosal healing. The research team included Benjamin Lebwohl, MD, MS; Fredrik Granath, PhD; Anders Ekbom, MD, PhD; Karin E. Smedby, MD, PhD; Joseph A. Murray, MD; Alfred I. Neugut, MD, PhD; Peter H.R. Green, MD; and Jonas F. Ludvigsson, MD, PhD. The are variously affiliate with the Columbia University College of Physicians and Surgeons, New York, New York; Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; Mayo Clinic College of Medicine, Rochester, Minnesota; and Örebro University Hospital, Örebro, Sweden. For their population-based cohort study, the team looked at data from all 28 pathology departments in Sweden. They evaluated at data for 7625 patients with celiac disease who received follow-up biopsy after initial diagnosis. Measurements: They used expected rates to assess risk for LPM, compared with that of the general population. They then used Cox regression to compare rates of LPM in patients with persistent villous atrophy against rates for patients with mucosal healing. Of the 7625 patients with celiac disease and follow-up biopsy, 3308 (43%) showed persistent villous atrophy. Overall risk levels for LPM were higher for celiac patients who had received biopsy (standardized incidence ratio [sIR], 2.81 [95% CI, 2.10 to 3.67]) than for the general population. LPM risk levels were higher for celiac patients with persistent villous atrophy (SIR, 3.78 [CI, 2.71 to 5.12]) than for those with mucosal healing (SIR, 1.50 [CI, 0.77 to 2.62]). Compared with mucosal healing, persistent villous atrophy was associated with an increased risk for LPM (hazard ratio , 2.26 [CI, 1.18 to 4.34]). Risk for T-cell lymphoma was higher (HR, 3.51 [CI, 0.75 to 16.34]), but not for B-cell lymphoma (HR, 0.97 [CI, 0.21 to 4.49]). One limitation of the study is that it gathered no data about patient adherence to a gluten-free diet. Higher risk for LPM in celiac disease is connected with follow-up biopsy results, with a higher risk among patients with persistent villous atrophy. Follow-up biopsy may be an effective way to classify celiac disease patients by risk for subsequent LPM. Source: Ann Intern Med. 2013;159(3):169-175. doi:10.7326/0003-4819-159-3-201308060-00006
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Celiac.com 10/07/2013 - People with non-celiac gluten-sensitivity often report gut and non-gut symptoms shortly after eating gluten; symptoms disappear on gluten-free diets, although these patients have no serologic markers of celiac disease, and no intestinal damage. However, there is no evidence to suggest any changes to blood or mucosa in those individuals. To better understand non-celiac gluten sensitivity, a research team recently assessed immunologic responses of duodenal mucosa samples and peripheral blood basophils, isolated from NCGS patients, after exposure to gliadin. The research team included Cristina Bucci, Fabiana Zingone, Ilaria Russo, Ivonne Morra, Raffaella Tortora, Norberto Pogna, Giulia Scalia, Paola Iovino, and Carolina Ciacci. They are affiliated with CEINGE in Naples, Italy; the Consiglio per la Ricerca e la Sperimentazione in Agricoltura in Rome, Italy; the Gastrointestinal Unit of the Department of Medicine and Surgery at the University of Salerno in Salerno, Italy; and with the Gastrointestinal Unit at the Department of Clinical and Experimental Medicine of Federico II University of Naples. Between January 2010 and July 2011, the research team gathered mucosa samples from 34 celiac disease patients who followed gluten-free diets for at least 6 months, 35 patients with untreated celiac disease, 16 patients with non-celiac gluten sensitivity (NCGS) and 34 healthy control subjects. The team diagnosed non-celiac gluten sensitivity based on patient symptoms and current diagnositic guidelines. For each of the 119 patients, the team conducted a complete clinical evaluation to exclude celiac disease while on a gluten-containing diet, a skin prick test to exclude wheat allergy, and upper endoscopy at 2 tertiary medical centers in Italy. After incubating each biopsy sample with gliadin, the team measured inflammatory markers, including anti-phosphotyrosine-monoclonal antibody (PY99), HLA-DR, intercellular cell adhesion molecule-1 (ICAM-1), CD3, CD25 and CD69. After incubation with gliadin, mucosa samples from the 69 patients with celiac disease showed increased immunofluorescence intensity for early and delayed markers of inflammation. They also found low levels of some of these markers in three patients with non-celiac gluten sensitivity and three controls. The team found normal mucosal architecture in 56.3% of patients with non-celiac gluten sensitivity. The remaining seven patients showed increased intraepithelial infiltration, but without eosinophils. They found no villous atrophy in patients with non-celiac gluten sensitivity, and no significant increases in the levels of CD63 and CD203c. The team did find that one patient each in the NCGS and control groups, whose results indicated only weak PY99 and ICAM-1 positivity, also had Helicobacter pylori infection. Unlike mucosa from patients with celiac disease, once incubated with gliadin, mucosa from patients with NCGS does not express markers of inflammation, nor does the gliadin activate their basophils. The in vitro gliadin challenge therefore should not be used to diagnose NCGS. This study does suggest that wheat components, other than proteins, might be associated with GI symptoms in patients with IBS, and should be assessed for a possible role in the pathogenesis of NCGS. Source: Clinical Gastroenterology and Hepatology. Volume 11, Issue 10 , Pages 1294-1299.e1, October 2013
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Scand J Gastroenterol 1999 Sep;34(9):909-14 AW Morrow Gastroenterology and Liver Centre, Dept of Histopathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. SPECIAL NOTE: European Codex Alimentarius quality wheat starch was used in this study. (Celiac.com 06/25/2000) BACKGROUND: It is expected that in patients with coeliac disease the small bowel mucosal mucosa will return to normal if they adhere to a gluten-free diet (GFD). However, in many this is not the case. This study aims to determine whether this persistent villous atrophy (VA) could be due to continued ingestion of the trace amounts of gluten in gluten-free foods, as defined by the WHO/FAO Codex Alimentarius. METHODS: Duodenal biopsy specimens from 89 adults with long-standing coeliac disease were examined, and the findings correlated with their form of gluten-free diet. RESULTS: In 51 subjects the duodenal specimen was normal, whereas in 38 there was villous atrophy (partial, 28; subtotal, 8; total, 2). There was no relationship between the presence or absence of VA and ingestion of either a GFD as defined by the Codex Alimentarius (Codex-GFD; 39 patients) or a GFD that contained no detectable gluten (NDG diet: 50 patients). Intraepithelial lymphocyte counts were higher, and lactase levels lower, in subjects with an abnormal biopsy specimen than in those in whom it was normal. However, within each of these biopsy groups there was no difference in these variables between patients on a Codex-GFD and those on an NDG-GFD. IgA antigliadin antibody was detected in 4 of 29 patients on a Codex-GFD and in 3 of 13 on a NDG-GFD (NS). CONCLUSION: The persistent mucosal abnormalities seen in patients with coeliac disease on a GFD are not due to the ingestion of trace amounts of gluten. The consequences of these abnormalities have yet to be determined.
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Celiac.com 03/28/2012 - A clinical research team wanted to determine if adding ascorbate (vitamin C) to gliadin-stimulated biopsy culture could reduce the mucosal immune response to gliadin in people with celiac disease. The research team included D. Bernardo, B. Martínez-Abad, S. Vallejo-Diez, E. Montalvillo, V. Benito, B. Anta, L. Fernández-Salazar, A. Blanco-Quirós, J. A. Garrote, and E. Arranz. They are affiliated with the Mucosal Immunology Lab of the Department of Paediatrics & Immunology at Spain's Universidad de Valladolid-CSIC. Their quest was fueled by the understanding that the IL-15/NF-κB axis plays a key role in celiac disease. Because ascorbate is known to inhibit effects on NF-κB, the IL-15/NFκB axis looks like a good possible molecular target for reducing gliadin-induced inflammation in celiac disease. For their study, the team conducted in vitro gliadin challenges (100 μg/ml) on duodenal biopsy explants from treated patients with celiac disease. Challenges were conducted with and without 20mM ascorbate. As an internal control, the team used an extra tissue explant in basal culture. The team then measured secretion levels of nitrites (3h), and IFNγ, TNFα, IFNα, IL-17, IL-13, and IL-6 (24h) on the supernatants. They measured IL-15 using western-blot on whole protein duodenal explants. When the team added ascorbate to in vitro culture gliadin-challenged biopsies, they found that the ascorbate blocked secretion of nitrites (p=0.013), IFNγ (p=0.0207), TNFα (p=0.0099), IFNα (p=0.0375), and IL-6 (p=0.0036), as compared with samples from culture that received no ascorbate. They also found that the addition of ascorbate reduced cytokine secretion to levels even lower than those observed in basal cultures (IFNγ: p=0.0312; TNFα: p=0.0312; IFNα: p=0.0312; and IL-6: p=0.0078). Moreover, the gliadin-challenge triggered IL-15 production in biopsies from treated celiac disease patients, while IL-15 was completely blocked in the cultures that received ascorbate. Interestingly, ascorbate completely blocked IL-15 production even in the only treated celiac disease-patient who showed basal IL-15 production. From these results, the team concludes that ascorbate reduces the mucosal inflammatory response to gluten in an in vitro biopsy culture. As such, ascorbate might offer supplementary benefits in future celiac disease therapy. Source: Allergol Immunopathol (Madr). 2012 Jan-Feb;40(1):3-8.
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Celiac.com 03/08/2012 - Eating gluten-free for an entire lifetime is no easy task. Many people with celiac disease and gluten-sensitivities would love an alternative to a gluten-free diet, and a number of companies are looking to develop alternative therapies that would enable people to consume gluten without suffering damage. Even though nearly all drug-development programs include gluten challenges, very little is known about the duration of gluten challenge and gluten dosage. That is, how quickly does gluten cause damage, and at what dosages? A team of researchers recently studied the ways in which antibodies respond and mucosa change when the small bowel is exposed to gluten in people with celiac disease. The study team included Marja-Leena Lähdeaho, Markku Mäki, Kaija Laurila, Heini Huhtala, and Katri Kaukinen. To assess the amount of gluten-exposure needed to cause some small-bowel mucosal deterioration, the team conducted a gluten-challenge on twenty-five adult celiac patients. Each patient received either a low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. The team assessed patient symptoms, including small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology. Their results showed that both moderate and low amounts of gluten induced small-bowel damage in 67% of celiac patients. However, moderate gluten doses also caused mucosal inflammation and gastrointestinal symptoms in seven patients that lead to their premature withdrawal from the study. Interestingly, 22% of patients who developed significant small-intestinal damage showed no symptoms. The team concludes that, for most people with celiac disease, even low amounts of gluten can cause significant mucosal changes. However, since many people with celiac disease show no such response, sample sizes must be large enough to be statistically significant. Source: BMC Gastroenterology. 2011;11(129).
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Celiac.com 04/13/2011 - When people with celiac disease consume gluten, their intraepithelial lymphocytes (IELs) wreak havoc in their guts by promoting inflammation and attacking the epithelial cells lining the intestines. This autoimmune activity is mediated by arachidonic acid (AA), a cytokine produced by the IELs. But there is data that the enterocytes "the very intestinal epithelial cells attacked by the IELs" can also produce and secrete AA in response to inflammation. Do they do so in celiac disease? A recent study reported in Clinical Nutrition set out to determine just that. Using Caco-2 cells, a human intestinal epithelial cell line commonly used as an in vitro model of celiac disease, Vincentini et al. are the first to find that when these enterocytes were exposed to gliadin peptides, they did in fact generate and release arachidonic acid. Docosahexaenoic acid (DHA) is a long chain polyunsaturated fatty acid that counteracts many of the inflammatory effects precipitated by AA. When Caco-2 cells were treated with gliadin peptides and DHA, they produced much less AA (although they still made more than untreated cells). Treatment with DHA also reduced the production of other molecules involved in inflammation that were increased by exposure to gliadin, including cyclooxygenase (COX)-2, prostaglandin E2 (PGE2), and interleukin (IL)-8. PGE2 is particularly interesting, as it can increase the intestinal paracellular permeability that has been suggested to be the initial event in the pathogenesis of celiac disease. The authors suggest that by blocking the release of AA, DHA might be a tenable therapeutic option for modulating mucosal inflammation in newly diagnosed celiac patients. Source: Vincentini O, Quaranta MG, Viora M, Agostoni C, and Silano M. Docosahexaenoic acid modulates in vitro the inflammation of celiac disease in intestinal epithelial cells via the inhibition of cPLA2. Clin Nutr. 2011 Mar 19.
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Celiac.com 02/23/2011 - In most adults with celiac disease, clinical symptoms disappear with a gluten-free diet. However, the exact effects of a gluten-free diet on rates of mucosal recovery in adults with celiac disease is less certain. A group of clinicians recently set out to assess rates of mucosal recovery under a gluten-free diet in adults with celiac disease, and to gauge the clinical prospects of ongoing mucosal damage in celiac patients who follow a gluten-free diet. The study group included Alberto Rubio-Tapia, MD; Mussarat W. Rahim, MBBS; Jacalyn A. See, MS, RD, LD; Brian D. Lahr, MS; Tsung-Teh Wu, MD; and Joseph A. Murray, MD. Each patient in the study had biopsy-proven celiac disease, and was assessed at the Mayo Clinic. Also, each patient received duodenal biopsies at diagnosis. After beginning a gluten-free diet, each patient had at least one follow-up intestinal biopsy to assess mucosal recovery. The study team focused on mucosal recovery and overall mortality. Of 381 adult patients with biopsy-proven celiac disease, a total of 241 (175 women - 73%) had both a diagnostic and follow-up biopsy available for re-review. Using the Kaplan–Meier rate of confirmed mucosal recovery to assess these 241 patients, the study group found that 34% of the patients enjoyed mucosal recovery at 2 years after diagnosis (95% with a confidence interval (CI): 27–40 % ), and 66% of patients enjoyed mucosal recovery at 5 years (95% CI: 58–74 % ). More than 80% of patients showed some clinical response to the gluten-free diet, but clinical response was not a reliable marker of mucosal recovery ( P = 0.7). Serological response was, by far, the best marker for confirmed mucosal recovery ( P = 0.01). Patients who complied poorly with a gluten-free diet ( P < 0.01), those with severe celiac disease defined by diarrhea and weight loss ( P < 0.001), and those with total villous atrophy at diagnosis ( P < 0.001) had high rates of persistent mucosal damage. With adjustments for gender and age, patients who experienced confirmed mucosal recovery had lower mortality rates overall (hazard ratio = 0.13, 95 % CI: 0.02 – 1.06, P = 0.06). One of the most important findings from this study was that a large number of adults with celiac disease have no mucosal recovery, even after treatment with a gluten free diet. Compared to those patients who suffered persistent damage, patients who experienced confirmed mucosal recovery had lower rates of mortality independent of age and gender. The group notes that systematic follow-up via intestinal biopsy may be advisable for adults with celiac disease. Source: Am J Gastroenterol. 9 February 2010; doi: 10.1038/ajg.2010.10
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Celiac.com 04/16/2010 - In most adults with celiac disease, clinical symptoms disappear with a gluten-free diet. However, the exact effects of a gluten-free diet on rates of mucosal recovery in adults with celiac disease is less certain. A group of clinicians recently set out to estimate the rate of mucosal recovery under a gluten-free diet in adult subjects with celiac disease, and to gauge the clinical prospects of ongoing mucosal damage in celiac patients following a gluten-free diet. The study group included: Alberto Rubio-Tapia, MD; Mussarat W. Rahim, MBBS; Jacalyn A. See , MS , RD, LD; Brian D. Lahr , MS; Tsung-Teh Wu, MD; and Joseph A. Murray, MD. Each patient in the study had biopsy-proven celiac disease, and was assessed at the Mayo Clinic. Also, each patient received duodenal biopsies at diagnosis. After beginning a gluten-free diet, each patient had at least one follow-up intestinal biopsy to assess mucosal recovery. The study team focused on mucosal recovery and overall mortality. Of 381 adult patients with biopsy-proven celiac disease, a total of 241 (175 women - 73%) had both a diagnostic and follow-up biopsy available for re-review. Using the Kaplan–Meier rate of confirmed mucosal recovery on these 241 patients, the study group found that 34% of patients enjoyed mucosal recovery at 2 years following diagnosis (95% with a confidence interval (CI): 27–40 % ), and 66% of patients enjoyed mucosal recovery at 5 years (95% CI: 58–74 % ). More than 80% of patients showed some clinical response to the gluten-free diet, but clinical response was not a reliable marker of mucosal recovery ( P = 0.7). Serological response was, by far, the best marker for confirmed mucosal recovery ( P = 0.01). Patients who complied poorly with a gluten-free diet ( P < 0.01), those with severe celiac disease defined by diarrhea and weight loss ( P < 0.001), and those with total villous atrophy at diagnosis ( P < 0.001) had high rates of persistent mucosal damage. With adjustments for gender and age, patients who experienced confirmed mucosal recovery had lower mortality rates overall (hazard ratio = 0.13, 95 % CI: 0.02 – 1.06, P = 0.06). One of the most important findings from this study was that a large number of adults with celiac disease see no mucosal recovery, even after treatment with a GFD. Compared to those patients who suffered persistent damage, patients who experienced confirmed mucosal recovery had lower rates of mortality independent of age and gender. The group notes that systematic follow-up via intestinal biopsies may be advisable in patients diagnosed with celiac disease as adults. SOURCE: Am J Gastroenterol. 9 February 2010; doi: 10.1038/ajg.2010.10
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Celiac.com 03/15/2010 - A team of researchers recently set out to investigate mucosal expression of claudins 2, 3 and 4 in the proximal and distal parts of duodenum in children with celiac disease. The team included Dorottya Nagy Szakál, Hajnalka GyÅ‘rffy, András Arató, Áron Cseh, Kriszta Molnár, Mária Papp, Antal DezsÅ‘fi, and Gábor Veres. They are variously associated with the Department of Pediatrics, and the Department of Pathology at Semmelweis University in Budapest, Hungary, and the Department of Medicine at the University of Debrecen in Debrecen, Hungary. Duodenal biopsy is an important tool for properly diagnosing celiac disease. However, the issue of finding the best site for taking biopsy samples that will give the best results for diagnosing celiac disease is still not fully resolved. Claudins (CLDNs), belong to a large group of related adherent junction proteins, which are known to express characteristic patterns in inflammatory disorders. However, doctors presently know nothing about CLDN expression in people with celiac disease. To address the situation, the team performed a comparative study to examine the CLDN 2, 3 and 4 expressions in both the proximal and distal parts of duodenum in children with celiac disease and in control subjects. For the study, they enrolled a total of forty-seven children. Thirty-three had newly diagnosed celiac disease, while fourteen healthy children served as control subjects. The team took biopsies from proximal and distal part of duodenum, and used immunohistochemistry to detect CD3+ intraepithelial lymphocytes and CLDN 2, 3 and 4 protein expressions. Whether taken from proximal or distal part of duodenum, biopsies revealed no differences under macroscopic imaging, routine histology and Marsh grading. However, in comparison to controls, patients with severe celiac disease showed significantly higher CLDN 2 expression in bulb and in distal duodenum, while non-severe celiac patients showed higher distal CLDN 2 expression. The data showed similar associations regarding CLDN 3 expression. All groups showed similar expression of CLDN 4. The data showed that both proximal and distal mucosal duodenal biopsies are suitable for diagnosing villous atrophy in patients with celiac disease. Finally, the team noted that increased expressions of CLDN 2 and 3 imply structural changes of tight junction in celiac disease, which may play a role in increased permeability and proliferation observed in celiac disease. Source: Virchows Archive, Volume 456, Number 3 / March, 2010
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Celiac.com 02/24/2010 - Proper clinical diagnosis of celiac diseasestill relies on confirmation of histological evidence of villousatrophy via biopsy. Getting a good sample can sometimes be tricky. Ifhistological sections are not optimally oriented, then diagnosis may bemore difficult. As a result, doctors can sometimes fail to confirm theproper diagnosis. A team of researchers recently set out tostudy the viability of confirming histological evidence of villousatrophy in real time, during upper gastrointestinal endoscopy, in liveduodenal mucosa of patients with celiac disease, using endocytoscopy, anovel diagnostic technique allowing in vivo real-time visualization ofmucosa under 450x magnification. The research team included T. Matysiak-Budnik, E. Coron1, J.-F. Mosnier, M. Le Rhun1, H. Inoue,and J.-P. Galmiche. They are associated variously with the Institutdes Maladies de l'Appareil Digestif - INSERM U913, CIC 04 et Serviced'Hépato-Gastroentérologie, Hôtel Dieu, CHU de Nantes, France, theService d'Anatomie Pathologique, E.A. Biometadys, CHU de Nantes,France, and the Digestive Disease Center, Showa University NorthernYokohama Hospital, Japan The team studied sixteen subjects withclinically proven celiac disease, together with seven controls subjectswith no celiac disease. They took endocytoscopic images from multipleareas and then made a blind comparison against standard histology. Endocytoscopy revealed three distinct patterns of in vivo histology. First,in all controls and eight celiac disease patients (n = 15),endocytoscopy revealed the presence of normal-appearing, long, thinvilli, lined with clearly distinguishable surface epithelial cells,considered to be normal duodenal mucosa. Second, in four celiacdisease patients, endocytoscopy revealed the presence of thick,shortened villi, reflecting partial villous atrophy. Finally,in four celiac disease patients, endocytoscopy revealed the totalabsence of villi, along with the presence of enlarged crypt orifices,reflecting total villous atrophy. The team found solid agreement between endocytoscopy and standard histology in all 16 patients with celiac disease. Fromtheir results, they conclude that endocytoscopy permits live,real-time, noninvasive imaging and assessment of villous architecture,and looks to be a promising method for in vivo evaluation of duodenalmucosa in celiac disease. Source: Endoscopy: DOI: 10.1055/s-0029-12438
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Celiac.com 03/16/2009 - Current treatment for celiac disease consists of a lifetime gluten-free diet. However, once the diagnosis is made, most people don’t really receive regular follow-up or monitoring of their treatment unless they have some obvious complaint. That’s beginning to change, and more doctors are beginning to advocate long-term celiac care, which includes regular tests to assess dietary compliance. To accomplish this goal, doctors are working to determine the best program of follow-up treatment. A team of Austrian researchers recently set out to determine which noninvasive test for celiac disease is best for assessing mucosal status in people with celiac disease. The research team was made up of doctors Andreas K. W. Vécsei, Ulrike B. Graf, and H. Vogelsang, associated with St. Anna Children's Hospital, Vienna, Austria and the Department of Gastroenterology and Hepatology, Clinic of Internal Medicine III, Medical University of Vienna, Vienna, Austria. The research team set out to clarify which noninvasive follow-up methods for testing blood serum or intestinal permeability (IPT) – best match the patient’s histology, and whether the accuracy of these tests is affected by the interval between diagnosis and follow-up affects. The team mined a computer database to compile information from adult patients, diagnosed with celiac disease between December 1989 and July 2006, who underwent follow up via biopsy, IPT, and serological testing via IgG anti-gliadin antibodies (AGA-IgG), AGA-IgA, and endomysial antibodies (EMA). They measured effectiveness of noninvasive test results based on the presence of villous atrophy upon biopsy. The team divided patients into two groups. The first, group A, comprised patients followed up within 24 months of diagnosis, and group B, comprising patients followed up after 24 months. In all, the team was able to evaluate forty-seven patients. The tests showed the following results: Lactulose/mannitol (L/M) ratio showed a sensitivity of 85% and a specificity of 46.2% for mucosal atrophy, while saccharose excretion showed a sensitivity of 60% and a specificity of 52.6%. AGA-IgA and AGA-IgG showed 15% and 20%, respectively, and both showed specificity of 100%. AGA was of limited usefulness due to low number of positive results. EMA assay was 50% sensitive and 77.8% specific. In group A (n = 23) L/M ratio performed best in terms of sensitivity (88.9%), whereas EMA achieved a higher specificity (71.4%). In group B, the sensitivity of the L/M ratio decreased to 85.7%, while the specificity of EMA increased to 91.7%. The team concluded that these results show that none of the non-invasive tests was an accurate replacement for follow-up biopsy in detecting severe mucosal damage. Until an accurate test is developed, long-term follow-up monitoring of gluten-free status in people with celiac disease will remain difficult to do reliably without biopsy. Endoscopy 2009; 41: 123-128
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Celiac.com 11/02/2007 - Researchers at the University of Chicago using vitamin D receptor "knockout" mice demonstrated vitamin D may have a key role in maintaining the intestinal mucosal barrier and the integrity of tight junctions. The "knockout" mice were genetically altered to produce mice lacking vitamin D receptors normally expressed by cells in most body tissues. A dextran sulfate sodium solution was used to induce colitis in both normal control mice and "knockout" mice. Normal mice resisted intestinal mucosal injury from the dextran sulfate sodium solution, but "knockout" mice "developed severe diarrhea, rectal bleeding and marked body weight loss, leading to death in 2 weeks" and displayed severe colonic ulceration, impaired wound-healing, and tight junction disruption. Additional study in cell cultures found vitamin D markedly enhanced and preserved tight junction integrity in the presence of dextran sulfate sodium and also stimulated epithelial healing. The study concluded vitamin D deficiency may compromise the mucosal barrier, increasing susceptibility to mucosal damage and the risk of bowel disorders. It is possible a vitamin D deficiency early in life could be a factor in triggering the onset of celiac disease as well as slowing the recovery of the mucosa after celiac disease is diagnosed and treated. Reduced sun exposure due to modern changing life styles might account for an increasing incidence celiac disease and other autoimmune disorders. Vitamin D deficiency at the time gluten is introduced into an infant's diet could also play a role in celiac disease onset. A previous study performed in Sweden found babies born in summer more susceptible to celiac disease than babies born in winter. If gluten is first introduced to babies some 6 months after birth, seasonal variation of vitamin D levels might account for the difference, i.e. summer-born babies would receive their first gluten in midwinter when sun exposure is minimal. Since breastfed babies obtain vitamin D from mother's milk, nursing mothers need to be sure to maintain high vitamin D levels during winter months. A study just released by the National Cancer Institute examined the relationship between serum 25(OH)D levels and total cancer mortality in 16818 participants and concluded "results do not support an association between 25(OH)D and total cancer mortality." However, the study did find "colorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/L or higher associated with a 72% risk reduction compared with lower than 50 nmol/L." The fact that vitamin D appears to lower colon cancer mortality risk is consistant with the preservation role vitamin D appears to play in maintaining the intestinal mucosal barrier. Note that this study does not consider whether receiving daily doses of vitamin D supplements much higher than current recommendations would provide a cancer risk benefit. --------- Am J Physiol Gastrointest Liver Physiol. 2007 Oct 25. Novel Role of the Vitamin D Receptor in Maintaining the Integrity of the Intestinal Mucosal Barrier. Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J, Bissonnette M, Li YC. Medicine, The University of Chicago, Chicago, Illinois, United States; Chicago, Illinois, United States. http://ajpgi.physiology.org/cgi/content/abstract/00398.2007v1 . ---------- J Epidemiol Community Health. 2003 Jan;57(1):36-9. Children born in the summer have increased risk for coeliac disease. Ivarsson A, Hernell O, Nystrom L, Persson LA. Department of Public Health and Clinical Medicine, Epidemiology, Umea University, Umea, Sweden. http://jech.bmj.com/cgi/content/full/57/1/36 . ---------- J Natl Cancer Inst. 2007 Oct 30. Prospective Study of Serum Vitamin D and Cancer Mortality in the United States. D. Michal Freedman, Anne C. Looker, Shih-Chen Chang, Barry I. Graubard. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD. http://jnci.oxfordjournals.org/cgi/content/abstract/djm204 .
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