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Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.
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Amelogênese Imperfeita , Autoanticorpos , Doença Celíaca , Poliendocrinopatias Autoimunes , Humanos , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/imunologia , Autoanticorpos/imunologia , Doença Celíaca/complicações , Doença Celíaca/imunologia , Imunoglobulina A/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , Proteínas/imunologia , Proteínas/metabolismo , Ameloblastos/metabolismo , Esmalte Dentário/imunologia , Esmalte Dentário/metabolismo , Proteína AIRE/deficiência , Antígenos/imunologia , Antígenos/metabolismo , Intestinos/imunologia , Intestinos/metabolismoRESUMO
Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.
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Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genéticaRESUMO
BACKGROUND: Mechanisms underlying bile duct injury in biliary atresia (BA) remain unclear and mechanisms of bile duct repair are unknown. This study aimed to explore the roles of microtubule instability and Wnt and Hippo signaling pathways in a biliatresone-induced BA model. METHODS: Using primary murine neonatal cholangiocytes in both 2D and 3D cultures, and ex-vivo extra hepatic bile ducts (EHBD) which also has peri-cholangiocyte area, we analyzed injury and recovery processes. Injury was induced by the toxin biliatresone and recovery was induced by toxin wash-out. RESULTS: Microtubule stabilizer paclitaxel prevented biliatresone-induced injury, both to cholangiocytes as well as reduced periductal αSMA stain, this process is mediated by decreased glutathione levels. RhoU and Wnt11 (Wnt signaling) and Pard6g and Amotl1 (Hippo signaling) are involved in both injury and recovery processes, with the latter acting upstream to Wnt signaling. CONCLUSIONS: Early stages of biliatresone-induced EHBD injury in cholangiocytes and periductal structures are reversible. Wnt and Hippo signaling pathways play crucial roles in injury and recovery, providing insights into BA injury mechanisms and potential recovery avenues. IMPACT: Microtubule stabilization prevents cholangiocyte injury and lumen obstruction in a toxic model of biliary atresia (biliatresone induced). Early stages of biliatresone-induced injury, affecting both cholangiocytes and periductal structures, are reversible. Both Wnt and Hippo signaling pathways play a crucial role in bile duct injury and recovery, with a noted interplay between the two. Understanding mechanisms of cholangiocyte recovery is imperative to unveil potential therapeutic avenues.
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INTRODUCTION: Adherence to the Mediterranean diet (MD) was shown to be associated with decreased disease activity in adult patients with Crohn's disease (CD). Nevertheless, data on its association with fecal calprotectin (FC), particularly in children, remain limited. This study aimed to assess the association between adherence to the MD and FC as an indicator of mucosal healing in patients who are predominantly in remission while undergoing biological therapy. METHODS: This was a cross-sectional study among children with CD. Adherence to MD was evaluated using both the KIDMED questionnaire and a food frequency questionnaire (FFQ). Israeli Mediterranean Diet Adherence Screener (I-MEDAS) score was calculated, and FC samples were obtained. RESULTS: Of 103 eligible patients, 99 were included (mean age 14.3 ± 2.6 years; 38.4% females); 88% were in clinical remission, and 30% presented with elevated FC. The mean KIDMED score was higher among patients who had FC <200 µg/g compared to patients with FC >200 µg/g (5.48 ± 2.58 vs. 4.37 ± 2.47, respectively; p = 0.04). A moderate correlation between the KIDMED score and the I-MEDAS score was observed (r = 0.46; p = 0.001). In a multivariate regression analysis, adherence to MD was associated with decreased calprotectin levels, OR 0.75 [95% CI: 0.6-0.95], p = 0.019. Vegetable consumption was found to be inversely associated with elevated FC (0.9 portion/day [0.3-2.9] in FC >200 µg/g vs. 2.2 portions/day [0.87-3.82] in FC <200 µg/g; p = 0.049). CONCLUSIONS: In children with CD who are mostly in clinical remission under biological therapy, high adherence to MD is associated with decreased FC levels. Encouraging vegetable consumption, especially during remission, may benefit these patients.
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Doença de Crohn , Dieta Mediterrânea , Adulto , Feminino , Criança , Humanos , Adolescente , Masculino , Doença de Crohn/tratamento farmacológico , Biomarcadores , Complexo Antígeno L1 Leucocitário , Estudos Transversais , Terapia Biológica , Fezes/químicaRESUMO
OBJECTIVES: Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. METHODS: Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. RESULTS: Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. CONCLUSIONS: Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.
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Antineoplásicos , Doença de Crohn , Masculino , Humanos , Criança , Adolescente , Feminino , Doença de Crohn/tratamento farmacológico , Fator de Necrose Tumoral alfa/uso terapêutico , Infliximab/uso terapêutico , Fibronectinas/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Antineoplásicos/uso terapêutico , Necrose , Colágeno , Resultado do TratamentoRESUMO
OBJECTIVES: Multiple studies in patients with Crohn's disease (CD) treated with anti-tumor necrosis factor alpha agents have shown that proactive therapeutic drug monitoring (TDM) during the maintenance phase leads to improved outcomes. We aimed to assess whether accelerated infliximab administration during induction resulted in improved outcomes. METHODS: This retrospective study included CD patients aged 5-17.9 years that were treated with infliximab. We compared outcomes of patients treated during induction with 5-8 mg/kg dosing at Weeks 0, 2, 6, and 14 (Group 1), versus accelerated dosing (≥8 mg/kg and/or >4 infusions until Week 14, Group 2) of infliximab. Primary outcome was steroid-free clinical remission by Week 52. RESULTS: Sixty-eight patients were included, of whom seven discontinued infliximab before Week 14, due to infusion reactions, immunogenic failure, or primary nonresponse. Comparison of Group 1 (n = 25) and Group 2 (n = 36) showed similar clinical characteristics, as well as inflammatory markers, at infliximab initiation. Despite receiving significantly more infliximab, and reaching a higher trough level by Week 14 (10.3 ± 1.2 vs. 3.3 ± 0.7, p < 0.001), the median Pediatric Crohn's disease Activity Index (PCDAI) was slightly higher in Group 2 versus Group 1 (14 [5-20] vs. 5 [0-15], p = 0.02). However, at Weeks 26 and 52 the PCDAI and inflammatory markers were comparable between the groups. Moreover, about 70% in both groups achieved the desirable trough infliximab levels by Week 52. CONCLUSION: Accelerated infliximab dosing during induction did not result in improved outcomes up to 12 months follow-up. Prospective studies are required to determine the exact timing in which proactive TDM should be applied.
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BACKGROUND: Biliary strictures are a significant cause of morbidity and graft loss in pediatric liver transplant recipients. Risk factors for the development of biliary strictures are not fully established. We aimed to evaluate the incidence of biliary strictures and treatment modalities outcomes and to identify potential risk factors for occurrence. METHODS: Pediatric patients who underwent liver transplantation in the single tertiary pediatric liver transplant center in Israel were evaluated. We compared demographics, presentation, laboratory results, imaging, treatment, and outcomes between patients with and without biliary stricture. Multivariate regression analyses were used to identify risk factors for biliary strictures. RESULTS: Among 121 pediatric liver transplant patients, 65 (53.7%) were males; the median age at the time of liver transplantation was 43 (3-215) months. Fifteen patients (12.4%) had biliary strictures following transplantation. One (7%) patient with biliary stricture was treated via endoscopic retrograde cholangiopancreatography, and 12 patients (80%) underwent interventions via a percutaneous transhepatic approach. Nine of the 12 patients were treated successfully, requiring one or multiple procedures, while the remaining had surgery or laser therapy. Risk factors for the development of biliary strictures were biliary leak, acute cellular rejection, and the presence of two biliary anastomoses. CONCLUSIONS: In our cohort, the presence of two biliary anastomoses and post-transplant complications including acute cellular rejection and early biliary leaks were associated with biliary strictures in pediatric liver transplantation recipients. Percutaneous transhepatic interventions result in good outcomes in most patients.
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Transplante de Fígado , Masculino , Humanos , Criança , Pré-Escolar , Feminino , Transplante de Fígado/efeitos adversos , Constrição Patológica/epidemiologia , Constrição Patológica/etiologia , Constrição Patológica/terapia , Incidência , Fatores de Risco , Encaminhamento e ConsultaRESUMO
OBJECTIVES: Autoimmune gastritis (AIG) is a rare chronic inflammatory disorder with potential long-term sequelae including gastric neoplasia. There is limited data on the natural history of pediatric AIG. We aimed to characterize the clinical course and outcomes of children with AIG. METHODS: This was a multicenter retrospective study that included pediatric patients diagnosed with AIG between January 1, 2000 and December 31, 2021. Diagnosis of AIG was based on the demonstration of histological corpus-predominant atrophic gastritis, with or without positive antiparietal cell (APCA) or anti-intrinsic factor (IF) antibodies. Demographic, clinical, laboratory, endoscopic, and histologic data were retrieved, along with follow-up data. RESULTS: Thirty-three patients, (23 females, [69.7%], median age 12.0 [interquartile range 7.0-15.0] years at diagnosis) were identified. Twenty-two patients (66.7%) had positive APCA and/or anti-IF serology. The most common presenting manifestation was iron deficiency anemia (75%), and accompanying autoimmune disorders were significantly more common in patients with positive serology (62% vs. 18%, p < 0.05). Pseudo-pyloric or intestinal-type metaplasia was present at diagnosis in eight patients (24%), and 11 additional patients (33%) developed metaplasia during a median follow-up time of 27 (17.5-48.3) months. One patient developed a type 1 gastric neuroendocrine tumor. Helicobacter pylori was identified in only one patient, while two patients had prior eradication. Endoscopic and histologic improvements weren't identified in any patients. CONCLUSIONS: AIG should be considered in patients with autoimmunity and resistant iron-deficiency anemia. H. pylori infection may not be associated with pediatric AIG. The development of neuroendocrine tumor in one patient, and the high rates of metaplasia, highlight the importance of surveillance.
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OBJECTIVE: We aimed to compare symptom frequency and severity in children with functional abdominal pain disorders (FAPDs) and to evaluate anxiety, quality of life (QoL) and global health during Coronavirus disease 2019 (COVID-19) related quarantine and after 17 months. METHODS: Children diagnosed with FAPDs between October 2019 and February 2020 at 5 different centers were enrolled and prospectively interviewed during the COVID-19 quarantine and 17 months later when schools, hospital services, and routine activities had re-opened to the public. The patients were asked to complete the Rome IV questionnaire, the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) Generic Core Scale, the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and global health questionnaires. Data about COVID-19 infection and its clinical outcome were also collected. RESULTS: Ninety-nine out of 180 (55%) children completed the follow-up. The number of patients reporting a worsening of their symptoms was significantly higher at follow-up when compared to the quarantine period (24/99 [24.2%] vs. 12/99 [12.1%]; p = 0.04). The PedsQL 4.0 subtotal score at follow-up significantly decreased at 17 months of follow-up (65.57 [0-100]) when compared to the quarantine (71 [0-100], p = 0.03). Emotional functioning was the most significantly reduced (Follow-up: 64.7 [0-100] vs. Quarantine: 75 [0-100]; p = 0.006). We did not identify significant differences in symptoms and QoL between COVID-19 infected children and the remaining cohort at the two time points. CONCLUSIONS: An improvement of symptoms and QoL was observed during the quarantine, followed by a worsening at-follow-up. These findings reinforce the hypothesis that the nest effect overweighted COVID-19 fears during the quarantine and highlight the importance of psychological factors in symptom exacerbation.
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Dor Abdominal , Ansiedade , COVID-19 , Qualidade de Vida , Quarentena , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , COVID-19/complicações , Criança , Feminino , Masculino , Dor Abdominal/etiologia , Adolescente , Quarentena/psicologia , Ansiedade/epidemiologia , Seguimentos , Estudos Prospectivos , SARS-CoV-2 , Inquéritos e Questionários , Índice de Gravidade de Doença , PandemiasRESUMO
A previous guideline on cow's milk allergy (CMA) developed by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) was published in 2012. This position paper provides an update on the diagnosis, treatment, and prevention of CMA with focus on gastrointestinal manifestations. All systematic reviews and meta-analyses regarding prevalence, pathophysiology, symptoms, and diagnosis of CMA published after the previous ESPGHAN document were considered. Medline was searched from inception until May 2022 for topics that were not covered in the previous document. After reaching consensus on the manuscript, statements were formulated and voted on each of them with a score between 0 and 9. A score of ≥6 was arbitrarily considered as agreement. Available evidence on the role of dietary practice in the prevention, diagnosis, and management of CMA was updated and recommendations formulated. CMA in exclusively breastfed infants exists, but is uncommon and suffers from over-diagnosis. CMA is also over-diagnosed in formula and mixed fed infants. Changes in stool characteristics, feeding aversion, or occasional spots of blood in stool are common and in general should not be considered as diagnostic of CMA, irrespective of preceding consumption of cow's milk. Over-diagnosis of CMA occurs much more frequently than under-diagnosis; both have potentially harmful consequences. Therefore, the necessity of a challenge test after a short diagnostic elimination diet of 2-4 weeks is recommended as the cornerstone of the diagnosis. This position paper contains sections on nutrition, growth, cost, and quality of life.
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Gastroenterologia , Hipersensibilidade a Leite , Animais , Bovinos , Feminino , Humanos , Lactente , Aleitamento Materno , Leite/efeitos adversos , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/prevenção & controle , Qualidade de Vida , Revisões Sistemáticas como Assunto , Metanálise como AssuntoRESUMO
The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.
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Recém-Nascido Prematuro , Probióticos , United States Food and Drug Administration , Humanos , Probióticos/uso terapêutico , Estados Unidos , Recém-Nascido , Microbioma Gastrointestinal , Sociedades Médicas , Europa (Continente)RESUMO
This position paper by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Coeliac Disease (SIG-CD) presents an update to the 2016 recommendations concerning early diet and the risk of coeliac disease (CD). This update adheres to the policy that mandates reviewing guidelines every 5 years, particularly when new data emerge. The 2024 statements and recommendations are essentially similar to the 2016 recommendations. Breastfeeding, whether any amount, exclusive, or of any duration, does not reduce the risk of developing CD. Introducing gluten into an infant's diet at any time between completed 4 months (≥17 weeks) and 12 months of age does not affect the cumulative incidence of CD, although earlier introduction may lead to earlier seroconversion and CD. In observational studies involving cohorts with a known risk for CD, consuming a high amount of gluten compared to a low amount during weaning and in the subsequent childhood years-specifically the first 2-3 years, and even up to 5 years in some studies-was associated with an increased risk for CD. However, the specific optimal amounts of gluten consumption remain undetermined due to insufficient evidence on safe thresholds, and the impact of restricting gluten in the diet of healthy children of unknown risk for CD is unknown. Thus, any recommendation on the gluten amount is currently unjustifiable for the general population and infants with known HLA risk types. There is no specific guidance on the type of gluten-containing foods to be introduced at weaning.
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Aleitamento Materno , Doença Celíaca , Glutens , Criança , Pré-Escolar , Humanos , Lactente , Doença Celíaca/etiologia , Doença Celíaca/dietoterapia , Dieta/efeitos adversos , Dieta/normas , Dieta Livre de Glúten , Glutens/efeitos adversos , Fatores de RiscoRESUMO
The Cow's Milk-related Symptom Score (CoMiSS) is an awareness tool for evaluating cow's milk-related symptoms. Previous studies have focused on providing CoMiSS values for healthy and symptomatic infants aged 0-6 months. However, there is a notable gap in the literature concerning CoMiSS values for infants older than 6 months. This cross-sectional study aimed to determine CoMiSS values in presumed healthy infants who have completed 6 months and are up to 12 months old, hereafter referred to as 6 to 12 months old. Physicians from six European countries prospectively determined CoMiSS values in infants attending well-child clinics. Exclusion criteria included preterm delivery, acute or chronic disease, and the consumption of a therapeutic formula, dietary supplements (except vitamins), or medication. The following information was collected: gestational age, gender, age, type of feed (breast milk or infant formula), and complementary feeding. Descriptive statistics were summarized with mean and standard deviation for normally distributed continuous variables, median and IQR for non-normally distributed variables, and differences in CoMiSS values were analyzed with appropriate tests. Data from 609 infants were obtained. The overall median (Q1-Q3) CoMiSS values were 3 (1-5). Significant differences were found across age groups (p < 0.001), but not across groups based on gender (p = 0.551) or feeding type (p = 0.880). Conclusions: This study provided CoMiSS values in presumed healthy infants aged 6-12 months. Additional studies should be conducted to establish the use of CoMiSS to assess cow's milk-related symptoms in infants 6 months and older. What is Known: ⢠The Cow's Milk-related Symptom Score (CoMiSS) is an awareness tool for evaluating symptoms related to cow's milk. ⢠CoMiSS values for presumed healthy infants aged 0-6 months infants are already available. What is New: ⢠CoMiSS values in European infants aged 6-12 months are provided. ⢠These CoMiSS values differed across various age groups but not across groups based on gender or feeding type.
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Hipersensibilidade a Leite , Leite , Lactente , Recém-Nascido , Feminino , Animais , Bovinos , Humanos , Estudos Transversais , Hipersensibilidade a Leite/diagnóstico , Leite Humano , Alérgenos , Fórmulas InfantisRESUMO
Celiac disease (CeD) is likely to be associated with growth impairment and poor weight gain. However, long-term growth patterns following diagnosis are poorly characterized. We evaluated long-term anthropometric changes in a large cohort of pediatric patients with CeD. A retrospective chart review of patients diagnosed with CeD between 1999 and 2018 was conducted. Demographic and clinical data were collected, and anthropometrics were analyzed from diagnosis and throughout follow-up. The study included 500 patients (59.8% females, median (IQR) age at diagnosis 5.7 (3.7-8.9) years), with a mean follow-up of 5.5 (range 1.5-16.2) years. Weight, height, and BMI Z-score-for-age (WAZ, HAZ, and BMIZ) increased significantly from a mean (± SD) of - 0.82 (± 1.21), - 0.73 (± 1.16), and - 0.32 (± 1.11) at diagnosis to - 0.41 (± 1.23), - 0.45(± 1.16), and - 0.17 (± 1.14) at last follow-up, respectively (p < 0.001 for WAZ and HAZ and p = 0.002 for BMIZ). The largest improvements were observed in patients diagnosed before 3 years of age (p < 0.01). Patients for whom the final adult height was available (n = 86) improved from HAZ mean (± SD) - 0.89 ± 1.37 at diagnosis to - 0.51 ± 1.28 at adulthood measurement, p < 0.05. Wasting was present in 19.7% and stunting in 16.4% of the cohort at diagnosis and normalized in 77.3% and 64.8%, respectively, within a median (IQR) time of 0.79 (0.42-4.24) and 2.3 (0.72-6.02) years, respectively. Gluten-free diet adherence and frequency of visits were not associated with normalization of wasting or stunting in all age groups. Conclusion: Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. Younger age at diagnosis is associated with greater improvement in weight and linear growth, emphasizing the importance of early diagnosis of CeD. What is Known: ⢠Celiac disease (СeD) is likely to be associated with growth impairment and poor weight gain. ⢠Long-term changes in anthropometric indices after diagnosis of CeD are not well characterized. What is New: ⢠Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. ⢠Young age at diagnosis is associated with larger improvement in weight and linear growth.
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Doença Celíaca , Humanos , Doença Celíaca/diagnóstico , Doença Celíaca/complicações , Doença Celíaca/fisiopatologia , Doença Celíaca/dietoterapia , Feminino , Masculino , Criança , Estudos Retrospectivos , Pré-Escolar , Seguimentos , Adolescente , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/diagnóstico , Índice de Massa Corporal , Estatura , Antropometria/métodos , Aumento de Peso/fisiologia , Peso CorporalRESUMO
AIM: Although sexual health (SH) impairment and sexually transmitted infections (STI) are occasionally encountered in patients with inflammatory bowel disease (IBD), paediatric gastroenterologists (PedGI) do not often discuss these issues. Literature about SH in the paediatric IBD population is limited. We aimed to assess PedGI knowledge and common practice related to sexual advice and STI workups in patients with IBD. METHODS: A questionnaire comprising 25 questions addressing sexual activity in youth, SH, recommendations, and workup for STI in adolescents with IBD was sent to all registered PedGI in Israel. RESULTS: Fifty-two physicians completed the questionnaire (27 males,52%). Only 50% correctly predicted the mean age that Israeli youth start practicing sex. Seventy-five per cent responded that providers should discuss sexual activity with their patients, but only 19% do so, most often in response to a patient's query. Ninety six percent answered that they do not have enough knowledge about SH in IBD. Finally, only 2% obtain rectal swabs for STI in patients with refractory proctitis. CONCLUSION: Sexual issues and recommendations are not routinely discussed by the majority of PedGI in paediatric IBD clinics. Providers should obtain more knowledge in the field and initiate discussion of these issues with adolescent patients with IBD.
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Doenças Inflamatórias Intestinais , Saúde Sexual , Humanos , Adolescente , Masculino , Doenças Inflamatórias Intestinais/complicações , Feminino , Padrões de Prática Médica/estatística & dados numéricos , Infecções Sexualmente Transmissíveis , Gastroenterologistas , Inquéritos e Questionários , Israel , Pediatria , Comportamento Sexual , GastroenterologiaRESUMO
Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes (BMAL1, CLOCK, PER1, PER2, CRY1, CRY2), inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) and their mutual regulatory genes (RORα, RORγ, REV-ERBα, PGC1α, PPARα, PPARγ, AMPK, SIRT1) in patients with active UC and healthy controls. The clock genes BMAL1, CLOCK, PER1 and CRY1 and the inflammatory genes IκB, IL10, NFκB1, NFκB2, IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα, RORγ, PGC1α, PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC.
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Proteínas CLOCK , Colite Ulcerativa , Criança , Humanos , Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/fisiologia , Colite Ulcerativa/genética , Inflamação/genética , Interleucina-10 , Interleucina-6 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , PPAR alfa , PPAR gama , Fator de Necrose Tumoral alfa , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Criptocromos/genética , Criptocromos/metabolismoRESUMO
BACKGROUND & AIMS: Screening for celiac disease (CD) is recommended in children with affected first-degree relatives (FDR). However, the frequency of screening and at what age remain unknown. The aims of this study were to detect variables influencing the risk of CD development and develop and validate clinical prediction models to provide individualized screening advice. METHODS: We analyzed prospective data from the 10 years of follow-up of the PreventCD-birth cohort involving 944 genetically predisposed children with CD-FDR. Variables significantly influencing the CD risk were combined to determine a risk score. Landmark analyses were performed at different ages. Prediction models were created using multivariable Cox proportional hazards regression analyses, backward elimination, and Harrell's c-index for discrimination. Validation was done using data from the independent NeoCel cohort. RESULTS: In March 2019, the median follow-up was 8.3 years (22 days-12.0 years); 135/944 children developed CD (mean age, 4.3 years [range, 1.1-11.4]). CD developed significantly more often in girls (P = .005) and in Human Leukocyte Antigen (HLA)-DQ2 homozygous individuals (8-year cumulative incidence rate of 35.4% vs maximum of the other HLA-risk groups 18.2% [P < .001]). The effect of homozygosity DR3-DQ2/DR7-DQ2 on CD development was only present in girls (interaction P = .04). The prediction models showed good fit in the validation cohort (Cox regression 0.81 [0.54]). To calculate a personalized risk of CD development and provide screening advice, we designed the Prediction application https://hputter.shinyapps.io/preventcd/. CONCLUSION: Children with CD-FDR develop CD early in life, and their risk depends on gender, age and HLA-DQ, which are all factors that are important for sound screening advice. These children should be screened early in life, including HLA-DQ2/8-typing, and if genetically predisposed to CD, they should get further personalized screening advice using our Prediction application. TRIAL REGISTRATION NUMBER: ISRCTN74582487 (https://www.isrctn.com/search?q=ISRCTN74582487).
Assuntos
Doença Celíaca , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Doença Celíaca/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Fecal calprotectin (FC) is a marker of mucosal inflammation in inflammatory bowel disease (IBD). We aimed to assess the effect of anti-tumor necrosis factor alpha (TNFα) therapy on FC levels in children with IBD. METHODS: The medical records of pediatric patients treated with anti-TNFα agents (2015-2020) were reviewed retrospectively. 63 patients had FC levels measured prior to anti TNFα induction with sequential measurements during follow-up. The main outcome measures were time to FC response according to cutoffs of 250, 150, 100 and 50 µgr/gr. RESULTS: Mean age was 13.6 ± 3 years [females 28 (44.4%), Crohn's 55 (87%)]. Outcomes of < 250, < 150, < 100 and < 50 µgr/gr were achieved by 52 (82%), 51 (81%), 44 (70%) and 32 (50%), respectively. The median time for achieving these cutoffs was 4.8 (1.8-15.6), 7.9 (2.6-16.4), 10.0 (3.5-20.5) and 18.5 (7.0-64.7) months, respectively. Shorter time from diagnosis to treatment was associated with achievement of FC < 50 µgr/gr (p = 0.03). There was no association between age, disease type, anti-TNFα type, inflammatory markers, disease activity indices at baseline and induction anti-TNFα trough concentration and FC response. CONCLUSIONS: FC response was achieved by the majority of patients treated with anti-TNFα within a short period of time. FC normalization in responders required almost one year. IMPACT: Fecal calprotectin response was achieved by the majority of pediatric patients within a relatively short period of time after anti-TNFα induction and maintenance therapy. Fecal calprotectin normalization required an average period of approximately one year in responders. The faster response of fecal calprotectin is associated with shorter time from diagnosis to anti-TNFα treatment. Inflammatory bowel disease treating physicians should be aware of the relatively prolonged time to fecal calprotectin normalization and to allow enough time for anti-TNFα therapy to express its full potential prior to significant interventions.
Assuntos
Doença de Crohn , Doenças Inflamatórias Intestinais , Feminino , Humanos , Criança , Adolescente , Estudos Retrospectivos , Complexo Antígeno L1 Leucocitário , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doença de Crohn/diagnóstico , Fator de Necrose Tumoral alfa , Necrose , Fezes , BiomarcadoresRESUMO
The Nancy Histological Index (NHI) was developed to assess histological disease activity in adult ulcerative colitis (UC) patients. However, data in pediatrics is limited. Our aim was to determine whether the NHI correlates with different indices of disease activity in pediatric UC patients. We retrospectively reviewed the NHI in rectal biopsies from 61 pediatric UC patients (median age 14.3 years), of whom 34 (55.7%) were newly diagnosed. The median Pediatric Ulcerative Colitis Activity Index (PUCAI) score among participants was 30 (interquartile range 5-55). Most patients exhibited an NHI of 3 (41/61, 67.2%) or 4 (8/61, 13.1%), reflecting moderate-severe histologic inflammation. A moderate positive correlation was identified between the NHI and PUCAI, fecal calprotectin, and Mayo endoscopic scores ( r = 0.60, 0.54, and 0.56 respectively, P ≤ 0.001), but not with CRP or albumin. These results indicate that the NHI has a modest correlation with clinical, laboratory and endoscopic indices of disease activity in pediatric UC patients.
Assuntos
Colite Ulcerativa , Adulto , Humanos , Criança , Adolescente , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/patologia , Colonoscopia , Estudos Retrospectivos , Biópsia , Fezes/química , Índice de Gravidade de Doença , Biomarcadores/análise , Complexo Antígeno L1 LeucocitárioRESUMO
OBJECTIVES: In patients with inflammatory bowel diseases (IBD), data on trough concentration (TC) response to adjustments of anti-tumor necrosis factor (TNFα) are scarce. METHODS: We included pediatric patients with IBD who were treated with anti-TNFα agents and had sequential monitoring of TC pre- and post-adjustment. Patients with positive anti-drug-antibodies or with concomitant change in immunomodulatory treatment were excluded. RESULTS: For the entire cohort (86 patients), median age at diagnosis was 13.2 (interquartile range, 10.7-14.9) years [females, 48%; Crohn disease (CD), 72%]. For infliximab, 58 patients had 201 interval changes and 26 had dose increase. Increase in TC following dose increase could not be predicted due to significant variability (P = 0.9). For every 10% decrease in interval, TC was increased by 1.6 µg/mL or by 57.2% (P = 0.014). Perianal disease was associated with attenuated response. For every 10% increase in interval, TC was decreased by 0.66 µg/mL or by 4.2%. The diagnosis of CD was associated with reduced response to interval increase. For adalimumab, 28 patients had 31 and 12 events of interval decrease or increase, respectively. Interval decrease resulted in increased median TC from 4.5 (3.5-5.3) µg/mL to 8.1 (6.5-10.5) µg/mL (X1.8) while interval increase resulted in TC change from 15.5 (12.8-18.6) µg/mL to 9.7 (6.5-14.6) µg/mL (:1.6) (P < 0.001 for both). Increase in delta TC was associated with younger age, and with absence of perianal disease (P = 0.001). CONCLUSION: Changes in TC following treatment adjustment can be almost linearly predicted for adalimumab while response to infliximab adjustment are more variable.