Anti-TNF-α treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial

BACKGROUND: Endometriosis is associated with an inflammatory response. Hence infliximab, an anti-TNF-alpha monoclonal antibody, might relieve pain. METHODS: A randomized placebo-controlled trial was designed with 21 women with severe pain and a rectovaginal nodule of at least 1 cm. After 1 month of observation, three infusions of infliximab (5 mg/kg) or placebo were given. Surgery was performed 3 months later and follow-up continued for 6 months. The primary end-point was pain (dysmenorrhea, deep dyspareunia and non-menstrual pain) rated at each visit by the clinician and on a daily basis by the patient who in addition scored pain by visual analog pain scale and analgesia intake. Secondary end-points included the volume of the endometriotic nodule, pelvic tenderness and the visual appearance of endometriotic lesions at laparoscopy. RESULTS: Pain severity decreased during the treatment by 30% in both the placebo (P < 0.001) and infliximab groups (P < 0.001). However, no effect of infliximab was observed for any of the outcome measures. After surgery, pain scores decreased in both groups to less than 20% of the initial value. CONCLUSIONS: Infliximab appears not to affect pain associated with deep endometriosis. Treatment is associated with an important placebo effect. After surgery, pain decreases to less than 20%. Trials registration number ClinicalTrials.gov: NCT00604864

Aplicación racional de los nuevos criterios de la European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 para el diagnóstico de la enfermedad celíaca

Coeliac disease is a systemic immune-mediated disorder triggered by the ingestion of gluten, which is given in genetically predisposed subjects. It manifests with a wide variety of clinical symptoms, specific serological markers, HLA-DQ2/DQ8 haplotype, and enteropathy. The criteria followed for this have usually been those established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) since 1969. These criteria have advanced from the need of several intestinal biopsies to, thanks to the development of serological tests of high sensitivity and specificity, considering the enteropathy as one more element in this diagnosis and makes it possible to perform a diagnosis without the need of an intestinal biopsy in certain circumstances. The updated review of the 2012 criteria in 2019 provides new evidence on some aspects, such as the role of HLA, the diagnosis of asymptomatic patients, and the effectiveness of the serological markers. These aspects are reviewed in detail, with the aim of facilitating the rational application of the new 2020 criteria at all care levels. In this sense, Paediatric Primary Care is fundamental in the search for active cases and to perform a first serological study, being recommended that the diagnosis is always establishedby a Paediatric GastroenterologistLa enfermedad celíaca es un proceso sistémico de carácter inmunológico, desen-cadenado por el consumo de gluten, que se da en sujetos genéticamente predispuestos. Se expresa con una gran variedad de síntomas clínicos, marcadores serológicos específicos, hap-lotipo HLA-DQ2/DQ8 y enteropatía. El tratamiento consiste en eliminar de por vida el gluten de la dieta, por lo que es fundamental un diagnóstico adecuado. Los criterios seguidos para ello han sido habitualmente los establecidos por la European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) desde 1969. Estos criterios han ido evolucionando desde la necesidad de varias biopsias intestinales para el diagnóstico a, gracias al desarrollo de pruebas serológicas de alta sensibilidad y especificidad, considerar la enteropatía como un elemento más en este diagnóstico y posibilitar en determinadas circunstancias realizarlo sin necesidad de biopsia intestinal. La revisión actualizada en 2019 de los criterios 2012 aporta nueva evidencia sobre algunos aspectos, como el papel del HLA, el diagnóstico de los pacientes asintomáticos y la eficacia de los marcadores serológicos. Estos aspectos se revisan en detalle,con el objetivo de facilitar la aplicación de los nuevos criterios 2020 de una forma racional en todos los niveles asistenciales. En este sentido el pediatra de Atención Primaria es fundamental para la búsqueda activa de casos y realizar un primer estudio serológico, recomendándose que el diagnóstico sea siempre establecido por un pediatra gastroenterólog

Usefulness of the organ culture system in the in vitro diagnosis of coeliac disease: A multicentre study

Objective. Diagnosis of coeliac disease is based on the presence of villous atrophy which recovers following a gluten-free diet. The presence of circulating antiendomysial antibodies as well as their disappearance after a gluten-free diet supports the diagnosis. It has also been demonstrated that antiendomysial antibodies are detectable in supernatants of cultured intestinal biopsies from patients with coeliac disease. The objective of this study was to compare the histology and antiendomysial antibodies in culture supernatants of intestinal biopsies to validate the in vitro organ culture system as a future diagnostic tool for coeliac disease. Material and methods. Seventy-five antiendomysial serum-positive patients on a gluten-containing diet were evaluated. Patients underwent endoscopy with 5 biopsy fragments: 3 for histology, 1 cultured with and the other without gliadin-peptide activator. Antiendomysial antibodies were evaluated in all culture supernatants. Results. Sixty-eight patients had evidence of villous atrophy, while 73 out of 75 were positive to the organ culture system. The agreement rate between organ culture and histology results was 94%. Conclusions. As all the centres participating in the study obtained good agreement between organ culture and histology results, the new system could be considered a reliable tool for the diagnosis of coeliac disease. Nevertheless, it is possible to highlight cases with an organ culture-positive and -negative histology. This feature could be of considerable interest because, as the sensitivity of organ culture seems to be greater than the initial histology, the new system might be useful in uncertain cases where the risk of missing the diagnosis of coeliac disease is high

Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose

[EN] Background Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat. Methods In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations. Results In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009). Conclusions Although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored. Impact Faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physiopathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children with cystic fibrosis should be targeted.We acknowledge the support of the MyCyFAPP Project consortium. We especially thank the participation and the effort of the patients involved in the study and their families. This work was fully funded by the European Union and the Horizon 2020 Research and Innovation Framework Programme (PHC-26-2014 call Self management of health and disease: citizen engagement and mHealth) under grant number 643806.Calvo-Lerma, J.; Roca-Llorens, M.; Boon, M.; Colombo, C.; De Koning, B.; Fornés-Ferrer, V.; Masip, E.... (2021). Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose. Pediatric Research. 89(1):205-210. https://doi.org/10.1038/s41390-020-0860-3S205210891Turck, D. et al. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin. Nutr. 35, 557–577 (2016).Borowitz, D., Baker, R. D. & Stallings, V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 35, 246–259 (2002).Fieker., A., Philpott, J. & Armand, M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin. Exp. Gastroenterol. 4, 55 (2011).Sitrin, M. D. Digestion and Absorption of Carbohydrates and Proteins in the Gastrointestinal System 137–158 (Springer, Dordrecht, 2014).Gelfond, D. et al. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig. Dis. Sci. 58, 2275–2281 (2013).Robinson, P. J. et al. Duodenal pH in cystic fibrosis and its relationship to fat malabsorption. Dig. Dis. Sci. 35, 1299–1304 (1990).Hunter, J. E. Studies on effects of dietary fatty acids as related to their position on triglycerides. Lipids 36, 655–668 (2001).Hernell, O., Staggers, J. E. & Carey, M. C. Physical–chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestionin healthy adult human beings. Biochemistry 29, 2041–2056 (1990).Calvo-Lerma, J. et al. A first approach for an evidence-based in vitro method to adjust pancreatic enzyme replacement therapy in cystic fibrosis. PLoS ONE 14, e0212459 (2019).Aburub, A. Comparison of pH and motility of the small intestine of healthy subjects and patients with symptomatic constipation using the wireless motility capsule. Int. J. Pharm. 544, 158–164 (2018).Calvo-Lerma, J. et al. Innovative approach for self-management and social welfare of children with cystic fibrosis in Europe: development, validation and implementation of an mHealth tool (MyCyFAPP). Br. Med. J. Open. 7, e014931 (2017).Calvo-Lerma, J. et al. Clinical validation of an evidence-based method to adjust pancreatic enzyme replacement therapy through a prospective interventional study in paediatric patients with cystitic fibrosis. PLoS ONE 14, e0213216 (2019).Koumantakls, G. & Radciltf, F. J. Estimating fat in feces by near-infrared reflectance spectroscopy. Clin. Chem. 33, 502–506 (1987).Rivero-Marcotegui, A. et al. Water, fat, nitrogen, and sugar content in feces: reference intervals in children. Clin. Chem. 44, 1540–1544 (1998).Korpi-Steiner, N. L. et al. Comparative analysis of fecal fat quantitation via nuclear magnetic resonance spectroscopy (1H NMR) and gravimetry. Clin. Chim. Acta 400, 33–36 (2009).Dorsey, J. et al. Fat malabsorption in cystic fibrosis: comparison of quantitative fat assay and a novel assay using fecal lauric/behenic acid. J. Pediatr. Gastroenterol. Nutr. 50, 441–446 (2010).Proesmans, M. & De Boeck, K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur. J. Pediatr. 162, 760–763 (2003).Paz-Yépez, C. et al. Influence of particle size and intestinal conditions on in vitro lipid and protein digestibility of walnuts and peanuts. Food Res. Int. 119, 951–959 (2019).Moore, C. G. et al. Recommendations for planning pilot studies in clinical and translational sciences. Clin. Transl. Sci. 4, 332–337 (2011).Fitzpatrick, J. J. & Kazer, M. W. Encyclopedia of Nursing Research 3rd edn, Vol. 440 (Springer, New York, 2011).Isaac, S. & Michael, W. B. Handbook in Research and Evaluation (Educational and Industrial Testing Services, San Diego, 1995).Asensio-Grau, A. et al. Effect of cooking methods and intestinal conditions on lipolysis, proteolysis and xanthophylls bioaccessibility of eggs. J. Funct. Foods 46, 579–586 (2018).Asensio-Grau, A. et al. Fat digestibility in meat products: influence of food structure and gastrointestinal conditions. Int. J. Food Sci. Nutr. 70, 530–539 (2019).Regan, P. T. et al. Reduced intraluminal bile acid concentrations and fat maldigestion in pancreatic insufficiency: correction by treatment. Gastroenterology 7, 285–289 (1979).Fallingborg, J. et al. pH‐profile and regional transit times of the normal gut measured by a radiotelemetry device. Aliment. Phamacol. Ther. 3, 605–614 (1989).Fallingborg, J. Intraluminal pH of the human gastrointestinal tract. Dan. Med Bull. 46, 183–196 (1999).Calvo-Lerma, J. et al. In vitro digestion models to assess lipolysis: the impact of the simulated conditions for gastrointestinal pH, bile salts and digestion fluids. Food Res. Int. 125, 108511 (2019).Kalantzi, L. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm. Res. 23, 165–176 (2006).Zelles, L. & Bai, Q. Y. Fractionation of fatty acids derived from soil lipids by solid phase extraction and their quantitative analysis by GC-MS. Soil Biol. Biochem. 25, 495–507 (1993).Fiorentini, G. et al. Effect of lipid sources with different fatty acid profiles on intake, nutrient digestion and ruminal fermentation of feedlot nellore steers. Asian-Australas. J. Anim. Sci. 28, 1583 (2015).Perman, J. A., Modler, S. & Olson, A. C. Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora. Studies in vivo and in vitro. J. Clin. Invest. 67, 643–650 (1981).Sellin, J. H. & Hart, R. Glucose malabsorption associated with rapid intestinal transit. Am. J. Gastroenterol. 87, 5 (1992).Tran, T. M. D. et al. Effects of a proton-pump inhibitor in cystic fibrosis. Acta Pediatr. 87, 553–558 (1998).Ayoub, F., Lascano, J. & Morelli, G. Proton pump inhibitor use is associated with an increased frequency of hospitalization in patients with cystic fibrosis. Gastroenterol. Res. 10, 288 (2017)

Assessing gastro-intestinal related quality of life in cystic fibrosis: Validation of PedsQL GI in children and their parents

Background: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF. Methods: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months. Results: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20). Conclusions: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials

Reduced diversity and increased virulence-gene carriage in intestinal enterobacteria of coeliac children

<p>Abstract</p> <p>Background</p> <p>Coeliac disease is an immune-mediated enteropathology triggered by the ingestion of cereal gluten proteins. This disorder is associated with imbalances in the composition of the gut microbiota that could be involved in its pathogenesis. The aim of the present study was to determine whether intestinal <it>Enterobacteriaceae </it>populations of active and non-active coeliac patients and healthy children differ in diversity and virulence-gene carriage, so as to establish a possible link between the pathogenic potential of enterobacteria and the disease.</p> <p>Methods</p> <p><it>Enterobacteriaceae </it>clones were isolated on VRBD agar from faecal samples of 31 subjects (10 active coeliac patients, 10 symptom-free coeliac patients and 11 healthy controls) and identified at species level by the API 20E system. <it>Escherichia coli </it>clones were classified into four phylogenetic groups A, B1, B2 and D and the prevalence of eight virulence-associated genes (type-1 fimbriae [<it>fimA</it>], P fimbriae [<it>papC</it>], S fimbriae [<it>sfaD/E</it>], Dr haemagglutinin [<it>draA</it>], haemolysin [<it>hlyA</it>], capsule K1 [<it>neuB</it>], capsule K5 [<it>KfiC</it>] and aerobactin [<it>iutA</it>]) was determined by multiplex PCR.</p> <p>Results</p> <p>A total of 155 <it>Enterobacteriaceae </it>clones were isolated. Non-<it>E. coli </it>clones were more commonly isolated in healthy children than in coeliac patients. The four phylogenetic <it>E. coli </it>groups were equally distributed in healthy children, while in both coeliac patients most commensal isolates belonged to group A. Within the virulent groups, B2 was the most prevalent in active coeliac disease children, while D was the most prevalent in non-active coeliac patients. <it>E coli </it>clones of the virulent phylogenetic groups (B2+D) from active and non-active coeliac patients carried a higher number of virulence genes than those from healthy individuals. Prevalence of P fimbriae (<it>papC</it>), capsule K5 (<it>sfaD/E</it>) and haemolysin (<it>hlyA</it>) genes was higher in <it>E. coli </it>isolated from active and non-active coeliac children than in those from control subjects.</p> <p>Conclusion</p> <p>This study has demonstrated that virulence features of the enteric microbiota are linked to coeliac disease.</p

Ectopic endometrium in human foetuses is a common event and sustains the theory of müllerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer

<p>Abstract</p> <p>Background</p> <p>Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Women with endometriosis have an increased risk of different types of malignancies, especially ovarian cancer and non-Hodgkin's lymphoma. Though there are several theories, researchers remain unsure as to the definitive cause of endometriosis. Our objective was to test the validity of the theory of müllerianosis for endometriosis, that is the misplacing of primitive endometrial tissue along the migratory pathway of foetal organogenesis</p> <p>Methods</p> <p>We have collected at autopsy 36 human female foetuses at different gestational age. We have performed a morphological and immunohistochemical study (expression of oestrogen receptor and CA125) on the pelvic organs of the 36 foetuses included en-block and totally analyzed.</p> <p>Results</p> <p>In 4 out of 36 foetuses we found presence of misplaced endometrium in five different ectopic sites: in the recto-vaginal septum, in the proximity of the Douglas pouch, in the mesenchimal tissue close to the posterior wall of the uterus, in the rectal tube at the level of muscularis propria, and in the wall of the uterus. All these sites are common location of endometriosis in women.</p> <p>Conclusion</p> <p>We propose that a cause of endometriosis is the dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis.</p

Assessing gastro-intestinal related quality of life in cystic fibrosis: Validation of PedsQL GI in children and their parents

Background: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF. Methods: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months. Results: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20). Conclusions: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials