RESUMEN
BACKGROUND: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (INDO) and ibuprofen (IBU) has been shown to be an effective therapy for the closure of patent ductus arteriosus (PDA). However, this treatment has been associated with an increased risk of developing enteropathies in neonates. Whether the use of IBU is safer than INDO for the immature intestine remains to be elucidated. METHODS: The direct impact of IBU on the human immature intestinal transcriptome was investigated using serum-free organ culture. Differentially expressed genes were analyzed with Ingenuity Pathway Analysis software and compared with those previously reported with INDO. Validation of differentially expressed genes was confirmed by qPCR. RESULTS: We identified several biological processes that were significantly modulated by IBU at similar levels to what had previously been observed with INDO, while the expression of genes involved in "antimicrobial response" and "mucus production" was significantly decreased exclusively by IBU in the immature intestine. CONCLUSIONS: Our findings indicate that IBU has a harmful influence on the immature intestine. In addition to exerting many of the INDO observed deleterious effects, IBU alters pathways regulating microbial colonization and intestinal epithelial defense.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Ibuprofeno/efectos adversos , Mucosa Intestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/embriología , Antiinflamatorios no Esteroideos/farmacología , Medio de Cultivo Libre de Suero , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Conducto Arterioso Permeable/tratamiento farmacológico , Feto , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Glucólisis , Humanos , Ibuprofeno/farmacología , Mucosa Intestinal/crecimiento & desarrollo , Intestino Delgado/embriología , Metabolismo de los Lípidos , Análisis de Secuencia por Matrices de Oligonucleótidos , Técnicas de Cultivo de Órganos , Oxidorreductasas/metabolismo , Riesgo , TranscriptomaRESUMEN
The 2015 meeting of the Intestinal Transplant Association was held in Buenos Aires, Argentina. This was the 14th International Small Bowel Transplant Symposium, and it was the first meeting organized as a joint venture of the Transplantation Society, the Intestinal Transplant Association, and the Argentinean Transplant Society (Sociedad Argentina de Trasplantes). Innovative aspects of the classic meeting format included workshops sessions, debates, and multicenter studies. This report highlights the most prominent scientific contributions and results of the first such symposium in a Latin American country.
Asunto(s)
Internacionalidad , Enfermedades Intestinales/patología , Enfermedades Intestinales/cirugía , Intestino Delgado/patología , Intestino Delgado/trasplante , Argentina , Humanos , Enfermedades Intestinales/rehabilitaciónRESUMEN
BACKGROUND AND AIM: NO synthase 2 (NOS2) was recently identified as one the most overexpressed genes in intestinal samples of premature infants with necrotizing enterocolitis (NEC). NOS2 is widely implicated in the processes of epithelial cell injury/apoptosis and host immune defense but its specific role in inflammation of the immature human intestinal mucosa remains unclear. Interestingly, factors that prevent NEC such as epidermal growth factor (EGF) attenuate the inflammatory response in the mid-gestation human small intestine using serum-free organ culture while drugs that are associated with NEC occurrence such as the non-steroidal anti-inflammatory drug, indomethacin (INDO), exert multiple detrimental effects on the immature human intestine. In this study we investigate the potential role of NOS2 in modulating the gut inflammatory response under protective and stressful conditions by determining the expression profile of NOS2 and its downstream pathways in the immature intestine. METHODS: Gene expression profiles of cultured mid-gestation human intestinal explants were investigated in the absence or presence of a physiological concentration of EGF (50 ng/ml) or 1 µM INDO for 48 h using Illumina whole genome microarrays, Ingenuity Pathway Analysis software and quantitative PCR to investigate the expression of NOS2 and NOS2-pathway related genes. RESULTS: In the immature intestine, NOS2 expression was found to be increased by EGF and repressed by INDO. Bioinformatic analysis identified differentially regulated pathways where NOS2 is known to play an important role including citrulline/arginine metabolism, epithelial cell junctions and oxidative stress. At the individual gene level, we identified many differentially expressed genes of the citrulline/arginine metabolism pathway such as ARG1, ARG2, GLS, OAT and OTC in response to EGF and INDO. Gene expression of tight junction components such as CLDN1, CLDN2, CLDN7 and OCN and of antioxidant markers such as DUOX2, GPX2, SOD2 were also found to be differentially modulated by EGF and INDO. CONCLUSION: These results suggest that the protective effect of EGF and the deleterious influence of INDO on the immature intestine could be mediated via regulation of NOS2. Pathways downstream of NOS2 involved with these effects include metabolism linked to NO production, epithelial barrier permeability and antioxidant expression. These results suggest that NOS2 is a likely regulator of the inflammatory response in the immature human gut and may provide a mechanistic basis for the protective effect of EGF and the deleterious effects of INDO.
Asunto(s)
Antiinflamatorios/farmacología , Íleon/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal/efectos de los fármacos , Arginina/metabolismo , Citrulina/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Investigación Fetal , Fármacos Gastrointestinales/farmacología , Humanos , Íleon/efectos de los fármacos , Íleon/enzimología , Indometacina/farmacología , Óxido Nítrico Sintasa de Tipo II/análisis , Técnicas de Cultivo de ÓrganosRESUMEN
OBJECTIVES: The outcome of children with intestinal failure has improved during the past decade following the introduction of novel therapies by dedicated intestinal rehabilitation programs (IRP). The aim of the present study was to assess the impact of IRP on the outcome of intestinal transplant (IT) candidates and the transplant waiting list. METHODS: A retrospective cohort study of children assessed for IT (nâ=â84) during a 10-year period. Comparisons were made among the following 3 time periods: before the establishment of our center's IRP (1999-2002; nâ=â33), early IRP (2003-2005; nâ=â18), and late IRP (2006-2009; nâ=â33). The following endpoints were used: patient outcome following IT assessment (not listed, listed and removed from the list, received transplant, died while on the list), patient characteristics at IT assessment, and patient status at the end of the study. RESULTS: The late-IRP era was associated with an increase in patients who were not listed (42% vs 28% at other periods, Pâ=âNS) and patients who were removed from the IT waiting list because of clinical improvement (Pâ<â0.0005), and a decrease in those who died before transplant (15% vs >60% at other periods, Pâ<â0.0005). The cause of death shifted from traditional causes such as liver failure or sepsis to other comorbid conditions (Pâ<â0.005). Improved liver function at listing was also observed during late IRP (Pâ<â0.005). CONCLUSIONS: Treatment by IRP, coupled with recent advances in the medical management of intestinal failure, is associated with improved survival and outcome of patients waiting for IT, and may lead to overall reduction in the number of IT in the future.
Asunto(s)
Enfermedades Intestinales/terapia , Intestinos/cirugía , Trasplante de Órganos , Niño , Preescolar , Femenino , Humanos , Lactante , Enfermedades Intestinales/cirugía , Intestinos/patología , Masculino , Estudios Retrospectivos , Terapias en Investigación , Listas de EsperaRESUMEN
A 14-month-old infant presented with gastroenteritis with febrile pancytopenia and was diagnosed with acute lymphocytic leukemia (ALL). Ten days post induction therapy, the patient developed hypertension that was ascribed to steroid therapy and treated with metoprolol and amlodipine. As leukocyte numbers began to recover the asymptomatic patient became anuric. Ultrasound showed echoic floating structures in the bladder. Following cystoscopy and retrograde pyelography examination, purulent debris was irrigated from the bladder and grew Pseudomonas aeruginosa. Ciprofloxacin therapy was initiated and renal function was restored within 2 days. The case highlights the potential for renal obstruction after neutropenia recovery in children undergoing induction therapy for ALL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciprofloxacina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Infecciones por Pseudomonas/diagnóstico , Obstrucción Ureteral/cirugía , Infecciones Urinarias/diagnóstico , Anuria/etiología , Humanos , Hipertensión/etiología , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/aislamiento & purificación , Resultado del Tratamiento , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/microbiología , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiologíaRESUMEN
The development of autoimmune type 1 diabetes involves complex interactions among several genes and environmental agents. Human patients with type 1 diabetes show an unusually high frequency of wheat gluten-sensitive enteropathy; T-cell response to wheat proteins is increased in some patients, and high concentrations of wheat antibodies in blood have been reported. In both major models of spontaneous type 1 diabetes, the BioBreeding (BB) rat and non-obese diabetic mouse, at least half of the cases are diet-related. In studies of BB rats fed defined semipurified diets, wheat gluten was the most potent diabetes-inducing protein source. A major limitation in understanding how wheat or other dietary antigens affect type 1 diabetes has been the difficulty in identifying specific diabetes-related dietary proteins. To address this issue, we probed a wheat cDNA expression library with polyclonal IgG antibodies from diabetic BB rats. Three clones were identified, and the intensity of antibody binding to one of them, WP5212, was strongly associated with pancreatic islet inflammation and damage. The WP5212 putative protein has high amino acid sequence homology with a wheat storage globulin, Glb1. Serum IgG antibodies from diabetic rats and humans recognized low molecular mass (33-46 kDa) wheat proteins. Furthermore, antibodies to Glb1 protein were found in serum from diabetic patients but not in age-, sex-, and HLA-DQ-matched controls. This study raises the possibility that in some individuals, type 1 diabetes may be induced by wheat proteins. Also, it provides a first candidate wheat protein that is not only antigenic in diabetic rats and human patients but is also closely linked with the autoimmune attack in the pancreas.