RESUMEN
Chagas disease, caused by the Trypanosoma cruzi parasite in the Americas affects â¼ 7 million people, 30% with cardiac tissue damage and 10-15% with digestive disorders. In this study, we have developed a protocol to detect the presence of the parasite and estimate its load in resected dysfunctional tissue segments of chronically infected patients with digestive megacolon. We have included samples from 43 individuals, 38/5 with positive/negative serology for Chagas disease and digestive syndromes. Samples of 1.5 to 2.0 cm2 were taken from different points of the dysfunctional digestive tract in specialized centres in Cochabamba, Bolivia. T. cruzi cultures were performed by inoculation with NNN-LIT culture medium, and genomic material was obtained from the samples for multiplex qPCR with TaqMan probes targeting satellite nuclear DNA. Cultures failed to isolate T. cruzi but qPCR reached a sensitivity of 42.1% (16/38) with all three spots and in triplicate. A new quantification methodology using synthetic satellite DNA as quantitation standard revealed parasite loads ranging from 2.2 × 102 to 1.0 × 106 satellite DNA copies/µl. Positive samples from the distal end showed a higher parasite load. The results of the present study strengthen and add further evidence to previous findings in an experimental mouse model of chronic T. cruzi infection, providing a valuable tool to improve scientific knowledge on the relevance of the digestive tract in parasite persistence, and underline the need of a better understanding of host-pathogen interaction in digestive tissues, considering pathophysiology, disease immunology and response to treatment.
Asunto(s)
Enfermedad de Chagas , Megacolon , Trypanosoma cruzi , Animales , Enfermedad de Chagas/parasitología , ADN Satélite , Humanos , Megacolon/genética , Ratones , Carga de Parásitos/métodos , Trypanosoma cruzi/genéticaRESUMEN
The Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, -/-) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.
Asunto(s)
Sistema Nervioso Entérico/metabolismo , Intestino Delgado/metabolismo , Cinesinas/genética , Megacolon/genética , Neuronas/metabolismo , Animales , Sistema Nervioso Entérico/patología , Regulación de la Expresión Génica , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Intestino Delgado/inervación , Intestino Delgado/patología , Cinesinas/deficiencia , Megacolon/metabolismo , Megacolon/mortalidad , Megacolon/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Deshidrogenasa/genética , NADPH Deshidrogenasa/metabolismo , Neuronas/patología , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Transducción de Señal , Especificidad de la Especie , Análisis de SupervivenciaRESUMEN
OBJECTIVE: We identified a pedigree over five generations with 49 members, some of whom had chronic megacolon presenting in adolescence or adulthood. We aimed to assess the genetic cause of chronic megacolon through clinical and DNA studies. DESIGN: After ethical approval and informed consent, family members provided answers to standard bowel disease questionnaires, radiological or surgical records, and DNA (buccal mucosal scraping). Exome DNA sequencing of colon tissue or blood DNA from seven family members with colon or duodenal dilatation, or no megacolon (n = 1) was carried out. Sanger sequencing was performed in 22 additional family members to further evaluate candidate variants. The study focused on genes of potential relevance to enteric nerve (ENS) maturation and Hirschsprung's disease or megacolon, based on the literature (GFRA1, NKX2-1, KIF26A, TPM3, ACTG2, SCN10A, and C17orf107 [CHRNE]) and other genetic variants that co-segregated with megacolon in the six affected family members. RESULTS: Information was available in all except five members alive at time of study; among 30 members who provided DNA, six had definite megacolon, one megaduodenum, seven significant constipation without bowel dilatation, and 16 normal bowel function by questionnaire. Among genes studied, SEMA3F (g.3:50225360A>G; c1873A>G) was found in 6/6 family members with megacolon. The SEMA3F gene variant was assessed as potentially pathogenic, based on M-CAP in silico prediction. SEMA3F function is associated with genes (KIT and PDGFRB) that impact intestinal pacemaker function. CONCLUSION: Familial chronic megacolon appears to be associated with SEMA3F, which is associated with genes impacting enteric nerve or pacemaker function.
Asunto(s)
Sistema Nervioso Entérico/fisiopatología , Enfermedad de Hirschsprung/genética , Megacolon/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Colon/patología , Colon/fisiopatología , Sistema Nervioso Entérico/patología , Femenino , Enfermedad de Hirschsprung/patología , Enfermedad de Hirschsprung/fisiopatología , Humanos , Masculino , Megacolon/patología , Megacolon/fisiopatología , Linaje , Secuenciación del ExomaRESUMEN
BACKGROUND: Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon. MATERIALS AND METHODS: Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-KitW-sh mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3). RESULTS: In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p < 0.05). While treating Tph1KO mice with 5-HT did not significantly increase parasitemia in the colon (p > 0.05), rescuing its synthesis promoted trypanosomiasis (p < 0.01). T. cruzi-related 5-HT release (p < 0.05) seemed not only to increase inflammatory signaling, but also to enlarge the pericryptal macrophage and mast cell populations (p < 0.01). Knocking out mast cells reduced trypanosomiasis (p < 0.01), although it did not further alter the neuroendocrine cell number and Tph1 expression (p > 0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p < 0.01). A similar finding was achieved when 5-HT synthesis was blocked in c-KitW-sh mice (p > 0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p < 0.01). CONCLUSION: We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon.
Asunto(s)
Enfermedad de Chagas/metabolismo , Colon/metabolismo , Parasitosis Intestinales/metabolismo , Mastocitos/metabolismo , Megacolon/metabolismo , Serotonina/biosíntesis , Trypanosoma cruzi/patogenicidad , Adulto , Anciano , Animales , Estudios de Casos y Controles , Enfermedad de Chagas/genética , Enfermedad de Chagas/parasitología , Colon/parasitología , Interacciones Huésped-Patógeno , Humanos , Parasitosis Intestinales/genética , Parasitosis Intestinales/parasitología , Masculino , Mastocitos/parasitología , Megacolon/genética , Megacolon/parasitología , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Factores de Tiempo , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismoRESUMEN
The classic piebald mutation in the endothelin receptor type B (Ednrb) gene was found on rolling Nagoya genetic background (PROD-s/s) mice with white coat spotting. To examine whether genetic background influenced the phenotype in the piebald mutant mice, we generated a congenic strain (B6.PROD-s/s), produced by repeated backcrosses to the C57BL/6J (B6) strain. Although B6.PROD-s/s mice showed white coat spotting, 7% of B6.PROD-s/s mice died between 2 and 5 weeks after birth due to megacolon. The PROD-s/s, s/s and Japanese fancy mouse 1 (JF1) strains, which also have piebald mutations on different genetic backgrounds with B6, showed only pigmentation defects without megacolon. In expression analyses, rectums of B6.PROD-s/s with megacolon mice showed ~5% of the level of Ednrb gene expression versus B6 mice. In histological analyses, aganglionosis was detected in the rectum of megacolon animals. The aganglionic rectum was thought to lead to severe constipation and intestinal blockage, resulting in megacolon. We also observed an abnormal intestinal flora, including a marked increase in Bacteroidaceae and Erysipelotrichaceae and a marked decrease in Lactobacillus and Clostridiales, likely inducing endotoxin production and a failure of the mucosal barrier system, leading ultimately to death. These results indicate that the genetic background plays a key role in the development of enteric ganglion neurons, controlled by the Ednrb gene, and that B6 has modifier gene (s) regarding aganglionosis.
Asunto(s)
Piebaldismo/genética , Receptor de Endotelina B/metabolismo , Animales , ADN/genética , Femenino , Regulación de la Expresión Génica/fisiología , Genotipo , Masculino , Megacolon/genética , Ratones , Ratones Endogámicos C57BL , Repeticiones de Microsatélite/genética , Mutación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Endotelina B/genéticaRESUMEN
Chronic intestinal pseudo-obstruction (CIPO) can occur as a consequence of neuropathies including diffuse Intestinal Neuronal Dysplasia (IND), a relatively rare enteric nervous system (ENS) abnormality. Although various authors reported of diffuse IND associated either with intestinal malrotation or megacystis, the co-existence of these three entities in the same patient has never been described before. The aim of this paper is to report for the first time in literature a series of patient with such association, focusing on one who carries a de novo duplication of chromosome 12, suggesting a new syndromic association (megacolon, megacystis, malrotation).
Asunto(s)
Anomalías Múltiples/genética , Sistema Nervioso Entérico/anomalías , Enfermedades Fetales/diagnóstico , Tracto Gastrointestinal/anomalías , Megacolon/diagnóstico , Anomalía Torsional/diagnóstico , Preescolar , Duplicación Cromosómica , Cromosomas Humanos Par 12/genética , Hibridación Genómica Comparativa , Duodeno/anomalías , Resultado Fatal , Femenino , Enfermedades Fetales/genética , Enfermedades Fetales/terapia , Tracto Gastrointestinal/cirugía , Humanos , Ileostomía , Megacolon/genética , Megacolon/cirugía , Síndrome , Anomalía Torsional/genética , Anomalía Torsional/cirugía , Vejiga Urinaria/anomalíasRESUMEN
BACKGROUND: Hirschsprung disease (HD) results from aganglionosis of the colon, is linked to acute and chronic enterocolitis (known as Hirschsprung-associated enterocolitis) despite successful corrective surgery, and can lead to bacteremia and even death. The genetic and molecular mechanisms underlying these disorders are largely unknown. METHODS: We developed a microsurgical corrective pull-through procedure in mice, and applied that to Ednrb(-/-) mice, which manifest aganglionic megacolon that is very similar to HD. Wild-type littermates (Ednrb(+/+)) also underwent identical surgery. At prespecified time points postoperatively, mice were sacrificed, and histopathologic analyses of intestinal inflammation were performed. Mice of both genotypes were sacrificed after the postoperative recovery period to determine if corrective surgery itself caused inflammation. Stooling patterns were assessed as well to determine if intestinal function normalized after surgery. RESULTS: There was no difference in histopathological enterocolitis scores after recovery from surgery. Stooling patterns in Ednrb(-/-) and Ednrb(+/+) mice were similar postoperatively, suggesting normalization of intestinal function. However, with time, approximately 40% of Ednrb(-/-) mice developed clinical illness consistent with enterocolitis. No control (Ednrb(+/+)) mice developed clinical enterocolitis. Histopathological enterocolitis scores in the 40% of Ednrb(-/-) mice that developed clinical enterocolitis postoperatively were significantly worse than those of healthy postoperative Ednrb(-/-) mice. In contrast, none of the Ednrb(+/+) control mice exhibited postoperative long-term inflammation. CONCLUSIONS: Microsurgical pull-through operation in Ednrb(-/-) mice produces a mouse model that closely resembles key features of Hirschsprung-associated enterocolitis, enabling controlled study of genetic and molecular mechanisms in Ednrb(-/-) mice and other genotypes that produce similar phenotypes.
Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Enterocolitis/patología , Enterocolitis/prevención & control , Enfermedad de Hirschsprung/cirugía , Canal Anal/patología , Canal Anal/cirugía , Anastomosis Quirúrgica/métodos , Animales , Defecación/fisiología , Modelos Animales de Enfermedad , Enterocolitis/genética , Estudios de Seguimiento , Tránsito Gastrointestinal/fisiología , Genotipo , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Humanos , Megacolon/genética , Megacolon/patología , Megacolon/cirugía , Ratones , Ratones Endogámicos BALB C , Microcirugia/métodos , Periodo Posoperatorio , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND/PURPOSE: Ncx (Enx, Hox11L.1)-deficient (Ncx-/-) mice develop mega-ileo-ceco-colon with a larger number of neuronal cells in the enteric ganglia. We investigated mechanisms related to this abnormality and directed our attention to the effects on gastrointestinal tract functions. METHODS: The number of NADPH diaphorase or cuprolinic blue-positive neuronal cells in the enteric ganglia was examined during growth of the mice. Neuronal cell death of enteric ganglia was assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling. Function of the gastrointestinal tract was determined by measuring excretion time of the barium chloride given into the stomach. RESULTS: The number of neuronal cells decreased in control mice older than 2 weeks, and neuronal cell death was evident in the ganglia. However, the number of neuronal cells did not decrease in Ncx-/- mice, and cell death was rare. Excretion time of barium chloride was prolonged in all Ncx-/- mice examined and was improved by the administration of an inhibitor of nitric oxide synthase. CONCLUSIONS: Ncx participates in cell death of enteric neurons. Motor abnormality of the gastrointestinal tract in Ncx-/- mice may be attributed to the large number of neuronal cells.
Asunto(s)
Apoptosis/genética , Sistema Nervioso Entérico/patología , Proteínas de Homeodominio/fisiología , Megacolon/genética , Neuronas/patología , Animales , Animales Recién Nacidos , Animales Lactantes , Compuestos de Bario/farmacocinética , Caspasa 3/biosíntesis , Caspasa 3/genética , Recuento de Células , Linaje de la Célula , Movimiento Celular , Cloruros/farmacocinética , Colorantes/análisis , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/crecimiento & desarrollo , Inducción Enzimática , Tránsito Gastrointestinal/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Genes bcl-2 , Proteínas de Homeodominio/genética , Etiquetado Corte-Fin in Situ , Indoles/análisis , Intestino Delgado/crecimiento & desarrollo , Intestino Delgado/inervación , Megacolon/patología , Ratones , Ratones Noqueados , NADPH Deshidrogenasa/análisis , NG-Nitroarginina Metil Éster/farmacología , NG-Nitroarginina Metil Éster/uso terapéutico , Cresta Neural/citología , Compuestos Organometálicos/análisis , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Coloración y Etiquetado , Estómago/crecimiento & desarrollo , Estómago/inervaciónRESUMEN
Development of the vertebrate gut is controlled by paracrine crosstalk between the endodermal epithelium and the associated splanchnic mesoderm. In the adult, the same types of signals control epithelial proliferation and survival, which account for the importance of the stroma in colon carcinoma progression. Here, we show that targeting murine Foxf1 and Foxf2, encoding forkhead transcription factors, has pleiotropic effects on intestinal paracrine signaling. Inactivation of both Foxf2 alleles, or one allele each of Foxf1 and Foxf2, cause a range of defects, including megacolon, colorectal muscle hypoplasia and agangliosis. Foxf expression in the splanchnic mesoderm is activated by Indian and sonic hedgehog secreted by the epithelium. In Foxf mutants, mesenchymal expression of Bmp4 is reduced, whereas Wnt5a expression is increased. Activation of the canonical Wnt pathway -- with nuclear localization of beta-catenin in epithelial cells -- is associated with over-proliferation and resistance to apoptosis. Extracellular matrix, particularly collagens, is severely reduced in Foxf mutant intestine, which causes epithelial depolarization and tissue disintegration. Thus, Foxf proteins are mesenchymal factors that control epithelial proliferation and survival, and link hedgehog to Bmp and Wnt signaling.
Asunto(s)
Factores de Transcripción Forkhead/fisiología , Intestinos/embriología , Comunicación Paracrina/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Wnt/metabolismo , Animales , Apoptosis/genética , Proteína Morfogenética Ósea 4 , Proteínas Morfogenéticas Óseas/metabolismo , Adhesión Celular/genética , Núcleo Celular/química , Polaridad Celular , Proliferación Celular , Colon/anomalías , Colon/citología , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Factores de Transcripción Forkhead/genética , Dosificación de Gen , Regulación del Desarrollo de la Expresión Génica , Intestinos/anomalías , Intestinos/citología , Megacolon/genética , Mesodermo/química , Mesodermo/metabolismo , Ratones , Ratones Mutantes , Proteínas Proto-Oncogénicas/genética , Recto/anomalías , Recto/citología , Proteínas Wnt/genética , Proteína Wnt-5a , beta Catenina/análisis , beta Catenina/metabolismoRESUMEN
BACKGROUND/PURPOSE: The spontaneous rat mutation, familial megacecum and colon (fmc), is responsible for an autosomal recessive phenotype similar to intestinal pseudo-obstruction observed in Hox11L1-/- mice. We hypothesized that fmc is a mutant allele of the rat Hox11L1 gene and tested this hypothesis by direct sequencing. METHODS: DNA was extracted from fmc/fmc rats and wild-type littermates. All exons, introns, and DNA 5' to the transcriptional start site of rat Hox11L1 were directly sequenced, and data from the mutant and wild-type animals were compared with each other and corresponding genomic data from humans and mice. RESULTS: Alignment of sequences obtained from rat, human, and mouse indicates that putative regulatory elements of the Hox11L1 gene are conserved in rat, mice, and humans. No mutations were identified in the Hox11L1 allele of fmc/fmc rats. CONCLUSIONS: Despite the phenotypic similarities between fmc/fmc rats and Hox11L1-/- mice, fmc does not appear to be a mutant allele of the Hox11L1 gene.
Asunto(s)
Proteínas de Homeodominio/genética , Seudoobstrucción Intestinal/genética , Animales , Secuencia de Bases , Enfermedad Crónica , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Exones , Genotipo , Humanos , Megacolon/genética , Ratones , Datos de Secuencia Molecular , Fenotipo , Ratas , Análisis de Secuencia de ADN , Homología de SecuenciaRESUMEN
The neural and glial cells of the intrinsic ganglia of the enteric nervous system (ENS) are derived from the hindbrain neural crest at the vagal level. The Hoxb3 gene is expressed in the vagal neural crest and in the enteric ganglia of the developing gut during embryogenesis. We have identified a cis-acting enhancer element b3IIIa in the Hoxb3 gene locus. In this study, by transgenic mice analysis, we examined the tissue specificity of the b3IIIa enhancer element using the lacZ reporter gene, with emphasis on the vagal neural crest cells and their derivatives in the developing gut. We found that the b3IIIa-lacZ transgene marks only the vagal region and not the trunk or sacral region. Using cellular markers, we showed that the b3IIIa-lacZ transgene was expressed in a subset of enteric neuroblasts during early development of the gut, and the expression was maintained in differentiated neurons of the myenteric plexus at later stages. The specificity of the b3IIIa enhancer in directing gene expression in the developing ENS was further supported by genetic analysis using the Dom mutant, a spontaneous mouse model of Hirschsprung's disease characterized by the absence of enteric ganglia in the distal gut. The colonization of lacZ-expressing cells in the large intestine was incomplete in all the Dom/b3IIIa-lacZ hybrid mutants we examined. To our knowledge, this is the only vagal neural crest-specific genetic regulatory element identified to date. This element could be used for a variety of genetic manipulations and in establishing transgenic mouse models for studying the development of the ENS.
Asunto(s)
Elementos de Facilitación Genéticos/genética , Regulación del Desarrollo de la Expresión Génica/genética , Proteínas de Homeodominio/genética , Sistema Nervioso/embriología , Sistema Nervioso/metabolismo , Cresta Neural/embriología , Cresta Neural/metabolismo , Animales , Inmunohistoquímica , Operón Lac/genética , Megacolon/embriología , Megacolon/genética , Megacolon/metabolismo , Ratones , Ratones Transgénicos , Especificidad de ÓrganosRESUMEN
OBJECTIVE: To explore the relationship between human cytomegalovirus (HCMV) UL144 sequence variability and clinical disease. METHODS: HCMV UL144 open reading frame (ORF) was amplified by PCR assay in 72 low-passage isolates [65 congenitally infective children and 7 healthy children who were HCMV-DNA positive by quantitative PCR (qPCR)]. All positive PCR products were analyzed by heteroduplex mobility assay and single-stranded conformation polymorphism (HMA-SSCP) and 32 of them were sequenced. RESULTS: Fifty-five patient isolates and five healthy children isolates were HCMV-UL144 positive by PCR. Sequencing and HMA-SSCP analysis showed that significant strain-specific variability was present in the UL144 ORF. Phylogenetic analysis indicated that the nucleotide sequences could be separated into 3 major genotypes. Comparing between UL144 sequences and the corresponding symptoms showed that genotype 2 did not exist in megacolon isolates. And genotype 1 and 3 were the major types among microcephaly and jaundice isolates respectively. CONCLUSIONS: HCMV-UL144 existed in most of low passage isolates and sequences were hypervariable. The UL144 ORF and its predicted product with the high level of sequence variability in different kinds of isolates suggest that UL144 ORF might play a role in HCMV infectivity and subsequent diseases.
Asunto(s)
Infecciones por Citomegalovirus/genética , Citomegalovirus/genética , Variación Genética , Sistemas de Lectura Abierta/genética , Secuencia de Aminoácidos , Secuencia de Bases , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/virología , ADN Viral/genética , Genotipo , Humanos , Lactante , Recién Nacido , Ictericia/genética , Ictericia/virología , Megacolon/genética , Megacolon/virología , Microcefalia/genética , Microcefalia/virología , Datos de Secuencia Molecular , Filogenia , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Homología de Secuencia de AminoácidoRESUMEN
This report describes a new subgroup of familial visceral myopathy. Three patients from within this family were admitted to the hospital with pseudo-obstruction. Barium x-ray, abdominal plain film, esophageal manometry, colonoscopy, gastroscopy, and echocardiography were performed in all siblings for diagnostic evaluation. Two of our patients had surgery because of suspicion of acute abdomen. In one of them, full-thickness biopsy, which was performed during laparotomy, revealed findings that were compatible with familial visceral myopathy. Three siblings from this family with visceral myopathy, in which the parents were consanguineous, had megaduodenum, long-segment Barrett's esophagus, and different cardiac abnormalities.
Asunto(s)
Esófago de Barrett/genética , Cardiopatías Congénitas/genética , Seudoobstrucción Intestinal/genética , Megacolon/genética , Anomalías Múltiples/diagnóstico , Adulto , Esófago de Barrett/complicaciones , Esófago de Barrett/patología , Biopsia con Aguja , Duodeno , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/patología , Humanos , Inmunohistoquímica , Seudoobstrucción Intestinal/complicaciones , Seudoobstrucción Intestinal/patología , Masculino , Megacolon/complicaciones , Megacolon/patología , Linaje , Pronóstico , Medición de RiesgoRESUMEN
A 48-year-old woman with late infantile onset mental retardation developed megacolon. Although the patient had no typical clinical features of Hirschsprung disease-mental retardation syndrome, a new 3-base pair deletion, eliminating an Asn, was identified in the responsible gene ZFHX1B. This suggests that screening for ZFHX1B mutations is warranted even in the absence of typical clinical features of the syndrome.
Asunto(s)
Enfermedad de Hirschsprung/genética , Discapacidad Intelectual/genética , Clonación Molecular , ADN/genética , Endorribonucleasas , Femenino , Eliminación de Gen , Humanos , Megacolon/genética , Persona de Mediana Edad , Mutación/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome , Transactivadores/genéticaRESUMEN
We report a fetus with atelencephaly, bilateral radial aplasia/hypoplasia, ventriculoseptal defect and megacolon, this combination of anomalies being consistent with the diagnosis of XK-aprosencephaly syndrome. The facial dysmorphology of this fetus differs from that previously reported and together with reports on overlapping phenotypes suggests an extension of the XK-aprosencephaly spectrum.
Asunto(s)
Anomalías Múltiples/patología , Encéfalo/anomalías , Cara/anomalías , Megacolon/patología , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Feto Abortado/anomalías , Femenino , Humanos , Masculino , Megacolon/diagnóstico por imagen , Megacolon/genética , Fenotipo , Embarazo , Radio (Anatomía)/anomalías , Ultrasonografía PrenatalRESUMEN
Chronic idiopathic slow-transit constipation (ISTC) and idiopathic megacolon (IMC) are early-onset gastrointestinal motility disorders of unknown aetiology. The gene encoding the neurotrophic factor neurturin may be a candidate for these disorders, as neurturin-deficient mice have a similar enteric phenotype. In the present study, we tested this hypothesis. Genomic DNA from 26 cases of chronic idiopathic STC [with a family history of constipation in 15 (58%) and Hirschsprung's disease in two (8%)], and five cases of IMC [two familial (40%)] was screened by direct DNA sequencing using the fluorescent dideoxy terminator method. Results were compared with published sequence data and 24 control DNAs. Our results revealed several previously unreported common sequence polymorphisms, but overall frequencies were comparable between patients and controls. We conclude that mutation of neurturin is not a frequent cause of ISTC or IMC.
Asunto(s)
Estreñimiento/genética , Megacolon/genética , Mutación/genética , Factores de Crecimiento Nervioso/genética , Adulto , Exones/genética , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana Edad , NeurturinaRESUMEN
Myotonic dystrophy (MD) is an autosomal dominant inherit disease, slowly progressive, involving multiple organ systems. Disorders at any level of the gastrointestinal tract are relatively common and manifest as disturbances in motility, such as impaired esophageal transport, delayed gastric emptying, and megacolon. A 51 years-old man was admitted to our surgical department with obstructive symptoms. Diagnostic evaluation showed megacolon and the typical clinical features of the MD, such as weakness, myotonia, frontal baldness and testicular atrophy. Risk of perforation and dehydration led to emergency total colectomy with ileorectal stapled anastomosis. The patient didn't suffer for compliance related to surgical treatment but, after 1 month in intensive care, died of pneumonia and myocardial infarct. The overall frequency of perioperative complications in patients with MD ranges from 8.2 to 42.9%. The risk of perioperative pulmonary complications is particularly high. Thus, we believe that the conservative treatment of motility disorders of the bowel in patients with MD is to be justified and that surgical treatment should be reserved, as last resort, performing a early diagnosis and careful monitoring during perioperative period.
Asunto(s)
Megacolon/genética , Megacolon/cirugía , Distrofia Miotónica/complicaciones , Resultado Fatal , Humanos , Masculino , Megacolon/fisiopatología , Persona de Mediana Edad , Distrofia Miotónica/fisiopatología , Complicaciones Posoperatorias/etiologíaRESUMEN
Many pathological conditions result from the proliferation and de-differentiation of smooth muscle cells leading to impaired contractility of the muscle. Here we show that targeted expression of SV40 large T-antigen to visceral smooth muscle cells in vivo results in increased smooth muscle cell proliferation without de-differentiation or decreased contractility. These data suggest that the de-differentiation and proliferation of smooth muscle cells, seen in many pathological states, may be independently regulated. In the T-antigen transgenic mice the increased smooth muscle cell proliferation results in thickening of the distal colon. Consequently the distal colon becomes hyper-contractile and impedes the flow of digesta through the colon resulting in enlargement of the colon oral to the obstruction. These transgenic mice thus represent a novel model of megacolon that results from increased smooth muscle cell proliferation rather than altered neuronal innervation.