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Disorders of gastrointestinal motility are the major physiologic problem in chagasic megacolon. The contraction mechanism is complex and controlled by different cell types such as enteric neurons, smooth muscle, telocytes, and an important pacemaker of the intestine, the interstitial cells of Cajal (ICCs). The role of ICCs in the progression of acute and chronic Chagas disease remains unclear. In the present work, we investigate the aspects of ICCs in a long-term model of Chagas disease that mimics the pathological aspects of human megacolon. Different subsets of ICCs isolated from Auerbach's myenteric plexuses and muscle layers of control and Trypanosoma cruzi infected animals were determined by analysis of CD117, CD44, and CD34 expression by flow cytometer. Compared with the respective controls, the results showed a reduced frequency of mature ICCs in the acute phase and three months after infection. These results demonstrate for the first time the phenotypic distribution of ICCs associated with functional dysfunction in a murine model of chagasic megacolon. This murine model proved valuable for studying the profile of ICCs as an integrative system in the gut and as a platform for understanding the mechanism of chagasic megacolon development.

Background: In this prospective cohort study, we evaluated features of "adult-onset megacolon with focal hypoganglionosis.", Methods: We assessed the radiologic, endoscopic, and histopathologic phenotyping and treatment outcomes of 29 patients between 2017 and 2020. Data from community controls, consisting of 19,948 adults undergoing health screenings, were analyzed to identify risk factors. Experts reviewed clinical features and pathological specimens according to the London Classification for gastrointestinal neuromuscular pathology., Key Results: The median age of the patients with adult-onset megacolon with focal hypoganglionosis at symptom onset was 59 years (range, 32.0-74.9 years), with mean symptom onset only 1 year before diagnosis. All patients had focal stenotic regions with proximal bowel dilatation (mean diameter, 78.8 mm; 95% confidence interval [CI], 72-86). The comparison with community controls showed no obvious risk factors. Ten patients underwent surgery, and all exhibited significant hypoganglionosis: 5.4 myenteric ganglion cells/cm (interquartile range [IQR], 3.7-16.4) in the stenotic regions compared to 278 cells/cm (IQR, 190-338) in the proximal and 95 cells/cm (IQR, 45-213) in the distal colon. Hypoganglionosis was associated with CD3+ T cells along the myenteric plexus. Colectomy was associated with significant symptom improvement compared to medical treatment [change in the Global Bowel Satisfaction score, -5.4 points (surgery) vs. -0.3 points (medical treatment); p < 0.001]., Conclusions and Inferences: Adult-onset megacolon with focal hypoganglionosis has distinct features characterized by hypoganglionosis due to inflammation. Bowel resection appears to benefit these patients., (© 2023 John Wiley & Sons Ltd.)

Objective: Idiopathic megarectum is characterized by abnormal, pronounced rectal dilatation in the absence of identifiable organic pathology. Idiopathic megarectum is uncommon and under-recognized. This study aims to describe the clinical features and management of idiopathic megarectum., Methods: A retrospective review was undertaken on patients diagnosed with idiopathic megarectum with or without idiopathic megacolon over a 14-year period until 2021. Patients were identified from the hospital's International Classification of Diseases codes, and pre-existing clinic patient databases. Patient demographics, disease characteristics, healthcare utilization and treatment history data were collected., Results: Eight patients with idiopathic megarectum were identified; half of the patients were female, with the median age of symptom onset being 14 years (interquartile range [IQR] 9-24). The median rectal diameter measured was 11.5 cm (IQR 9.4-12.1). The most common presenting symptom was constipation, bloating and faecal incontinence. All patients required prior sustained periods of regular phosphate enemas and 88% were using ongoing oral aperients. Concomitant anxiety and or depression were found in 63% of patients and 25% were diagnosed with an intellectual disability. Healthcare utilization was high with a median of three emergency department presentations or ward admissions related to idiopathic megarectum per patient over the follow-up period; 38% of patients required surgical intervention during the period of follow-up., Conclusion: Idiopathic megarectum is uncommon and associated with significant physical and psychiatric morbidity and high healthcare utilization., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Chagas disease is caused by the parasite, Trypanosoma cruzi that causes chronic cardiac and digestive dysfunction. Megacolon, an irreversible dilation of the left colon, is the main feature of the gastrointestinal form of Chagas disease. Patients have severe constipation, a consequence of enteric neuron degeneration associated with chronic inflammation. Dysmotility, infection, neuronal loss and a chronic exacerbated inflammation, all observed in Chagas disease, can affect enteroendocrine cells (EEC) expression, which in turn, could influence the inflammatory process. In this study, we investigated the distribution and chemical coding of EEC in the dilated and non-dilated portion of T. cruzi-induced megacolon and in non-infected individuals (control colon). Using immunohistochemistry, EECs were identified by applying antibodies to chromogranin A (CgA), glucagon-like peptide 1 (GLP-1), 5-hydroxytryptamine (5-HT), peptide YY (PYY) and somatostatin (SST). Greater numbers of EEC expressing GLP-1 and SST occurred in the dilated portion compared to the non-dilated portion of the same patients with Chagas disease and in control colon, but numbers of 5-HT and PYY EEC were not significantly different. However, it was noticeable that EEC in which 5-HT and PYY were co-expressed were common in control colon, but were rare in the non-dilated and absent in the dilated portion of chagasic megacolon. An increase in the number of CgA immunoreactive EEC in chagasic patients reflected the increases in EEC numbers summarised above. Our data suggests that the denervation and associated chronic inflammation are accompanied by changes in the number and coding of EEC that could contribute to disorders of motility and defence in the chagasic megacolon.

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.

Acquired isolated hypoganglionosis is a rare intestinal neurological disease, which presents in adulthood with the clinical symptoms of chronic constipation. A 39-year-old man underwent laparoscopic low anterior resection and covering ileostomy for locally advanced-rectal cancer. A 6-month course of postoperative adjuvant chemotherapy was completed, followed by closure of the ileostoma. After the closure, he developed severe colitis which required 1-month of hospitalization. Mucosal erosions and pseudo-membrane formation were evident on colonoscopy and severe mucosal damage characterized by infiltration of inflammatory cells and crypt degeneration were pathologically confirmed. Even after the remission of the colitis, he suffered from severe constipation and distention. At 4 years after the stoma closure, he decided to undergo laparoscopic total colectomy. Histopathologically, the nerve fibers and ganglion cells became gradually scarcer from the non-dilated to dilated regions. Immunohistochemical staining examination confirmed that the ganglion cells gradually decreased and became degenerated from the normal to dilated region, thereby arriving at the final diagnosis of isolated hypoganglionosis. The patient recovered without any complications and there has been no evidence of any relapse of the symptoms. We present a case of acquired isolated hypoganglionosis-related megacolon, which required laparoscopic total colectomy, due to severe enterocolitis following stoma closure.

Objective: To evaluate the density of anti-galectin-3-immunostained cells, collagen percentage, mast cell density and presence of pathological processes in intestinal muscle biopsies of patients., Methods: Thirty-five patients who underwent intestinal biopsy were selected from 1997 to 2015. Patients were divided into three groups: chagasic patients with mucosal lesion (n=13), chagasic patients with intact mucosa (n=12) and non-chagasic patients with no mucosal lesion (n=10). Histological processing of the biopsied fragments and immunohistochemistry for galectin-3 were performed. Additional sections were stained with hematoxylin and eosin to evaluate the general pathological processes, picrosirius for evaluation of collagen and toluidine blue to evaluate the mast cell density., Results: Patients of mucosal lesion group had a significantly higher frequency of ganglionitis and myositis when compared to the chagasic patients with intact mucosa and non-chagasic group. The density of anti-galectin-3-immunostained cells was significantly higher in the chagasic patients with intact mucosa group when compared to the non-chagasic group. The group of chagasic patients with intact mucosa presented a higher percentage of collagen in relation to the patients with mucosal lesion and to the non-chagasic group, with a significant difference. There was no significant difference in mast cell density among the three groups., Conclusion: The higher density of anti-galectin-3-immunostained cells in patients in the chagasic patients with intact mucosa group suggested the need for greater attention in clinical evaluation of these patients, since this protein is associated with neoplastic transformation and progression.

T-cell immune attack of cancer cells underlies the efficacy of immune checkpoint inhibitors in many cancer subtypes, but is not yet well established in the primary brain cancer glioblastoma. Immune checkpoint inhibitor treatments that disinhibit the immune system to enhance immune clearance of cancer have in rare cases resulted in T-cell attack of peripheral ganglia causing lymphocytic ganglionitis. In glioblastoma, lymphocytic ganglionitis has not been reported and checkpoint inhibitors are not routinely used. Here we report a case of glioblastoma not treated with checkpoint inhibitors in which the primary tumor and peripheral ganglia of the celiac and sympathetic chains, as well as myenteric plexus, are infiltrated by CD8 + cytotoxic T-cells. In addition to the marked lymphocytic infiltrates, this case is also notable for an unusually long survival (8 years) after diagnosis with glioblastoma, but an ultimately fatal outcome due to ileus. The findings suggest T-cell immune attack of glioblastoma may prolong survival, but also suggest T-cell autoimmune diseases such as lymphocytic ganglionitis could become a risk with the future use of immune-targeted therapies for glioblastoma., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Hirschsprung's disease-associated enterocolitis (HE) is a life-threatening septic complication of Hirschsprung's disease (HD), leading to bacterial translocation (BT) and sepsis. Many factors, such as intestinal stasis, HD-related inherited immune disorders and abnormal mucosal secretion have been implicated in its pathogenesis., Objectives: To investigate the effect of intestinal stasis as an independent factor in the pathogenesis of HE intestinal lesions and its systematic effects., Material and Methods: The rectal ganglion cells of 46 Wistar rats were chemically ablated through local benzalkonium chloride (BAC) injection, in order to create a HD model (megacolon rats) that does not carry the possible genetic burden of HD. The animals were sacrificed either on the 20th or 25th day after ablation and were examined for histopathological changes on the wall of the small intestine, presence of bacterial translocation in body organs, body biometrics, and white blood cell count (WBC) and hemoglobin concentration. The results were compared to control animals., Results: In the megacolon rats, severe damage on the small intestine as well as BT proportional to the extent of the intestinal damage and to the time elapsed after ablation was observed. Significant effects on the WBCs, hemoglobin concentration and biometric parameters were also observed., Conclusions: In megacolon rats, intestinal stasis can lead by itself to a full-blown HE. The HE lesions that promote BT are present even in regions distant from the aganglionic bowel and are proportional to the time elapsed under the influence of intestinal stasis. Systematic effects such as growth retardation are also produced.

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., (© 2019 John Wiley & Sons Ltd.)

Chagas disease is caused by Trypanosoma cruzi and remains one of the most neglected diseases in Latin America. One of its clinical forms is Chagas megacolon. Despite being known for more than half a century, detailed causes are still obscure. Recent evidence indicates a close relationship between the immune system and the enteric nervous system in the etiology of chagasic megacolon pathology. It is believed that low expression of the 5-HT 3A serotonin receptor on lymphocytes could be linked to megacolon development. To test this hypothesis, this work investigated the distribution of CD4, CD8, and CD20 lymphocytes and their 5-HT 3A receptor expression. The results demonstrated that Chagas patients without megacolon present a higher expression of the 5-HT 3A receptor in all analyzed lymphocytes compared with Chagas patients with megacolon. These data suggest that the high expression of this receptor may lead to immunomodulation and prevent the development of Chagas megacolon.

Diffuse intestinal ganglioneuromatosis is a rare condition associated with MEN2B. It is also seen in conditions like neurofibromatosis type 1 and Cowden syndrome. This is a report of a patient who underwent total colectomy with end ileostomy creation for a megacolon. He was diagnosed to have diffuse ganglioneuromatosis on histological examination of the resected segment of colon. The definitive management of diffuse ganglioneuromatosis is to resect and anastomose., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chagas disease is an infection caused by the parasite Trypanosoma cruzi that affects millions of people worldwide and is endemic in Latin America. Megacolon is the most frequent complication of the digestive chronic form and happens due to lesions of the enteric nervous system. The neuronal lesions seem to initiate in the acute phase and persist during the chronic phase, albeit the mechanisms involved in this process are still debated. Among the cells of the immune system possibly involved in this pathological process is the mast cell (MC) due to its well-known role in the bi-directional communication between the immune and nervous systems. Using ultrastructural analysis, we found an increased number of degranulated MCs in close proximity to nerve fibers in infected patients when compared with uninfected controls. We also immunostained MCs for the two pro-inflammatory molecules tryptase and chymase, the first being also important in neuronal death. The number of MCs immunostained for tryptase or chymase was increased in patients with megacolon, whereas increased tryptase staining was additionally observed in patients without megacolon. Moreover, we detected the expression of the tryptase receptor PAR2 in neurons of the enteric nervous system, which correlated to the tryptase staining results. Altogether, the data presented herein point to the participation of MCs on the denervation process that occurs in the development of T. cruzi-induced megacolon.

Background: Acquired Megacolon (AMC) is a condition involving persistent dilatation and lengthening of the colon in the absence of organic disease. Diagnosis depends on subjective radiological, endoscopic or surgical findings in the context of a suggestive clinical presentation. This review sets out to investigate diagnostic criteria of AMC., Methods: The literature was searched using the databases - PubMed, Medline via OvidSP, ClinicalKey, Informit and the Cochrane Library. Primary studies, published in English, with more than three patients were critically appraised based on study design, methodology and sample size. Exclusion criteria were studies with the following features: post-operative; megarectum-predominant; paediatric; organic megacolon; non-human; and failure to exclude organic causes., Results: A review of 23 articles found constipation, abdominal pain, distension and gas distress were predominant symptoms. All ages and both sexes were affected, however, symptoms varied with age. Changes in anorectal manometry, histology and colonic transit are consistently reported. Studies involved varying patient numbers, demographics and data acquisition methods., Conclusions: Outcome data investigating the diagnosis of AMC must be interpreted in light of the limitations of the low-level evidence studies published to date. Proposed diagnostic criteria include: (1) the exclusion of organic disease; (2) a radiological sigmoid diameter of ~ 10 cm; (3) and constipation, distension, abdominal pain and/or gas distress. A proportion of patients with AMC may be currently misdiagnosed as having functional gastrointestinal disorders. Our conclusions are inevitably tentative, but will hopefully stimulate further research on this enigmatic condition.

Chronic constipation (CC) and idiopathic megacolon (IMC) occur frequently in cats. The aim of the study was to investigate the effects of a multi-strain probiotic (SLAB51™) in constipated cats (n=7) and in patients with megacolon and constipation (n=3). Ten pet cats with a diagnosis of chronic constipation, non-responsive to medical management received orally 2×10 11 bacteria daily for 90 days. For microbiota analysis, selected bacterial groups were analysed by qPCR. Histological samples in megacolons were evaluated for interstitial cells of Cajal (ICC), enteric neurons, and neuronal apoptosis. Biopsies were compared at baseline (T0) and after the end of treatment (T1), and with those obtained from healthy control tissues (archived material from five healthy cats). Constipated cats displayed significantly lower ICC, and cats with idiopathic megacolon had significantly more apoptotic enteric neurons than controls. After treatment with SLAB51™, significant decreases were observed for feline chronic enteropathy activity index (FCEAI) (P=0.006), faecal consistency score, and mucosal histology scores (P<0.001). In contrast, a significant increase of ICC was observed after probiotic therapy. Lactobacillus spp. and Bacteroidetes were increased significantly after treatment (comparing constipated cats before and after treatment, and control healthy cats to constipated cats after treatment), but no other differences in microbiota were found between healthy controls and constipated cats. Treatment with SLAB51™ in cats with chronic constipation and idiopathic megacolon showed significant clinical improvement after treatment, and histological parameters suggest a potential anti-inflammatory effect of SLAB51™, associated with a reduction of mucosal infiltration, and restoration of the number of interstitial cells of Cajal.

Abnormal dilation of the colon and rectum can develop from a range of disease processes. When encountered at autopsy, its contribution to death requires assessment and a thorough investigation of its origins. Elimination of known causes elicits a diagnosis of idiopathic megacolon. This entity is uncommonly encountered and presents with similar gross anatomic findings as Hirschsprung disease. Although death is infrequent, it most commonly results from disruption of the bowel wall and subsequent peritonitis. The authors report 2 rare deaths from idiopathic megacolon with retained integrity of the bowel wall. The first was a 9-year-old girl who was administered a laxative and subsequently died the following day. She expressed difficulty passing stool since birth with a marked decline at the age of 7 years. The second case was a 16-year-old adolescent girl with recent diarrhea who collapsed after showering. She, too, had a long history of chronic constipation. Years before death, her rectum and sigmoid colon were found to be dilated on x-ray for an unrelated event, but follow-up was never pursued. Cases such as these require a thorough review of the medical history and exclusion of established conditions, such as infectious, inflammatory, metabolic, and neurogenic origins.

Patients suffering from chagasic megacolon must have an intact mucosal barrier as they survive this chronic disease for decades. A key structure of the mucosal barrier are epithelial cells. Vasoactive-intestinal-peptide (VIP)-positive nerve fibres are involved in influencing, e.g., epithelial cell proliferation, mucus secretion (e.g., mucin 2 and trefoil factor 3 of goblet cells) and inflammation or autoimmunity, all putative and/or known factors altered in chagasic megacolon. We analyzed qualitatively and quantitatively goblet cells, their specific markers, such as mucin 2 (MUC2) and trefoil factor 3 (TFF3) and enterocytes, the relation of VIP-immunoreactive nerve fibres to the epithelia, the distribution of gelsolin, a protein involved in chronic inflammation processes in the epithelia, and the proliferation rate of epithelial cells by combined 4',6-diamidino-2-phenylindole (DAPI) and phosphohistone-H3 (PHH3) staining. Goblet cells were the dominating epithelial cell type. They accounted for 38.4% of all epithelial cells in controls and changed to 58.9% in the megacolonic parts. In contrast to the overall expression in goblet cells of control epithelia, TFF3 was confined to goblet cells at the base of the crypts whereas MUC2 was found only in luminal goblet cells. Gelsolin-positive goblet cells were predominantly recognized within the controls. Finally, the mean value of mitosis increased from 1.5% within the controls up to 2.6% in the anal parts of the chagasic sepcimens. Taken together, increased cell proliferation, preponderance of goblet cells, differential MUC 2, and TFF 3 expression might all be factors maintaining an intact mucosal barrier within chagasic megacolon.

A 7-year-old boy with chief complaint of chronic pelvic pain was referred to our nuclear medicine department for bone scintigraphy. The images showed a focus of radiotracer activity in the right side of pelvic cavity, which is further confirmed as urinary bladder by single-photon emission computed tomography (SPECT) and delayed images. Because of high possibility of mass effect in pelvic cavity, pelvic magnetic resonance imaging (MRI) was performed, and it revealed an unusual dilatation of rectosigmoid colon with no evidence of pelvic mass.

Chagas' disease is still reaching about 10 million people in the world. In South America, one of the most severe forms of this disease is the megacolon, characterized by severe constipation, dilated sigmoid colon and rectum and severe malnutrition. Previous data suggested that mast cells and serotonin (5-hydroxytryptamine [5-HT]) expression could be involved in intestinal homeostasis control, avoiding the chagasic megacolon development. The aim at this study was to characterize the presence of mast cells and expression of serotonin in chagasic patients with and without megacolon and evaluate the relation between mast cells, serotonin and megacolon development. Our results demonstrated that patients without megacolon feature a large amount of serotonin and few mast cells, while patients with megacolon feature low serotonin expression and a lot of mast cells. We believe that serotonin may be involved in the inflammatory process control, triggered by mast cells, and the presence of this substance in large quantities of the intestine could represent a mechanism of megacolon prevention., (© 2017 John Wiley & Sons Ltd.)

Objective: To investigate the application value of colonic transit test (CTT) combined with anorectal manometry (ARM), barium enema (BE) and defecography (DFG) in accurately evaluating colonic lesions of slow transit constipation complicated with adult megacolon., Methods: Clinical data of 47 above patients admitted between October 2007 and February 2015 in the People's Hospital of Hunan Province were analyzed retrospectively. All the patients were examined with≥2 times of CTT combined with ARM and BE, and 42 cases received additional DFG at the same time, to evaluate colonic lesions before operation. Operative biopsy pathology was used as the standard. The sensitivity, specificity, positive predictive value(PPV) and negative predictive value(NPV) of positioning in the ascending colon and caecum, transverse colon and descending colon were calculated, and the consistency was represented by Kappa test(Kappa value≥0.75 indicates good consistency, meanwhile higher Kappa value indicates better consistency). The Heikkinen score was used to evaluate defecation function at postoperative 6 months., Results: The age of 47 patients was from 18 to 56 years old. Compared with intraoperative findings and biopsy pathology, the diagnostic coincidence rate was 89.4% by CTT combined with BE and DFG positioning, which suggested pathology-changed colonic segment locating in the ascending colon and cecum (n=12), transverse colon (n=26) and descending colon (n=9), while intraoperative findings and biopsy pathology suggested pathology-changed colonic segment locating in the ascending colon and cecum (n=11), transverse colon (n=23) and descending colon (n=13). The sensitivity was 88.3%, specificity 93.5%, PPV 92.1%, NPV 94.9% and Kappa value was 0.827(P<0.001). Procedures performed included segmental colectomy (n=8), subtotal colectomy (n=29), total colectomy (n=10). There was no serious complication during and after operation. Defecatory function was excellent in 24 cases (60.0%), good in 10 (25.0%), and moderate in 6 (15.0%) evaluated by Heikkinen score at postoperative 6 months. A total of 40 patients were followed up from 1 to 7 years (median 3 years) and there was no long-term diarrhea and recurrence of constipation or giant colon after operation., Conclusion: Preoperative detection of CTT combined with ARM, BE and DFG in patients with slow transit constipation complicated with adult megacolon can make a more precise assessment of the extent of colonic lesions in advance, which has a good clinical predictive value.

We developed a novel murine model of long-term infection with Trypanosoma cruzi with the aim to elucidate the pathogenesis of megacolon and the associated adaptive and neuromuscular intestinal disorders. Our intent was to produce a chronic stage of the disease since the early treatment should avoid 100% mortality of untreated animals at acute phase. Treatment allowed animals to be kept infected and alive in order to develop the chronic phase of infection with low parasitism as in human disease. A group of Swiss mice was infected with the Y strain of T. cruzi. At the 11th day after infection, a sub-group was euthanized (acute-phase group) and another sub-group was treated with benznidazole and euthanized 15 months after infection (chronic-phase group). Whole colon samples were harvested and used for studying the histopathology of the intestinal smooth muscle and the plasticity of the enteric nerves. In the acute phase, all animals presented inflammatory lesions associated with intense and diffuse parasitism of the muscular and submucosa layers, which were enlarged when compared with the controls. The occurrence of intense degenerative inflammatory changes and increased reticular fibers suggests inflammatory-induced necrosis of muscle cells. In the chronic phase, parasitism was insignificant; however, the architecture of Aüerbach plexuses was focally affected in the inflamed areas, and a significant decrease in the number of neurons and in the density of intramuscular nerve bundles was detected. Other changes observed included increased thickness of the colon wall, diffuse muscle cell hypertrophy, and increased collagen deposition, indicating early fibrosis in the damaged areas. Mast cell count significantly increased in the muscular layers. We propose a model for studying the long-term (15 months) pathogenesis of Chagasic megacolon in mice that mimics the human disease, which persists for several years and has not been fully elucidated. We hypothesize that the long-term inflammatory process mediates neuronal damage and intramuscular and intramural denervation, leading to phenotypic changes in smooth muscle cells associated with fibrosis. These long-term structural changes may represent the basic mechanism for the formation of the Chagasic megacolon.

Background: Abdominal x-ray (AXR) can identify complications in acute severe colitis (ASC) and may assist in selecting high-risk children for early aggressive treatment. We aimed to describe AXR findings in pediatric ASC and to explore radiological predictors of response to intravenous corticosteroid (IVCS) therapy., Methods: A total of 56 children with ASC were included in a multicenter, retrospective 1-year cohort study (41% boys, mean age 12.1 ± 4.2). Radiographs of responders to IVCS and those requiring second-line salvage therapy by discharge were analyzed independently by 2 blinded radiologists., Results: A total of 33 responders to IVCS were compared with 23 nonresponders. The day-3 Pediatric Ulcerative Colitis Activity Index (PUCAI) score was significantly higher in nonresponders (63 ± 16 vs 46 ± 21, P = 0.001). The mean transverse colon luminal diameter was 30 ± 16 mm in responders and 38 ± 16 mm in nonresponders (P = 0.94). The upper range of transverse colonic diameter in children <12 years was ∼40 mm, whereas in older children it was 60 mm as accepted in adults. Ulcerations and megacolon seen on AXR were associated with nonresponse to IVCS (P = 0.006 and 0.064, respectively)., Conclusions: The presence of mucosal ulcerations and megacolon on AXR could be considered in the risk stratification of children with ASC for early aggressive treatment, together with the previously known day-3 and day-5 Pediatric Ulcerative Colitis Activity Index scores, albumin, and C-reactive protein.

An 8-year-old spayed female domestic shorthair cat was presented with a 4- to 5-month history of a progressively growing mass above her anus and an inability to defecate for 3 to 4 wk. External perianal and internal regional masses were subsequently identified and diagnosed as tumors of neuroendocrine origin through surgical excision and histopathologic evaluation. The cat was treated with 2 courses of chemotherapy and radiation therapy.

Chagasic megacolon is accompanied by extensive myenteric and, simultaneously, moderate submucosal neuron loss. Here, we examined changes of the innervation pattern of the lamina propria (LP) and muscularis mucosae (MM). Two alternating sets of cryosections were taken from seven non-chagasic colonic and seven chagasic megacolonic specimens (the latter included both the dilated megacolonic and the non-dilated transitional oral and anal zones) and were immunohistochemically triple-stained for smooth-muscle actin (SMA), synaptophysin (SYN) and glial acid protein S100 and, alternatively, for SMA, vasoactive intestinal peptide (VIP) and somatostatin (SOM). Subsequent image analysis and statistical evaluation of nervous tissue profile areas revealed that, in LP, the most extreme differences (i.e. increase in thickness or decrease in nerve, glia and muscle tissue profile area, respectively) compared with control values occurred in the dilated megacolonic zone itself. In contrast, the most extreme differences in the MM were in the anal-to-megacolonic zone (except the profile area of muscle tissue, which was lowest in the megacolonic zone). This parallels our previous results in the external muscle coat. A partial and selective survival of VIP-immunoreactive in contrast to SOM-immunoreactive nerve fibres was observed in both mucosal layers investigated. Thus, VIPergic nerve elements might be crucial for the maintenance of the mucosal barrier. The differential changes of neural tissue parameters in LP and MM might reflect a multifactorial rather than a pure neurogenic development of megacolon in chronic Chagas' disease.

Megacolon, the irreversible dilation of a colonic segment, is a structural sign associated with various gastrointestinal disorders. In its hereditary, secondary form (e.g. in Hirschsprung's disease), dilation occurs in an originally healthy colonic segment due to an anally located, aganglionic zone. In contrast, in chronic Chagas' disease, the dilated segment itself displays pathohistological changes, and the earliest and most prominent being found was massive loss of myenteric neurons. This neuron loss was partial and selective, i.e. some neurons containing neuronal nitric oxide synthase and/or vasoactive intestinal peptide (VIP) were spared from neuron death. This disproportionate survival of inhibitory neurons, however, did not completely correlate with the calibre change along the surgically removed, megacolonic segments. A better correlation was observed as to potentially contractile muscle tissue elements and the interstitial cells of Cajal. Therefore, the decreased densities of α-smooth muscle actin- and c-kit-immunoreactive profiles were estimated along resected megacolonic segments. Their lowest values were observed in the megacolonic zones itself, whereas less pronounced decreases were found in the non-dilated, transitional zones (oral and anal to dilation). In contrast to the myenteric plexus, the submucosal plexus displayed only a moderate neuron loss. Neurons co-immunoreactive for VIP and calretinin survived disproportionately. As a consequence, these neurons may have contributed to maintain the epithelial barrier and allowed the chagasic patients to survive for decades, despite their severe disturbance of colonic motility. Due to its neuroprotective and neuroeffectory functions, VIP may play a key role in the development and duration of chagasic megacolon.

Background: Migration from Latin American countries has increased the number of cases of chagasic megacolon in Western countries. Megacolon is a late complication of Chagas disease, resulting from irreversible destruction of the intramural intestinal nervous system with extensive loss of neurons, ganglionitis, and myositis at the sites of the myenteric and submucosal plexuses. Several surgical procedures involving partial or total resection of the dilated colon have been proposed for treating chagasic megacolon, but intra-operative evaluation of neuronal degeneration in the residual colon has not been commonly done., Methods: Case report and literature review., Case Report: We describe a case of chagasic megacolon treated successfully with a modified Habr-Gama technique, with the intra-operative examination of frozen sections of the residual segments of the colon for the presence of neurons., Conclusions: The recurrence of constipation after surgical treatment can result from the progression of chagasic neuronal degeneration in the preserved colon, and may be preventable by intra-operative evaluation of whether signs of neuronal degeneration or inflammation are absent in the anastomosed colonic tract.

Background: Idiopathic megacolon (IMC) is an intractable motility disorder in which chronic symptoms of colonic dysmotility appear with no mechanical cause. Although a pathological analysis is essential to understand the mechanism of IMC, no study has compared the histopathologic findings between dilated and non-dilated loops in IMC cases, and little is known about the proportion of each disease subtype., Methods: Fifty-three full-thickness samples (dilated loops, n = 31; non-dilated loops, n = 22) from 31 IMC cases and 16 samples (dilated loops; n = 8, non-dilated loops; n = 8) from eight controls were collected. All the samples were stained with hematoxylin-eosin (HE), Hu C/D antibody, and CD117 antibody to assess degenerative myopathy, degenerative neuropathy, inflammatory neuropathy, hypoganglionosis, and mesenchymopathy according to the London Classification. Findings of the dilated and non-dilated loop samples were compared, and the proportions of each subtype were analyzed., Key Results: Based on a control study, <60 ganglion cells/cm was defined as hypoganglionosis in our series. Myopathy was observed in 11 patients (35.5%), neuropathy was in 19 patients (61.3%), and mesenchymopathy was in 10 patients (32.2%). An overlap between subtypes was observed in some cases. Surprisingly, the non-dilated loop samples exhibited very similar histopathologic abnormalities to those observed in the dilated loop samples in most cases., Conclusions & Inferences: Our study is the first to compare the histopathologic findings between dilated and non-dilated loops in IMC patients. Histopathologic abnormalities precede the clinical manifestation of IMC, and may consequently lead to gradual colonic dilatation; however, detailed mechanism including dilation triggering factor needs further elucidation., (© 2014 John Wiley & Sons Ltd.)

Introduction: In this study, we investigated radiological changes in the sigmoid colon in chagasic patients by comparing their colon lengths and caliber with those of non-chagasic living in the same region and non-chagasic living at high altitudes., Methods: A total of 317 individuals were evaluated using clinical, serological and radiological methods and divided into three groups: 1) one hundred and nine non-chagasic individuals from Uberaba, Brazil; 2) sixty-one non-chagasic from Puno, Peru; 3) one hundred forty-seven chagasics examined in Uberaba, being 62 without megacolon (3A), 72 with megacolon (3B) and 13 with doubtful diagnosis of megacolon (3C)., Results: In group 2, the sigmoid colon had a significantly larger caliber (p=0.001) and the rectosigmoid colon was longer (p<0.001) than group 1. In subgroup 3A, the sigmoid colon (p<0.001) and rectum (p<0.001) had a significantly larger caliber and the rectosigmoid was longer (p<0.001) than that of the non-chagasic individuals. In subgroup 3B, the rectosigmoid was longer in all patients, and the caliber of the sigmoid was significantly larger than that of subjects in subgroups 3A and 3C (p<0.001)., Conclusions: Morphometric analysis confirms that Chagas disease may increase the caliber and length of the rectosigmoid. Our results suggest that altitude, ethnicity and diet may have influenced the size and length of the rectosigmoid of andean patients.

To investigate the expression levels of neurexins and neuroligins in the enteric nervous system (ENS) in Hirschsprung Disease (HSCR). Longitudinal muscles with adherent mesenteric plexus were obtained by dissection of the fresh gut wall of mice, guinea pigs, and humans. Double labeling of neurexin I and Hu (a neuron marker), neuroligin 1 and Hu, neurexin I and synaptophysin (a presynaptic marker), and neuroligin 1 and PSD95 (a postsynaptic marker) was performed by immunofluorescence staining. Images were merged to determine the relative localizations of the proteins. Expression levels of neurexin and neuroligin in different segments of the ENS in HSCR were investigated by immunohistochemistry. Neurexin and neuroligin were detected in the mesenteric plexus of mice, guinea pigs, and humans with HSCR. Neurexin was located in the presynapse, whereas neuroligin was located in the postsynapse. Expression levels of neurexin and neuroligin were significant in the ganglionic colonic segment of HSCR, moderate in the transitional segment, and negative in the aganglionic colonic segment. The expressions of neurexin and neuroligin in the transitional segments were significantly down-regulated compared with the levels in the normal segments (P < 0.05). Expression levels of neurexin and neuroligin in ENS are significantly down-regulated in HSCR, which may be involved in the pathogenesis of HSCR.

Chagas' disease is one of the most serious parasitic diseases of Latin America, with a social and economic impact far outweighing the combined effects of other parasitic diseases such as malaria, leishmaniasis and schistosomiasis. In the chronic phase of this disease, the destruction of enteric nervous system (ENS) components leads to megacolon development. Previous data presented that the regeneration tax in the ENS neurons is augmented in chagasic patients. Although, there are several neuronal types with different functions in the intestine a detailed study about the regeneration of every neuronal type was never performed before. Therefore, the aim of this study was to evaluate the regeneration tax of every neuronal cell type in the ENS from chagasic patients with megacolon and non-infected individuals. A neuronal regeneration marker (GAP-43) was used in combination with a pan-neuronal marker (Peripherin) and several neuropeptides markers (cChat, Substance P, NPY, VIP and NOS), and it was considered as positive just with the combination of these markers. Our results demonstrated that the regeneration levels of cChat, Substance P, and NPY were similar in chagasic patients and non-infected individuals. However, levels of VIP and NOS neuropeptides were increased in chagasic patients when compared with non-infected individuals. We believe that the augment in the regeneration occur due to an increased destruction of selective neuronal types. These results corroborates with previous studies that pointed out to selective destruction of VIP and NOS neurons in chagasic patients., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Aim: Megacolon, chronic dilation of a colonic segment,is accompanied by extensive myenteric neuron loss. However, this fails to explain unequivocally the formation of megacolon. We aimed to study further enteric structures that are directly or indirectly involved in colonic motility., Method: From surgically removed megacolon segments of seven Chagasic patients, three sets of cryosections from oral, megacolonic and anal zones were immunohistochemically quadruple-stained for smooth-muscle actin (SMA), synaptophysin (SYN, for nerve fibres), S100 (glia) and c-Kit (interstitial cells of Cajal, ICCs). Values of area measurements were related to the appropriate muscle layer areas and these proportions were compared with those of seven non-Chagasic control patients., Results: Whereas nerve and glia profile proportions did not mirror unequivocally the changes of Chagasic colon calibre (nondilation/dilation/nondilation), the proportions of SMA (i.e. muscle tissue density) and c-Kit (i.e. ICC density) did so: they decreased from the oral to the megacolonic segment but increased to the anal zones (muscle tissue density: control 68.3%, oral 54.3%, mega 42.1%, anal 47.6%; ICC-density: control 1.8%, oral 1.1%, mega 0.4, anal 0.8%)., Conclusion: Of the parameters evaluated, muscle tissue and ICC densities may be involved in the formation of Chagasic megacolon, although the mechanism of destruction cannot be deduced., (Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.)

In addition to neurons, interstitial cells of Cajal (ICC) play an important role in coordinating intestinal motility with a pacemaker function. This study aimed to quantitatively analyze ICC, neurons, and muscular area, the latter to correct for quantitation errors resulting from dilation in case of a megacolon and from the dispersion of ICC that can be attributed to muscular hypertrophy. We analyzed 30 colon samples: ten chagasic megacolon (CM), ten chagasic colons without megacolon (CXM), and ten nonchagasic control patients (NC). We measured the area of muscularis propria and counted the number of neurons of the myenteric plexus in a histological section of an intestinal ring and the number of ICC at the level of the myenteric plexus and circular muscle layer, the latter in a section immunohistochemically stained for CD117. Muscular hypertrophy occurred only in the CM group. Compared to the NC group, we found in the CM group a statistically significant reduction of 80 % in the number of neurons, 60 % in the number of ICC in the myenteric plexus, and 38 % in the area of circular muscle. In the CXM group, these numbers were highly variable, and their reduction, less pronounced. We conclude that the number of ICC is significantly reduced in CM patients, and that this might contribute to the pathophysiology of CM. However, the development of CM requires severe denervation, whereas CXM generally exhibits less than 50 % denervation, favoring the hypothesis that the reduction in ICC number is, in part, a consequence of denervation.

Background/aims: In Chagasic megacolon, there is a reduction in the population of interstitial cells of Cajal. It was aimed to evaluate density of Cajal cells in the resected colon of Chagasic patients compared to control patients and to verify possible association between preoperative and postoperative bowel function of megacolon patients and cell count., Methodology: Sixteen megacolon patients (12 female; mean age 54.4 (31-73)) were operated on. Pre- and postoperative evaluation using Cleveland clinic constipation score was undertaken. Resected colons were examined. Cajal cells were identified by immunohistochemistry (anti-CD117). The mean cell number was compared to resected colons from 16 patients (7 female; mean age 62.8 (23-84)) with non-obstructive sigmoid cancer. Association between pre- and postoperative constipation scores and cell count for megacolon patients was evaluated using the Pearson test (r)., Results: A reduced number of Cajal cells (per field: 2.84 (0-6.6) vs. 9.68 (4.3-13); p<0.001) were observed in the bowel of megacolon patients compared to cancer patients. No correlation between constipation score before (r=- 0.205; p=0.45) or after surgery (r=0.291; p=0.28) and cell count in megacolon was observed., Conclusions: Patients with megacolon display marked reduction of interstitial cells of Cajal. An association of constipation severity and Cajal cells depopulation was not demonstrated.

Introduction: Megacolon, chronic dilation of a colonic segment, is a frequent sign of Chagas disease. It is accompanied by an extensive neuron loss which, as shown recently, results in a partial, selective survival of nitrergic myenteric neurons. Here, we focused on the balance of intramuscular excitatory (choline acetyltransferase [ChAT]-immunoreactive) and inhibitory (neuronal nitric oxide synthase [NOS]- as well as vasoactive intestinal peptide [VIP]-immunoreactive) nerve fibres., Materials and Methods: From surgically removed megacolonic segments of seven patients, three sets of cryosections (from non-dilated oral, megacolonic and non-dilated anal parts) were immunhistochemically triple-stained for ChAT, NOS and VIP. Separate area measurements of nerve profiles within the circular and longitudinal muscle layers, respectively, were compared with those of seven non-chagasic control patients. Additionally, wholemounts from the same regions were stained for NOS, VIP and neurofilaments (NF)., Results: The intramuscular nerve fibre density was significantly reduced in all three chagasic segments. The proportions of inhibitory (NOS only, VIP only, or NOS/VIP-coimmunoreactive) intramuscular nerves were 68 %/58 % (circular/longitudinal muscle, respectively) in the controls and increased to 75 %/69 % (oral parts), 84 %/76 % (megacolonic) and 87 %/94 % (anal) in chagasic specimens. In the myenteric plexus, NF-positive neurons co-staining for NOS and VIP also increased proportionally. The almost complete lack of dendritic structures in ganglia of chagasic specimens hampered morphological identification., Discussion and Conclusion: We suggest that preponderance of inhibitory, intramuscular nerve fibres may be one factor explaining the chronic dilation. Since the nerve fibre imbalance is most pronounced in the anal, non-dilated segment, other components of the motor apparatus (musculature, interstitial cells, submucosal neurons) have to be considered.

Chronic Chagas' disease is frequently characterized by massive myenteric neuron loss resulting in megacolon with severely and irreversibly disturbed motility. Here, we focused on two submucosal neuron populations, immunoreactive for calretinin (CALR) or somatostatin (SOM), and their respective mucosal nerve fibres in chagasic megacolon. Surgically removed megacolonic segments of seven chagasic patients were compared with seven age- and region-matched non-chagasic control segments. Evaluation included immunohistochemical triple-staining of cryosections for CALR, SOM and peripherin or for CALR and vasoactive intestinal peptide (VIP) and of submucosal whole-mounts for CALR, SOM and the pan-neuronal marker anti-HuC/D. Submucosal neuron counts in chagasic tissue revealed neuron numbers reduced to 51.2 % of control values. In cryosections, nerve fibre area measurements revealed 8.6 % nerve fibre per mucosal area in control segments, but this value decreased to 1.5 % in megacolonic segments. In both evaluations, a disproportionate decrease of SOM-reactive nerve elements was observed. The proportions of SOM-positive neurons related to the total neuron number declined to 2 % (control 10 %) and the proportion of SOM-reactive mucosal nerve fibres related to the whole mucosal area to 0.014 % (control 1.8 %)in chagasic tissue. The second set of cryosections revealed extensive colocalization of CALR with VIP in both surviving submucosal perikarya and mucosal nerve fibres. We suggest that VIP, a neuroprotective and neuroeffectory peptide typically contained in submucosal neurons, allows both the VIP-containing neurons to endure and the patients to survive by maintaining their mucosal barrier, despite the almost complete loss of colonic motility for decades.

Multiple endocrine neoplasia (MEN) type 2B is the rarest and most aggressive form of MEN syndrome. MEN 2B patients manifest characteristic oral and facial features besides the neural crest cell-derived tumors, including medullary carcinoma, pheochromocytoma, mucosal neuroma, and ganglioneuromatosis of the gut. We report a case of MEN 2B diagnosed on the basis of the warning signs of mucosal neuroma and multiple neural hyperplasias in the maxillary bone resected during orthognathic surgery. A subsequent systemic examination under the pathologic diagnosis of neural lesions revealed medullary thyroid carcinoma, megacolon, thickened corneal nerves, and RET gene mutation, thus verifying the diagnosis of MEN 2B. An immunohistochemical study revealed an increased number of unmyelinated Schwann cells in the hyperplastic nerves. We suggest that intraosseous neural hyperplasia is a specific finding of the MEN 2B syndrome in addition to the known oral and facial manifestations., (Copyright © 2011 Mosby, Inc. All rights reserved.)

One frequent chronic syndrome of Chagas' disease is megacolon, an irreversible dilation of a colonic segment. Extensive enteric neuron loss in the affected segment is regarded as key factor for deficient motility. Here, we assessed the quantitative balance between cholinergic and nitrergic neurons representing the main limbs of excitatory and inhibitory colonic motor innervation, respectively. From surgically removed megacolonic segments of four patients, each three myenteric wholemounts (from non-dilated oral, megacolonic and non-dilated anal parts) was immunohistochemically triple-stained for choline acetyltransferase, neuronal nitric oxide synthase (NOS) and the panneuronal human neuronal protein Hu C/D. Degenerative changes were most pronounced in the megacolonic and anal regions, e.g. bulked, honeycomb-like ganglia with few neurons which were partly enlarged or atrophic or vacuolated. Neuron counts from each 15 ganglia of 12 megacolonic wholemounts were compared with those of 12 age- and region-matched controls. Extensive neuron loss, mainly in megacolonic and anal wholemounts, was obvious. In all three regions derived from megacolonic samples, the proportion of NOS-positive neurons (control: 55%) was significantly increased: in non-dilated oral parts to 61% (p = 0.003), in megacolonic regions to 72% (p < 0.001) and in non-dilated anal regions to 78% (p < 0.001). We suggest the chronic dilation of megacolonic specimens to be due to the preponderance of the nitrergic, inhibitory input to the intestinal muscle. However, the observed neuronal imbalance was not restricted to the dilated regions: the non-dilated anal parts may be innervated by ascending, cholinergic axons emerging from less affected, more anally located regions.

Objective: To observe the influence of electroacupuncture (EA) of different acupoints on changes of mean arterial pressure (MAP), heart rate (HR) and heart rate variability (HRV) in colorectal distension (CRD) rats, so as to analyze the specificity of actions of acupoints in relieving visceral pain and regulating activities of the autonomic nerve system., Methods: Forty-five Wistar rats were randomized into control, Zusanli (ST 36), non-acupoint, Neiguan (PC 6) and Taichong (LR 3) groups (n = 9/group). Under anesthesia, CRD was given to the rats by using an aerostat for 5 min. EA (2 Hz/15 Hz, 2 mA) was applied to bilateral ST 36, non-acupoint (1.0 cm lateral to ST 36), PC 6 and LR 3 for 15 min, respectively. Electrocardiogram of the cervico-chest lead was recorded by using a bioelectric amplifier, and MAP recorded by using a pressure transducer and an amplifier. Low frequency and high frequency of HRV were analyzed by Chart 5.0., Results: Following CRD, the HR, MAP, LF and LF/HF levels increased significantly in all the 5 groups (P < 0.05), while HF had no apparent changes (P > 0.05). Compared with the control group, 5 min and 15 min after EA ,and 10 min after ceasing EA, MAP values of ST 36 and PC 6 groups were decreased obviously (P < 0.05). The HR values of ST 36 and PC 6 groups at 15 min after EA and 10 min after ceasing EA were decreased markedly in comparison with those of each of the other groups during CRD (P < 0.05). The LF levels of both ST 36 and PC 6 groups at 5 min after EA, and those of ST 36, PC 6 and LR 3 at 15 min after EA were significantly lower than those of control group (P < 0.05). LF/HF levels of ST 36 and PC 6 at 10 min after ceasing EA were obviously lower than those of control group (P < 0.05). No significant differences were found among ST 36, non-acupoint, PC 6 and LR 3 groups in HR, LF and LF/HF (P > 0.05)., Conclusion: EA of ST 36 and PC 6 can suppress CRD-induced increase of MAP, HR and LF/HF, suggesting beneficial effects of EA in relieving visceral pain and mediating autonomic nerve system. The aforementioned effects of EA of LR 3 and non-acupoint are not obvious.

A pair of 2 serial abdominal images show Ogilvie syndrome in a patient after cardiac surgery with the subtle but classic x-ray transition from a nonperforated to a perforated colon., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Chagasic megacolon has been reported in the southern cone countries of South America and is mainly associated with Trypanosoma cruzi II infection. Herein, we report the first case in Colombia of chagasic megacolon with cardiomyopathy associated with the T. cruzi I lineage. This finding suggests that in Colombia, as well as in other northern countries of South America and throughout Central America, where T. cruzi I is endemic, cardiomyopathy may not be the only clinical form of Chagas disease.

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., (Copyright 2010 Elsevier Inc. All rights reserved.)