RESUMO
INTRODUCTION: A proximal resection margin greater than 5 cm from the intra-operative histologically determined transition zone has been deemed necessary to minimize the risk of transition zone pull-through. This extended resection may require the sacrifice of vascular supply and even further bowel resection. The impact of extended proximal resection margin on post-operative complications and functional outcomes is unclear. METHODS: A retrospective chart review of patients who underwent primary pull-through for Hirschsprung disease at a single institution between January 2008 and December 2022 was performed. An adequate proximal margin was defined by a circumferential normally ganglionated ring and absence of hypertrophic nerves. The extended margin was defined as the total length of proximal colon with normal ganglion cells and without hypertrophic nerves. Fecal incontinence severity was assessed with the Pediatric Fecal Incontinence Severity Score (PFISS). RESULTS: Eighty seven patients met criteria for inclusion. Median age at primary pull-through was 17 days (IQR 10-92 days), 55% (n = 48) of patients had an extended proximal margin (EPM) ≤ 5 cm, and 45% (n = 39) had an EPM > 5 cm. An EPM ≤5 cm was not associated with increased rates of Hirschsprung associated enterocolitis (≤5 cm 43%, >5 cm 39%, P = 0.701), diversion post pull-through (≤5 cm 10%, >5 cm 5%, P = 0.367) or reoperation for transition zone pull-through (≤5 cm 3%, >5 cm 0%, P = 0.112). EPM ≤5 cm had more frequent involuntary daytime bowel movements (P = 0.041) and more frequent voluntary bowel movements (P = 0.035). There were no differences in other measures of fecal incontinence severity. CONCLUSIONS: Shorter proximal extended margins beyond the adequate ganglionated margin do not significantly impact post-operative complication rates and have an unclear effect on fecal incontinence. TYPE OF STUDY: Case Control. LEVEL OF EVIDENCE: Level III.
Assuntos
Incontinência Fecal , Doença de Hirschsprung , Criança , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , Incontinência Fecal/etiologia , Incontinência Fecal/complicações , Margens de Excisão , Doença de Hirschsprung/complicações , Hipertrofia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Hirschsprung-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality amongst patients with Hirschsprung disease (HD); rectal Botulinum toxin (Botox) has been reported a possible prevention strategy. We aimed to evaluate our institution's historic cohort of HD patients, first to determine our incidence of HAEC and second to begin assessing the effect of Botox on HAEC incidence. METHODS: Patients with HD seen at our institution between 2005 and 2019 were reviewed. Incidence of HD and frequencies of HAEC and Botox injections were tallied. Associations between initial Botox treatment or transition zone and HAEC incidence were evaluated. RESULTS: We reviewed 221 patients; 200 were included for analysis. One hundred thirteen (56.5%) patients underwent primary pull-through at a median age of 24 days (IQR 91). Eighty-seven (43.5%) patients with initial ostomy had their intestinal continuity reestablished at a median of 318 days (IQR 595). Ninety-four (49.5%) experienced at least one episode of HAEC and 62 (66%) experienced multiple episodes of HAEC. Nineteen (9.6%) patients had total colonic HD and had an increased total incidence of HAEC compared to patients without total colonic HD (89% vs 44%, p < 0.001). Six (2.9%) patients received Botox injections at the time of pull-through or ostomy takedown; one experienced an episode of HAEC (versus 50.7% of the patients who were confirmed to have not received Botox injections at their surgery, p = 0.102). CONCLUSION: Further prospective study on Botox's effect on Hirschsprung-associated enterocolitis is required and is the next step in our investigation. LEVEL OF EVIDENCE: Level III.
Assuntos
Toxinas Botulínicas Tipo A , Enterocolite , Doença de Hirschsprung , Humanos , Lactente , Estudos Retrospectivos , Estudos Prospectivos , Toxinas Botulínicas Tipo A/uso terapêutico , Doença de Hirschsprung/complicações , Doença de Hirschsprung/cirurgia , Enterocolite/epidemiologia , Enterocolite/etiologia , Enterocolite/cirurgia , Reto , Complicações Pós-Operatórias/epidemiologiaRESUMO
OBJECTIVE: This paper aims to evaluate the pediatric surgery training pipeline vis-à-vis the pediatric surgery match and operative experience of pediatric surgery fellows. SUMMARY OF BACKGROUND DATA: Pediatric surgery remains a competitive surgical subspecialty. However, there is concern that operative experience for pediatric surgery fellows is changing. This paper examines the selectivity of the pediatric surgery match, along with the operative experience of pediatric surgery fellows to characterize the state of pediatric surgery training. METHODS: The pediatric surgery fellowship match was analyzed from the National Resident Matching Program data from 2010 to 2019. Selectivity among fellowships was compared using analysis of variance with Dunnett test. Operative log data for pediatric fellows was analyzed using the Accreditation Council for Graduate Medical Education case logs from 2009 to 2019. Linear regression analysis was used to evaluate trends in operative volume over time. RESULTS: Pediatric surgery had the highest proportion of unmatched applicants (47.2% ± 5.3%) and lowest proportion of unfilled positions (1.4% ± 1.6%) when compared to other National Resident Matching Program surgical fellowships. Accreditation Council for Graduate Medical Education case log analysis revealed a statistically significant decrease in cases for graduating fellows (-5.3 cases/year, P < 0.05). Total index cases decreased (-4.7 cases/year, P < 0.01, R 2 = 0.83) such that graduates in 2019 completed 59 fewer index operations than graduates in 2009. CONCLUSION: Although pediatric surgery fellowship remains highly selective there has been a decline in the operative experience for graduating fellows. This highlights the need for evaluation of training paradigms and operative exposure in pediatric surgery to ensure the training of competent pediatric surgeons.
Assuntos
Especialidades Cirúrgicas , Cirurgiões , Humanos , Criança , Bolsas de Estudo , Acreditação , Educação de Pós-Graduação em MedicinaRESUMO
The current available literature evaluating pediatric multidisciplinary aerodigestive programs for the management of aerodigestive disorders in infants was reviewed. Multidisciplinary aerodigestive programs have emerged to provide coordinated and comprehensive care for the growing population of children with aerodigestive conditions, including complex airway, pulmonary, gastrointestinal, and feeding disorders, which are prevalent among infants discharged from the neonatal intensive care unit (NICU). The team approach central to aerodigestive clinics offers a comprehensive diagnostic workup and unified management plan through consolidated interdisciplinary clinics, combined endoscopic procedures, and regular team discussions, leading to improved resource utilization and health care outcomes. We review common conditions presenting in the NICU that benefit from the aerodigestive model of care, including esophageal atresia, prematurity, bronchopulmonary dysplasia with or without tracheostomy or ventilator dependence, and dysphagia.
Assuntos
Transtornos de Deglutição , Atresia Esofágica , Doenças Respiratórias , Lactente , Recém-Nascido , Criança , Humanos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Unidades de Terapia Intensiva Neonatal , Sistema RespiratórioRESUMO
Total Colonic Hirschsprung Disease (HD) can be challenging from a diagnostic and management standpoint and occurs in around 8% of cases of HD. Long term outcomes are difficult to compare due to variation in length of aganglionosis, chosen surgical techniques, and terminology utilized in the literature. In this review we highlight some of the management controversies and clinical challenges and emphasize future areas of suggested collaboration and research.
Assuntos
Doença de Hirschsprung , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/cirurgia , HumanosRESUMO
BACKGROUND: The 2020 Pediatric Surgery (PS) fellowship selection process was heavily impacted by the COVID-19 pandemic. A review of lessons learned can help determine best practices for the future. The purpose of the study was to analyze the virtual interview experience and assess opportunities to improve the post-pandemic fellowship recruitment process. STUDY DESIGN: Using a 28-question survey of Program Directors (PDs) of PS fellowships as well as a 44-question survey of applicants to PS fellowships in the US and Canada, we gathered information on the recruitment process during the COVID-19 pandemic (2020). Dichotomous, multiple choice and open-ended questions about the changes in process, platforms used, format, comparison to on-site interviews and overall satisfaction were used for objective and subjective feedback. RESULTS: A 95% participation rate was recorded for the PD survey. 24 out of 55 programs (44%) changed their on-site interviews to virtual format due to the pandemic. Most PDs described their overall impression of virtual interviews as satisfactory (66%, 16/24) and did not have an impact on the applicant's success in the match (35/54; 65%). About 50% of PDs preferred to have on-site interviews with virtual screening in the future. While the participation rate from applicants was much less (26 of 70), responses confirmed our survey results. Majority preferred on-site interviews (17/26), 6 of which preferred virtual screening followed by on-site interviews. CONCLUSION: Components of virtual screening and interviews were found to have benefits financially and from both time and stress perspectives, and thus might survive past the pandemic. LEVELS OF EVIDENCE LEVEL IV: .
Assuntos
COVID-19 , Internato e Residência , Especialidades Cirúrgicas , COVID-19/epidemiologia , Criança , Bolsas de Estudo , Humanos , Pandemias , Inquéritos e QuestionáriosRESUMO
BACKGROUND: One of the most competitive surgical sub-specialty fellowships remains Pediatric Surgery (PS), which requires candidates to develop a strong and research-oriented curriculum vitae. Although some objective factors of matriculation are known, factors for the interview selection and ranking per the program directors (PDs) have not been reviewed in over a decade. METHODS: A web-based survey of US and Canadian PS program directors (PDs) (n = 58) was used to evaluate a comprehensive list of factors in the selection criteria for PS fellowships. A mix of dichotomous, ranking, five-point Likert scale, and open-ended questions evaluated applicant characteristics, ABSITE scores, research productivity, interview day, and rank order criteria. RESULTS: Fifty-five programs responded to the survey for a 95% participation rate. PDs desired an average of two years in dedicated research and weighted first authorship and total number of publications heavily. Only 38% of programs used an ABSITE score cutoff for offering interviews; however, the majority agreed that an overall upward trend was important. Quality letters of recommendation, especially from known colleagues, carried weight when deciding to offer interviews. Interview performance, being a team player, observed interpersonal interactions, perceived operative skills and patient care, and leadership were some of the notable factors when finalizing rank lists. CONCLUSIONS: A multitude of factors define a successful matriculant, including quality of letters of recommendation, quality and quantity of publications, supportive phone calls, observed interactions, interview performance, perceptions of being team player with leadership skills as well as perceptions of good operative skills and patient care. LEVEL OF EVIDENCE: Type II. TYPE OF STUDY: Prognostic (retrospective).
Assuntos
Internato e Residência , Especialidades Cirúrgicas , Canadá , Criança , Bolsas de Estudo , Humanos , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Repair of pectus excavatum has cosmetic benefits, but the physiologic impact remains controversial. The aim of this study was to characterize the relationship between the degree of pectus excavatum and cardiopulmonary dysfunction seen on cardiac magnetic resonance (CMR) imaging, cardiopulmonary exercise testing (CPET), and pulmonary function testing (PFT). METHODS: A single-center analysis of CMR, CPET, and PFT was conducted. Regression models evaluated relationships between pectus indices and the clinical end points of cardiopulmonary function. RESULTS: Data from 345 CMRs, 261 CPETs, and 281 PFTs were analyzed. Patients were a mean age of 15.2 ± 4 years, and 81% were aged <18 years. The right ventricular ejection fraction (RVEF) was <0.50 in 16% of patients, left ventricular ejection fraction (LVEF) was <0.55 in 22%, RVEF Z-score was < -2 in 32%, and the LVEF Z-score was < -2 in 18%. CPET revealed 33% of patients had reduced aerobic fitness. PFT results were abnormal in 23.1% of patients. Adjusted analyses revealed the Haller index had significant (P < .05) inverse associations with RVEF and LVEF. CONCLUSIONS: The severity of pectus excavatum is associated with ventricular systolic dysfunction. Pectus excavatum impacts right and left ventricular systolic function and can also impact exercise tolerance. The Haller index and correction index may be the most useful predictors of impairment.
Assuntos
Tórax em Funil , Adolescente , Adulto , Criança , Tórax em Funil/complicações , Ventrículos do Coração , Humanos , Volume Sistólico , Função Ventricular Esquerda , Função Ventricular Direita , Adulto JovemRESUMO
BACKGROUND/PURPOSE: In an effort to standardize educational experience, address future physician shortages, and improve quality of care to patients, many surgical specialties are discussing how to maximize exposure to index cases. One solution being explored is telementoring, which requires a well-developed educational curriculum with intraoperative objectives. The American College of Surgery Telementoring Task Force selected anorectal malformation and posterior sagittal anorectoplasty (PSARP) for the repair of imperforate anus as the initial educational focus for this pilot. The purpose of this study was to obtain international consensus on intraoperative learning objectives for a complex surgical procedure. METHODS: A multidisciplinary team of medical educators and pediatric surgery experts created an outline of essential curricular content and intraoperative learning objectives for PSARP in three clinical scenarios. Twelve international subject matter experts were identified meeting strict inclusion criteria. Intraoperative checklists were revised using the modified-Delphi process. RESULTS: After five rounds of modifications to the intraoperative checklists, international consensus was achieved for three different clinical scenarios requiring a PSARP: perineal or vestibular fistula, low prostatic fistula, and bladder neck fistula. CONCLUSIONS: A modified-Delphi approach was successful in generating guidelines for surgical techniques that can be used to standardize intraoperative teaching and expectations for trainees. TYPE OF STUDY: Diagnostic study LEVEL OF EVIDENCE: Level V (expert opinion).
Assuntos
Malformações Anorretais , Procedimentos de Cirurgia Plástica , Fístula Retal , Canal Anal/cirurgia , Malformações Anorretais/cirurgia , Criança , Consenso , Humanos , Fístula Retal/cirurgia , Reto/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The cumulative incidence and predictors of future diagnosis of Crohn's disease (CD) following presentation with perianal symptoms, such as anorectal abscess, fistula or fissure, is unknown. METHODS: A 5-year retrospective review of children presenting with perianal symptoms without prior CD diagnosis was performed. Institutional cumulative incidence of CD was calculated to determine the risk of CD presenting with perianal symptoms. RESULTS: 1140 children presented for evaluation of an anorectal abscess (n = 232), fistula (n = 49), or fissure (n = 859). Thirty-five were later diagnosed with CD, resulting in an incidence of 3%. Prognostic indicators of future CD diagnosis included increased age per every additional year (RR 1.19, 95% CI: 1.14-1.25, p < 0.001), male sex (RR 2.12, 95% CI 1.07-4.22, p = 0.024), or perianal fistula (RR 4.67, 95% CI 2.26-9.67, p = 0.022). Among those diagnosed with CD, 57% experienced and had a documented history of a CD-associated symptom prior to perianal symptom onset. Absence of symptoms resulted in delayed diagnosis (43 vs 3 days, p < 0.02). CONCLUSION: Of children presenting with a perianal symptom, three percent will eventually be diagnosed with CD. At highest risk (35%) were males aged 10 years or older with a perianal fistula; which should prompt expeditious workup.
Assuntos
Doenças do Ânus , Doença de Crohn , Fístula Retal , Doenças do Ânus/diagnóstico , Doenças do Ânus/etiologia , Criança , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Humanos , Masculino , Períneo , Fístula Retal/diagnóstico , Fístula Retal/etiologia , Estudos RetrospectivosRESUMO
PURPOSE: Pectus excavatum (PE) is a chest wall deformity of variable severity and symptomatology. Existing female-specific literature highlights breast asymmetry and cosmetic reconstruction. We sought to evaluate gender differences in cardiopulmonary function. METHODS: Cardiac MRIs, pulmonary function tests (PFTs), and cardiopulmonary exercise tests (CPETs) were reviewed in 345 patients undergoing preoperative evaluation for PE. Regression modeling was used to evaluate associations between gender and clinical endpoints of cardiopulmonary function. RESULTS: Mean age was 15.2 years, 19% were female, 98% were white. Pectus indices included median Haller Index (HI) of 4.8, mean depression index (DI) of 0.63, correction index (CI) of 33.6%, and Cardiac Compression Index (CCI) of 2.79. Cardiac assessment revealed decreased right and left ventricular ejection fraction (RVEF, LVEF) in 16% and 22% of patients, respectively. PFTs and CPETs were abnormal in ~ 30% of patients. While females had deeper PE deformities-represented by higher pectus indices-they had superior function with higher RVEF, LVEF Z-scores, FEV1, VO2 max, O2 pulse, work, and breathing reserve (p < 0.05). CONCLUSION: Despite worse PE deformity and symptomatology, females had a better cardiopulmonary function and exercise tolerance than males. Further research is needed to assess the precise mechanisms of this phenomenon and postoperative outcomes in this population.
Assuntos
Tolerância ao Exercício/fisiologia , Tórax em Funil/fisiopatologia , Frequência Cardíaca/fisiologia , Volume Sistólico/fisiologia , Parede Torácica/fisiopatologia , Função Ventricular Esquerda/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Tórax em Funil/epidemiologia , Humanos , Incidência , Imageamento por Ressonância Magnética , Masculino , Fatores Sexuais , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Pediatric surgery (PS) is among the most competitive fellowship opportunities for general surgery residents. Prior investigations into factors associated with successful matriculation to PS have relied on surveys, which have inherent biases. STUDY DESIGN: Data were extracted from the Electronic Residency Application System for applicants from 2012 to 2017 and analyzed after stratification by matriculation status. RESULTS: Data were gathered on a total of 444 applicants, of which 238 matriculated. The applicant pool was predominantly Caucasian (63.5%), largely graduated from US allopathic school (81%) and had a slight male predominance (54%), although the number of female applicants increased significantly over the study period. Attendance at a US allopathic medical school (OR=4.55, p <0.001), university-based general surgery training (OR=3.02, p <0.001) and training at institutions that offer PS fellowships (OR=3.36, p<0.001) were associated with matriculation. Matriculants had a higher quantity of peer reviewed publications (median 11 vs. 6, p <0.001) and published in high impact factor journals (p<0.001). A total of 65 applicants reapplied at least once, of whom 32% successfully matriculated. CONCLUSIONS: PS applicants' medical school, residency, and research data points correlated with successful matriculation. These data may help guide general surgery residents and medical students aspiring to become pediatric surgeons. TYPE OF STUDY: Prognosis study (retrospective) LEVEL OF EVIDENCE: Level II.
Assuntos
Educação de Pós-Graduação em Medicina/estatística & dados numéricos , Bolsas de Estudo/estatística & dados numéricos , Pediatria/educação , Especialidades Cirúrgicas/educação , Cirurgiões/educação , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Hereditary multiple intestinal atresia (HMIA) is an extremely uncommon cause of congenital bowel obstruction. The morbidity and mortality of this disease differ significantly from those of isolated intestinal atresias and non-hereditary forms of multiple intestinal atresia. Most notably, despite successful operative repairs of the atresias found in this disease, HMIA maintains a 100% lethality rate from continued post-operative intestinal failure and an associated severe immunodeficiency. We present a case of HMIA evaluated with fetal MRI and subsequently diagnosed by a combination of corroborative postnatal imaging with surgical exploration and pathological examination.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Atresia Intestinal/genética , Atresia Intestinal/patologia , Imageamento por Ressonância Magnética/métodos , Diagnóstico Pré-Natal/métodos , Diagnóstico Diferencial , Humanos , Recém-Nascido , Masculino , Estatística como AssuntoRESUMO
A case of esophageal atresia associated with a foregut duplication cyst is reported and the literature reviewed. This is the first documented occurrence in conjunction with Down syndrome and the second case where both anomalies were treated at the initial surgery.
Assuntos
Anormalidades Múltiplas/patologia , Síndrome de Down/patologia , Atresia Esofágica/patologia , Cisto Esofágico/congênito , Fístula Traqueoesofágica/congênito , Fístula Traqueoesofágica/patologia , Anormalidades Múltiplas/cirurgia , Canal Anal/anormalidades , Animais , Broncoscopia , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Atresia Esofágica/cirurgia , Cisto Esofágico/embriologia , Cisto Esofágico/cirurgia , Esofagoplastia , Esôfago/anormalidades , Feminino , Cardiopatias Congênitas/induzido quimicamente , Comunicação Interventricular/patologia , Humanos , Achados Incidentais , Recém-Nascido , Rim/anormalidades , Deformidades Congênitas dos Membros/induzido quimicamente , Roedores , Coluna Vertebral/anormalidades , Toracotomia , Traqueia/anormalidades , Fístula Traqueoesofágica/cirurgiaRESUMO
Renal rhabdomyosarcoma (RMS) is a rare pediatric tumor. Pancake kidneys are unusual anatomic anomalies resulting when both upper and lower poles of the embryonic kidney become fused. We report on a 4-year-old boy who was discovered to have a stage 4, group IV renal embryonal RMS arising from a pancake kidney with metastases to the lung, pelvis, and bone marrow. Treatment included multimodal therapy, consisting of neoadjuvant chemotherapy, complete surgical resection, and adjuvant chemotherapy. He remains in clinical remission 7 months after resection.
Assuntos
Neoplasias Renais/patologia , Neoplasias Renais/terapia , Rim/anormalidades , Rabdomiossarcoma/secundário , Rabdomiossarcoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Medula Óssea/secundário , Neoplasias da Medula Óssea/terapia , Quimioterapia Adjuvante , Pré-Escolar , Humanos , Neoplasias Renais/cirurgia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/terapia , Masculino , Terapia Neoadjuvante , Neoplasias Pélvicas/secundário , Neoplasias Pélvicas/terapia , Rabdomiossarcoma/cirurgiaRESUMO
Murine small intestinal crypt development is initiated during the first postnatal week. Soon after formation, overall increases in the number of crypts occurs through a bifurcating process called crypt fission, which is believed to be driven by developmental increases in the number of intestinal stem cells (ISCs). Recent evidence suggests that a heterogeneous population of ISCs exists within the adult intestine. Actively cycling ISCs are labeled by Lgr5, Ascl2 and Olfm4; whereas slowly cycling or quiescent ISC are marked by Bmi1 and mTert. The goal of this study was to correlate the expression of these markers with indirect measures of ISC expansion during development, including quantification of crypt fission and side population (SP) sorting. Significant changes were observed in the percent of crypt fission and SP cells consistent with ISC expansion between postnatal day 14 and 21. Quantitative real-time polymerase chain reaction (RT-PCR) for the various ISC marker mRNAs demonstrated divergent patterns of expression. mTert surged earliest, during the first week of life as crypts are initially being formed, whereas Lgr5 and Bmi1 peaked on day 14. Olfm4 and Ascl2 had variable expression patterns. To assess the number and location of Lgr5-expressing cells during this period, histologic sections from intestines of Lgr5-EGFP mice were subjected to quantitative analysis. There was attenuated Lgr5-EGFP expression at birth and through the first week of life. Once crypts were formed, the overall number and percent of Lgr5-EGFP positive cells per crypt remain stable throughout development and into adulthood. These data were supported by Lgr5 in situ hybridization in wild-type mice. We conclude that heterogeneous populations of ISCs are expanding as measured by SP sorting and mRNA expression at distinct developmental time points.
Assuntos
Biomarcadores/metabolismo , Linhagem da Célula , Células Epiteliais/citologia , Intestinos/citologia , Células-Tronco/citologia , Animais , Células Epiteliais/metabolismo , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hibridização In Situ , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/metabolismoRESUMO
BACKGROUND: Surgical resection of the ileum, cecum, and proximal right colon (ICR) is common in the management of Crohn's disease, yet little is known about the effect of active inflammation on the adaptive response following intestinal loss. We recently developed a surgical model of ICR in germ-free (GF) IL-10 null mice that develop small intestinal inflammation only when mice undergo conventionalization with normal fecal microflora (CONV) before surgical intervention. In this study, we examined the effects of postsurgical small bowel inflammation on adaptive growth after ICR. METHODS: GF 129SvEv IL-10 null mice, 8-10 wk old, were allocated to GF or CONV groups. Nonoperated GF and CONV mice provided baseline controls. Two wk later, GF and CONV mice were further allocated to ICR or sham operation. Small intestine and colon were harvested 7 d after surgery for histological analysis. RESULTS: All mice within the gnotobiotic facility maintained GF status and did not develop small intestinal or colonic inflammation. CONV resulted in colitis in all groups, whereas small intestinal inflammation was only observed following ICR. Resection-induced small intestinal inflammation in CONV mice was associated with increases in proliferation, crypt depth, and villus height compared with GF mice after ICR. Resection-induced increases in crypt fission only occurred in CONV mice. CONCLUSION: ICR-dependent small intestinal inflammation in CONV IL-10 null mice dramatically enhances early adaptive growth of the small intestine. Additional studies utilizing our model may provide clinical insight leading to optimal therapies in managing IBD patients after surgical resection.
Assuntos
Colo/crescimento & desenvolvimento , Colo/cirurgia , Inflamação/fisiopatologia , Interleucina-10/genética , Intestino Delgado/crescimento & desenvolvimento , Intestino Delgado/cirurgia , Adaptação Fisiológica/fisiologia , Animais , Colo/microbiologia , Vida Livre de Germes , Interleucina-10/fisiologia , Intestino Delgado/microbiologia , Masculino , Camundongos , Camundongos Knockout , Modelos AnimaisRESUMO
The intestinal epithelium is in a constant state of renewal. The rapid turnover of cells is fed by a hierarchy of transit amplifying and stem/progenitor cells destined to give rise to the four differentiated epithelial lineages of the small intestine. Doxorubicin (Dox) is a commonly used chemotherapeutic agent that preferentially induces apoptosis in the intestinal stem cell zone (SCZ). We hypothesized that Dox treatment would initially decrease "+4" intestinal stem cell numbers with a subsequent expansion during mucosal repair. Temporal assessment following Dox treatment demonstrated rapid induction of apoptosis in the SCZ leading to a decrease in the number of intestinal stem/progenitor cells as determined by flow cytometry for CD45(-) SP cells, and immunohistochemistry of cells positive for putative +4 stem cell markers beta-cat(Ser552) and DCAMKL1. Between 96 and 168 h postinjection, overall proliferation in the crypts increased concomitant with increases in both absolute and relative numbers of goblet, Paneth, and enteroendocrine cells. This regeneration phase was also associated with increases of CD45(-) SP cells, beta-cat(Ser552)-positive cells, crypt fission, and crypt number. We used Lgr5-lacZ mice to assess behavior of Lgr5-positive stem cells following Dox and found no change in this cell population. Lgr5 mRNA level was also measured and showed no change immediately after Dox but decreased during the regeneration phase. Together these data suggest that, following Dox-induced injury, expansion of intestinal stem cells occurs during mucosal repair. On the basis of available markers this expansion appears to be predominantly the +4 stem cell population rather than those of the crypt base.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Linhagem da Célula , Quinases Semelhantes a Duplacortina , Doxorrubicina/administração & dosagem , Feminino , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Jejuno/efeitos dos fármacos , Jejuno/patologia , Antígenos Comuns de Leucócito/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Tempo , beta Catenina/metabolismoRESUMO
The epithelial cell lining of the gastrointestinal tract is the most rapidly proliferating tissue in the body. The constant state of renewal of differentiated epithelial cells is sustained by a continual supply of progeny from multipotent progenitors that originate from stem cells located within the intestinal crypts. In addition to supporting normal epithelial homeostasis, intestinal stem cells (ISC) are thought to play an important role in the rapid expansion of the gut during development, tissue regeneration following injury or surgical loss, and malignancy. Because of the lack of specific ISC markers required to isolate and characterize these cells, our current knowledge of the biology of ISC results largely from indirect measures of their behavior published during the past 40 years. The recent description of several potential ISC markers and the use of transgenic mice, both as a tool to lineage trace and to isolate specific cells expressing these markers, have provided a tremendous advancement to our current understanding of these cells. This brief review provides a general historical overview of our understanding of ISC and the tools available to study their behavior in the context of normal and pathological conditions, as well as potential future clinical applications that may result from this exciting area of research.