Mortality and intestinal failure in surgical necrotizing enterocolitis.

BACKGROUND/PURPOSE: To examine whether as initial surgical intervention for necrotizing enterocolitis, primary peritoneal drainage as compared to primary laparotomy is associated with increased mortality or intestinal failure. METHODS: Retrospective observational study of 240 infants with surgical necrotizing enterocolitis. RESULTS: There was no difference concerning the composite outcome of mortality before discharge or survival with intestinal failure after adjusting for known covariates (Odds Ratio 1.73, 95% CI 0.88, 3.40). More surviving infants in the peritoneal drainage with subsequent salvage or secondary laparotomy had intestinal failure compared to those who received a peritoneal drain without subsequent laparotomy and survived (12% vs. 14% vs. 1%, p=0.015). CONCLUSIONS: There is no difference between peritoneal drainage and laparotomy in infants with surgical necrotizing enterocolitis concerning the combined outcome of mortality or survival with intestinal failure. There is increased intestinal failure in surviving infants treated with peritoneal drain with either subsequent salvage or secondary laparotomy compared to peritoneal drainage alone.

Helicobacter felis--associated gastric disease in microbiota-restricted mice.

Human Helicobacter pylori infection leads to multiple pathological consequences, including gastritis and adenocarcinoma. Although this association has led to the classification of H. pylori as a type 1 carcinogen, it is not clear if additional nonhelicobacter gastric microbiota play a role in these diseases. In this study, we utilized either specific pathogen-free C57BL/6 mice (B6.SPF) or mice colonized with altered Schaedler flora (B6.ASF) to evaluate the role of nonhelicobacter gastric microbiota in disease development after Helicobacter felis infection. Despite similar histological changes, H. felis persisted in B6.ASF stomachs, while H. felis could no longer be detected in the majority of B6.SPF mice. The B6.SPF mice also acquired multiple Lactobacillus spp. in their stomachs after H. felis infection. Our data indicate that potential mechanisms responsible for the ineffective H. felis clearance in the B6.ASF model include the absence of new gastric microbiota to compete for the gastric niche, the lack of expression of new gastric mucins, and a reduced ratio of H. felis-specific IgG2c:IgG1 serum antibodies. These data suggest that although H. felis is sufficient to initiate gastric inflammation and atrophy, bacterial eradication and the systemic immune response to infection are significantly influenced by pre-existing and acquired gastric microbiota.

Characterization of a necrotizing enterocolitis model in newborn mice.

BACKGROUND: Necrotizingenterocolitis (NEC) is a major health concern for premature infants and its patho-genesis remains poorly understood. The current mouse NEC model has not well been characterized. OBJECTIVES: In this study, we develop a simple mouse model of NEC and determine the role of several factors modulating human NEC (i.e., breast milk, birth weight, cesarean section and bacteria) on intestinal injury. METHODS: In a first experiment, pups born naturally and dam fed for <12 hours were gavaged with adult commensal bacteria or E. Fecalis, and exposed to hypoxia-cold stress-formula feeding, and compared with controls without bacteria inoculation. 72-hour mortality was recorded, and small intestines were examined histologically. In a second experiment, we compared the incidence of NEC in mice dam fed for <12 hours to those dam fed for 12 to 24 hours or delivered by cesarean section prior to being submitted to the NEC protocol. RESULTS: In pups inoculated with 10(7) CFU of a standardized preparation of adult commensal bacteria or 10(5) CFU of E. Fecalis, the incidence of severe NEC (>grade 2) was 70% and 37% respectively vs 6% in the controls (no bacteria)(p<0.05). In pups dam fed for 12 to 24 hours, NEC incidence was 44(±12)% lower vs those dam fed less than 12 hours (p<0.05). We did not find any difference in the NEC incidence between naturally-born pups dam fed for less than 12 hours and these born by cesarean section. The incidence of severe NEC was higher in pups with low birth weight. CONCLUSIONS: we have simplified and characterized a neonatal mouse NEC model that shares several risk factors with human NEC. Now that transgenic mice are available, this model will be useful to study the role played by specific proteins in vivo in NEC development.

Role of postnatal acquisition of the intestinal microbiome in the early development of immune function.

OBJECTIVES: Therapy with broad-spectrum antibiotics is a common practice for premature infants. This treatment can reduce the biodiversity of the fecal microbiota and may be a factor in the cause of necrotizing enterocolitis. In contrast, probiotic treatment of premature infants reduces the incidence of necrotizing enterocolitis. We hypothesized that 1 mechanism for these observations is the influence of bacteria on postnatal development of the mucosal immune system. MATERIALS AND METHODS: Expression of immune molecules and microbial sensors was investigated in the postnatal mouse gastrointestinal tract by real-time polymerase chain reaction. Subsequently, 2-week-old specific pathogen-free and microbial-reduced (MR; antibiotic treated) mice were compared for immune molecule and microbial sensor expression, mesenteric lymph node T-cell numbers and activation, intestinal barrier function/permeability, systemic lymphocyte numbers, and T-cell phenotype commitment. RESULTS: Toll-like receptor 2, 4, and 5 expression was highest in 2-week-old specific pathogen-free mice, and this expression was decreased in MR mice. There was no difference in intestinal tight-junctional function, as evaluated by fluorescein isothiocyanate-dextran uptake, but MR mice had increased bacterial translocation across the intestinal epithelial barrier. MR mice had significantly fewer splenic B cells and mesenteric lymph node CD4+ T cells, but there were normal numbers of splenic T cells. These systemic T cells from MR mice produced more interleukin-4 and less interferon-gamma and IL-17, indicative of maintenance of the fetal, T-helper cell type 2 phenotype. CONCLUSIONS: The present study shows that intestinal commensal microbiota have an influence on early postnatal immune development. Determining specific bacteria and/or bacterial ligands critical for this development could provide insight into the mechanisms by which broad-spectrum antibiotics and/or probiotic therapy influence the development of the mucosal immune system and mucosal-related diseases.

Low intensity shear stress increases endothelial ELR+ CXC chemokine production via a focal adhesion kinase-p38{beta} MAPK-NF-{kappa}B pathway.

CXC chemokines with a glutamate-leucine-arginine (ELR) tripeptide motif (ELR(+) CXC chemokines) play an important role in leukocyte trafficking into the tissues. For reasons that are not well elucidated, circulating leukocytes are recruited into the tissues mainly in small vessels such as capillaries and venules. Because ELR(+) CXC chemokines are important mediators of endothelial-leukocyte interaction, we compared chemokine expression by microvascular and aortic endothelium to investigate whether differences in chemokine expression by various endothelial types could, at least partially, explain the microvascular localization of endothelial-leukocyte interaction. Both in vitro and in vivo models indicate that ELR(+) CXC chemokine expression is higher in microvascular endothelium than in aortic endothelial cells. These differences can be explained on the basis of the preferential activation of endothelial chemokine production by low intensity shear stress. Low shear activated endothelial ELR(+) CXC chemokine production via cell surface heparan sulfates, beta(3)-integrins, focal adhesion kinase, the mitogen-activated protein kinase p38beta, mitogen- and stress-associated protein kinase-1, and the transcription factor.

Mortality and morbidity by month of birth of neonates admitted to an academic neonatal intensive care unit.

BACKGROUND: Clinical expertise and skill of pediatric housestaff improve over the academic year, and performance varies despite supervision by faculty neonatologists. It is possible that variation in clinical expertise of housestaff affects important clinical outcomes in infants in ICUs. OBJECTIVE: Our goal was to test the hypothesis that there is a decrease in morbidity and mortality in infants admitted to an NICU over the course of the academic year. DESIGN/METHODS: A retrospective analysis was conducted using data on infants with birthweight 401 to 1500 g and >or=24 weeks' gestation (n = 3445) and infants with birth weights >1500 g (n = 7840) admitted to a regional NICU from January 1991 to June 2004. All infants were cared for by pediatric and neonatal housestaff supervised by neonatologists. Analysis of mortality and morbidity (intraventricular hemorrhage grades 3-4/periventricular leukomalacia, necrotizing enterocolitis >or= Bell stage 2, and bronchopulmonary dysplasia) over time were performed by repeated measures analysis of variance and the chi(2) test. RESULTS: Mortality rate in the 401 to 1500 g cohort, as well as the >1500 g cohort did not decrease over time during the academic year and was similar between the first (July-December) and second (January-June) halves of the academic year. There were no differences noted over the academic year for any of the morbidities. CONCLUSIONS: Morbidity and mortality in infants admitted to an academic NICU did not change significantly over the academic year. These observations suggest that the quality of care of critically ill neonates is not decreased early in the academic year.