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Distinct mucosal microbial communities in infants with surgical necrotizing enterocolitis correlate with age and antibiotic exposure.
Romano-Keeler J, Shilts MH, Tovchigrechko A, Wang C, Brucker RM, Moore DJ, Fonnesbeck C, Meng S, Correa H, Lovvorn HN, Tang YW, Hooper L, Bordenstein SR, Das SR, Weitkamp JH
(2018) PLoS One 13: e0206366
MeSH Terms: Age Factors, Anti-Bacterial Agents, Biodiversity, Enterocolitis, Necrotizing, Female, Humans, Infant, Infant, Newborn, Intestinal Mucosa, Male, Microbiota, Pregnancy
Show Abstract · Added October 27, 2018
OBJECTIVE - Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis.
DESIGN - We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome.
RESULTS - The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome.
CONCLUSION - The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin.
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12 MeSH Terms
Changing patterns of patent ductus arteriosus surgical ligation in the United States.
Reese J, Scott TA, Patrick SW
(2018) Semin Perinatol 42: 253-261
MeSH Terms: Cerebral Intraventricular Hemorrhage, Cross-Sectional Studies, Ductus Arteriosus, Patent, Enterocolitis, Necrotizing, Female, Humans, Infant, Extremely Low Birth Weight, Infant, Newborn, Infant, Very Low Birth Weight, Ligation, Male, Practice Patterns, Physicians', Retrospective Studies, Treatment Outcome, United States, Vocal Cord Paralysis
Show Abstract · Added November 26, 2018
Optimal management of patent ductus arteriosus (PDA) is unclear. One treatment, surgical ligation, is associated with adverse outcomes. We reviewed data from the Kids' Inpatient Database (2000-2012) to determine if PDA ligation rates: (1) changed over time, (2) varied geographically, or (3) influenced surgical complication rates. In 2012, 47,900 infants <1500g birth weight were born in the United States, including 2,800 undergoing PDA ligation (5.9%). Ligation was more likely in infants <1000g (85.9% vs. 46.2%), and associated with necrotizing enterocolitis (59.2% vs. 37.5%), BPD (54.6% vs. 15.2%), severe intraventricular hemorrhage (16.4% vs. 5.3%), and hospital transfer (37.6% vs. 16.4%). Ligation rates peaked in 2006 at 87.4 per 1000 hospital births, dropping to 58.8 in 2012, and were consistently higher in Western states. Infants undergoing ligation were more likely to experience comorbidities. Rates of ligation-associated vocal cord paralysis increased over time (1.2-3.9%); however, mortality decreased (12.4-6.5%). Thus, PDA ligation has become less frequent, although infants being ligated are smaller and more medically complex. Despite increase in some complications, mortality rates improved perhaps reflecting advances in care.
Copyright © 2018 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Neurodevelopmental considerations in surgical necrotizing enterocolitis.
Robinson JR, Kennedy C, van Arendonk KJ, Green A, Martin CR, Blakely ML
(2018) Semin Pediatr Surg 27: 52-56
MeSH Terms: Enterocolitis, Necrotizing, Humans, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases, Neurodevelopmental Disorders, Neuropsychological Tests, Postoperative Complications
Show Abstract · Added June 27, 2018
The majority of surviving infants with surgical necrotizing enterocolitis (NEC) will have some degree of neurodevelopmental impairment. The impact of specific medial and surgical treatments for infants with severe NEC remains largely unknown but is being actively investigated. It is incumbent upon all providers caring for these infants to continue to focus on long term neurodevelopmental outcomes and to develop more widespread methods of neurodevelopmental assessment.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
Surgical necrotizing enterocolitis.
Robinson JR, Rellinger EJ, Hatch LD, Weitkamp JH, Speck KE, Danko M, Blakely ML
(2017) Semin Perinatol 41: 70-79
MeSH Terms: Biomarkers, Drainage, Enterocolitis, Necrotizing, Enterostomy, Fatty Acid-Binding Proteins, Feces, Humans, Infant, Extremely Premature, Infant, Newborn, Infant, Premature, Diseases, Infant, Very Low Birth Weight, Laparotomy, Leukocyte L1 Antigen Complex, Patient Selection, Predictive Value of Tests, S100A12 Protein, Treatment Outcome
Show Abstract · Added January 16, 2017
Although currently available data are variable, it appears that the incidence of surgical necrotizing enterocolitis (NEC) has not decreased significantly over the past decade. Pneumoperitoneum and clinical deterioration despite maximal medical therapy remain the most common indications for operative treatment. Robust studies linking outcomes with specific indications for operation are lacking. Promising biomarkers for severe NEC include fecal calprotectin and S100A12; serum fatty acid-binding protein; and urine biomarkers. Recent advances in ultrasonography make this imaging modality more useful in identifying surgical NEC and near-infrared spectroscopy (NIRS) is being actively studied. Another fairly recent finding is that regionalization of care for infants with NEC likely improves outcomes. The neurodevelopmental outcomes after surgical treatment are known to be poor. A randomized trial near completion will provide robust data regarding neurodevelopmental outcomes after laparotomy versus drainage as the initial operative treatment for severe NEC.
Copyright © 2016 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Cytomegalovirus Enterocolitis in Immunocompetent Young Children: A Report of Two Cases and Review of the Literature.
Sue PK, Salazar-Austin NM, McDonald OG, Rishi A, Cornish TC, Arav-Boger R
(2016) Pediatr Infect Dis J 35: 573-6
MeSH Terms: Cytomegalovirus, Cytomegalovirus Infections, Diarrhea, Enterocolitis, Humans, Infant, Male
Show Abstract · Added May 5, 2016
Cytomegalovirus (CMV) causes significant morbidity and mortality in congenitally infected children and immunocompromised hosts. Among healthy individuals, CMV is generally thought to cause mild, self-limited illness. CMV enterocolitis, in particular, is rarely considered among immunocompetent children presenting with diarrhea. We describe 2 cases of invasive CMV colitis in immunocompetent infants presenting with diarrhea and review the literature to date on this topic. Although invasive CMV enterocolitis has been sporadically reported among immunocompetent children, it remains an underrecognized cause of infectious diarrhea in this population and indications for antiviral therapy are lacking. We propose that CMV should be included in the differential diagnosis of intractable diarrhea in immunocompetent children.
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7 MeSH Terms
Analysis of TcdB Proteins within the Hypervirulent Clade 2 Reveals an Impact of RhoA Glucosylation on Clostridium difficile Proinflammatory Activities.
Quesada-Gómez C, López-Ureña D, Chumbler N, Kroh HK, Castro-Peña C, Rodríguez C, Orozco-Aguilar J, González-Camacho S, Rucavado A, Guzmán-Verri C, Lawley TD, Lacy DB, Chaves-Olarte E
(2016) Infect Immun 84: 856-65
MeSH Terms: Animals, Bacterial Proteins, Bacterial Toxins, Clostridium difficile, Enterocolitis, Pseudomembranous, Genotype, Glycosylation, Host-Pathogen Interactions, Humans, Male, Mice, Virulence, rhoA GTP-Binding Protein
Show Abstract · Added April 4, 2016
Clostridium difficile strains within the hypervirulent clade 2 are responsible for nosocomial outbreaks worldwide. The increased pathogenic potential of these strains has been attributed to several factors but is still poorly understood. During a C. difficile outbreak, a strain from this clade was found to induce a variant cytopathic effect (CPE), different from the canonical arborizing CPE. This strain (NAP1V) belongs to the NAP1 genotype but to a ribotype different from the epidemic NAP1/RT027 strain. NAP1V and NAP1 share some properties, including the overproduction of toxins, the binary toxin, and mutations in tcdC. NAP1V is not resistant to fluoroquinolones, however. A comparative analysis of TcdB proteins from NAP1/RT027 and NAP1V strains indicated that both target Rac, Cdc42, Rap, and R-Ras but only the former glucosylates RhoA. Thus, TcdB from hypervirulent clade 2 strains possesses an extended substrate profile, and RhoA is crucial for the type of CPE induced. Sequence comparison and structural modeling revealed that TcdBNAP1 and TcdBNAP1V share the receptor-binding and autoprocessing activities but vary in the glucosyltransferase domain, consistent with the different substrate profile. Whereas the two toxins displayed identical cytotoxic potencies, TcdBNAP1 induced a stronger proinflammatory response than TcdBNAP1V as determined in ex vivo experiments and animal models. Since immune activation at the level of intestinal mucosa is a hallmark of C. difficile-induced infections, we propose that the panel of substrates targeted by TcdB is a determining factor in the pathogenesis of this pathogen and in the differential virulence potential seen among C. difficile strains.
Copyright © 2016 Quesada-Gómez et al.
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13 MeSH Terms
Reply to Planche et al.
Rao K, Young VB, Aronoff DM
(2015) Clin Infect Dis 61: 1211-2
MeSH Terms: Botulinum Toxins, Clostridium difficile, Enterocolitis, Pseudomembranous, Feces, Female, Humans, Male, Ribotyping
Added June 2, 2017
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8 MeSH Terms
Cloning and variation of ground state intestinal stem cells.
Wang X, Yamamoto Y, Wilson LH, Zhang T, Howitt BE, Farrow MA, Kern F, Ning G, Hong Y, Khor CC, Chevalier B, Bertrand D, Wu L, Nagarajan N, Sylvester FA, Hyams JS, Devers T, Bronson R, Lacy DB, Ho KY, Crum CP, McKeon F, Xian W
(2015) Nature 522: 173-8
MeSH Terms: Bacterial Toxins, Cell Differentiation, Cell Lineage, Cells, Cultured, Clone Cells, Clostridium difficile, Colon, Enterocolitis, Pseudomembranous, Epigenesis, Genetic, Epithelium, Fetus, Genomic Instability, Humans, Intestine, Small, Intestines, Organoids, Stem Cells
Show Abstract · Added September 28, 2015
Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, 'ground state' stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.
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17 MeSH Terms
Identification of toxemia in patients with Clostridium difficile infection.
Yu H, Chen K, Wu J, Yang Z, Shi L, Barlow LL, Aronoff DM, Garey KW, Savidge TC, von Rosenvinge EC, Kelly CP, Feng H
(2015) PLoS One 10: e0124235
MeSH Terms: Animals, Anti-Bacterial Agents, Antibodies, Bacterial, Antibodies, Neutralizing, Bacterial Proteins, Bacterial Toxins, Biological Assay, Blood Preservation, Cercopithecus aethiops, Clostridium difficile, Diverticulitis, Colonic, Enterocolitis, Pseudomembranous, Enterotoxins, False Negative Reactions, Female, Glycosylation, Humans, Immunocompromised Host, Immunoglobulin G, Multiple Trauma, Protein Processing, Post-Translational, Protein Stability, Risk Factors, Toxemia, Vero Cells, Young Adult, rac1 GTP-Binding Protein
Show Abstract · Added June 2, 2017
Toxemia can develop in Clostridium difficile-infected animals, and correlates with severe and fulminant disease outcomes. Circumstantial evidence suggests that toxemia may occur in patients with C. difficile infection (CDI), but positive diagnosis is extremely rare. We analyzed the potential for C. difficile toxemia in patients, determined its characteristics, and assessed challenges. C. difficile toxins in serum from patients were tested using an ultrasensitive cell-based assay and further confirmed by Rac1 glucosylation assay. The factors that hinder a diagnosis of toxemia were assessed, including investigation of toxin stability, the level of toxins-specific neutralizing antibodies in sera and its effect on diagnosis limits. CDI patients develop detectable toxemia in some cases (2.3%). Toxins were relatively stable in stored sera. Neutralizing anti-toxin antibodies were present during infection and positively correlated with the diagnosis limits. Thus, the masking effect of toxin-specific neutralizing antibodies is the major obstacle in diagnosing C. difficile toxemia using cell-based bioassays.
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27 MeSH Terms
Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.
Rao K, Micic D, Natarajan M, Winters S, Kiel MJ, Walk ST, Santhosh K, Mogle JA, Galecki AT, LeBar W, Higgins PD, Young VB, Aronoff DM
(2015) Clin Infect Dis 61: 233-41
MeSH Terms: Adult, Age Factors, Aged, Botulinum Toxins, Clostridium difficile, Enterocolitis, Pseudomembranous, Feces, Female, Humans, Immunoenzyme Techniques, Male, Middle Aged, Models, Statistical, Odds Ratio, Polymerase Chain Reaction, ROC Curve, Ribotyping, Risk Factors, Severity of Illness Index
Show Abstract · Added June 2, 2017
BACKGROUND - Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes.
METHODS - Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes.
RESULTS - In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8).
CONCLUSIONS - Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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19 MeSH Terms