Search

Background: Intravenous lipids are critical to the care of extremely premature and other high-risk infants., Objectives: This study evaluated safety and efficacy of parenteral nutrition (PN) with composite intravenous lipid emulsion (CO-ILE) with fish oil compared with pure soybean oil lipid emulsion (SOLE)., Methods: Randomized, controlled, double-blind, multicenter study (NCT02579265) in neonates/infants anticipated to require ≥28 d of PN due to gastrointestinal malformations or injury. Duration of the initial and extended treatment phase was 28 d and 84 d, respectively (for patients with PN indication after day 28)., Results: Eighty-three patients (mean postnatal age 11.4 d, 54 preterm) received CO-ILE and 78 patients received SOLE (mean postnatal age 8.3 d, 59 preterm). Thirty-three patients per group completed 28 d of treatment. Risk of having conjugated bilirubin values >2 mg/dL confirmed by a second sample 7 d after the first during the initial treatment phase (primary outcome) was 2.4% (2 of 83) with CO-ILE and 3.8% (3 of 78) with SOLE (risk ratio: 0.59; 95% confidence interval [CI]: 0.09, 3.76). Between days 29 and 84, the number of patients with confirmed conjugated bilirubin values >2 mg/dL did not increase in the CO-ILE group (n = 2) and increased in the SOLE group (n = 9). At the end of the initial treatment phase, conjugated bilirubin concentrations were 45.6% lower under CO-ILE than under SOLE (P = 0.006). There was no clinical or laboratory evidence of essential fatty acid deficiency in patients in the CO-ILE group. Median time to discharge alive was 56.7 d and 66.4 d with CO-ILE and SOLE, respectively (hazard ratio: 1.16; 95% CI: 0.81, 1.68)., Conclusions: CO-ILE was associated with a possible lower risk of cholestasis and significantly lower conjugated bilirubin concentration at the end of the initial treatment phase in high-risk neonates and infants as compared with patients treated with SOLE. In summary, these data indicate that CO-ILE can be considered safe and may be preferable over SOLE in high-risk neonates. This trial was registered at clinicaltrials.gov as NCT02579265., Competing Interests: Conflict of interest Steven Abrams’ institution received support from Fresenius Kabi for his time and effort as principal investigator of this study. Daniel Robinson is an institutional principal investigator, with no salary funding, for a consortium database sponsored by Mead Johnson Nutrition; previously received compensation as a member of the Data Safety Monitoring Board for a clinical investigation sponsored by Fresenius Kabi; and is a consultant for Baxter. Joern-Hendrik Weitkamp serves as consultant for Roche Diagnostics Operations, Inc. All other authors report no conflicts of interest. The institutions of the authors each received institutional research support from Fresenius Kabi for clinical conduct of the trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Necrotizing enterocolitis (NEC) is the most frequent and devastating gastrointestinal disease of premature infants. Although the precise mechanisms are not fully understood, NEC is thought to develop following a combination of prematurity, formula feeding, and adverse microbial colonization. Within the last decade, studies increasingly support an important role of a heightened mucosal immune response initiating a pro-inflammatory signaling cascade, which can lead to the disruption of the intestinal epithelium and translocation of pathogenic species. In this review, we first describe the cellular composition of the intestinal epithelium and its critical role in maintaining epithelial integrity. We then discuss cell signaling during NEC, specifically, toll-like receptors and nucleotide oligomerization domain-like receptors. We further review cytokines and cellular components that characterize the innate and adaptive immune systems and how they interact to support or modulate NEC development., (© 2018 Published by Elsevier Ltd.)

Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Histologic chorioamnionitis (HCA) is commonly associated with preterm birth and deleterious post-natal outcomes including sepsis and necrotizing enterocolitis. Transcriptomic analysis has been used to uncover gene signatures that permit diagnosis and prognostication, show new therapeutic targets, and reveal mechanisms that underlie differential outcomes with other complex disease states in neonates such as sepsis., Aims: To define the transcriptomic and inflammatory protein response in peripheral blood among infants with exposure to histologic chorioamnionitis., Study Design: Prospective, observational study., Subjects: Uninfected preterm neonates retrospectively categorized based on placental pathology with no HCA exposure (n=18) or HCA exposure (n=15)., Outcomes Measures: We measured the transcriptomic and inflammatory mediator response in prospectively collected whole blood., Results: We found 488 significant (p<0.001), differentially expressed genes in whole blood samples among uninfected neonates with HCA exposure that collectively represented activated innate and adaptive immune cellular pathways and revealed a potential regulatory role for the pleotropic microRNA molecule miR-155. Differentially secreted plasma cytokines in patients with HCA exposure compared to patients without HCA included MCP-1, MPO, and MMP-9 (p<0.05)., Conclusions: Exposure to HCA distinctively activates the neonatal immune system in utero with potentially long-term health consequences., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Chronic inflammation and decreased frequency of regulatory T cells (Tregs) in visceral adipose tissue contribute to the propagation of insulin resistance to diabetes mellitus. We tested the hypothesis that new-onset posttransplantation diabetes mellitus (PTDM) is associated with measurable changes in Treg subsets after allogeneic hematopoietic stem cell transplantation (HSCT). PTDM before day 100 and Treg phenotype at engraftment were determined in 36 HSCT recipients without preceding history of diabetes mellitus. Among patients with new-onset PTDM (N = 24), the frequency of circulating CLA(+) (skin-homing) Tregs was decreased (1.53% vs 3.99%; P = .002) and the percentage of α(4)β(7)(+) (gut-homing) Tregs was increased (17.9% vs 10.7%; P = .048). In multivariate analysis, patients with PTDM continued to demonstrate elevated ratios of α(4)β(7)(+) Tregs to CLA(+) Tregs (odds ratio, 18.1; P = .020). PTDM is associated with altered immune regulation after HSCT and could represent a target to modulate alloreactivity.

Salmonella panama is group-D nontyphi salmonella strongly associated with invasive infection, including meningitis. So far, no case of S. panama meningitis has been reported from the United States, and none has ever been reported in babies >3.5 months of age. To the best of our knowledge, we are reporting the first such case in English-language literature.

Technical difficulties have severely limited the yield of methods for the generation of human antiviral monoclonal antibodies (Mabs) in the past. We describe here a novel method for the efficient development of human Mabs against viruses. Rotavirus (RV) is a major cause of gastroenteritis in infants and adults worldwide. We generated fluorescent virus-like particles (VLPs) to identify and physically sort single RV-specific B cells from healthy adult blood donors, or RV-infected infants or adults. We expanded the sorted single B cells in culture, tested for RV-specific antibody secretion, and cloned and sequenced the antibody heavy and light chain variable region (VH and VL) genes. The percentage of wells that produced antibodies after sorting and expanding RV-specific adult B cell clones was high at 23%. The overall efficiency of RV-specific antibody gene recovery after the isolation, confirmation, and cloning of RV-specific VH segments was 1.3% of sorted cells in adults. RV-specific variable gene segments also were obtained from acutely infected infants, although infant B cells did not proliferate and differentiate in culture as well as adult B cells. We expressed recombinant Fabs incorporating the VH and VL genes from RV-specific B cell clones using a new modified bacterial Fab expression vector that we describe. Finally, we demonstrated binding of purified Fabs to RV proteins by immunofluorescence and ELISA. This method for the generation of recombinant human Mabs to RV from single antigen-specific B cell clones selected with fluorescent VLPs could be used to generate human Mabs to many other viruses whose proteins can self-assemble into VLPs.