Gram Negative Bacteria Are Associated with the Early Stages of Necrotizing Enterocolitis

Introduction: Necrotizing enterocolitis (NEC) affects 5–10 % of infants born weighing less than 1500 g. Most models of NEC recapitulate late-stage disease with gut necrosis and elevated inflammatory mediators. Evaluation of NEC at earlier, less lethal stages of disease will allow investigation of initial disease triggers and may advance our understanding of temporal relationships between factors implicated in NEC pathogenesis. In this manuscript, we describe our investigation of early NEC and test the hypothesis that bacteria and inflammatory mediators differ between animals with early NEC and disease fre

Platelet-Activating Factor Induces TLR4 Expression in Intestinal Epithelial Cells: Implication for the Pathogenesis of Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in neonatal intensive care units, however its pathogenesis is not completely understood. We have previously shown that platelet activating factor (PAF), bacteria and TLR4 are all important factors in the development of NEC. Given that Toll-like receptors (TLRs) are expressed at low levels in enterocytes of the mature gastrointestinal tract, but were shown to be aberrantly over-expressed in enterocytes in experimental NEC, we examined the regulation of TLR4 expression and signaling by PAF in intestinal epithelial cells using human and mouse in vitro cell lines, and the ex vivo rat intestinal loop model. In intestinal epithelial cell (IEC) lines, PAF stimulation yielded upregulation of both TLR4 mRNA and protein expression and led to increased IL-8 secretion following stimulation with LPS (in an otherwise LPS minimally responsive cell line). PAF stimulation resulted in increased human TLR4 promoter activation in a dose dependent manner. Western blotting and immunohistochemical analysis showed PAF induced STAT3 phosphorylation and nuclear translocation in IEC, and PAF-induced TLR4 expression was inhibited by STAT3 and NFκB Inhibitors. Our findings provide evidence for a mechanism by which PAF augments inflammation in the intestinal epithelium through abnormal TLR4 upregulation, thereby contributing to the intestinal injury of NEC

Champions, converts, doubters, and defectors: the impact of shifting perceptions on momentum for change

Maintaining momentum is a key influence on the ultimate success of large-scale change. In this paper, we develop theory to explain how stable vs. shifting change-supportive perceptions over time differentially influence the perceived momentum associated with goal-directed change (i.e., change-based momentum). We use cross-level polynomial regression and data obtained early and one year later within an organization implementing a lean manufacturing transformation to model changes in individual perceptions. Results suggest that momentum perceptions are higher for “Champions” (stable and high perceptions over time) as compared to “Converts” (increasing perceptions over time), but momentum perceptions are lower for “Defectors” (decreasing perceptions over time) as compared to “Doubters” (stable and low perceptions over time). We find that even if participants converge upon change-supportive perceptions later in the change process, early divergent perceptions influence subsequent momentum for the change. These findings highlight the important role of temporal shifts in perceptions for organizational change processes

Proteomic Profiling of Mesenchymal Stem Cell Responses to Mechanical Strain and TGF-β1

Mesenchymal stem cells (MSCs) are a potential source of smooth muscle cells (SMCs) for constructing tissue-engineered vascular grafts. However, the details of how specific combinations of vascular microenvironmental factors regulate MSCs are not well understood. Previous studies have suggested that both mechanical stimulation with uniaxial cyclic strain and chemical stimulation with transforming growth factor-β1 (TGF-β1) can induce smooth muscle markers in MSCs. In this study, we investigated the combined effects of uniaxial cyclic strain and TGF-β1 stimulation on MSCs. By using a proteomic analysis, we found differential regulation of several proteins and genes, such as the up-regulation of TGF-β1-induced protein ig-h3 (BGH3) protein levels by TGF-β1 and up-regulation of calponin 3 protein level by cyclic strain. At the gene expression level, BGH3 was induced by TGF-β1, but calponin 3 was not significantly regulated by mechanical strain or TGF-β1, which was in contrast to the synergistic up-regulation of calponin 1 gene expression by cyclic strain and TGF-β1. Further experiments with cycloheximide treatment suggested that the up-regulation of calponin 3 by cyclic strain was at post-transcriptional level. The results in this study suggest that both mechanical stimulation and TGF-β1 signaling play unique and important roles in the regulation of MSCs at both transcriptional and post-transcriptional levels, and that a precise combination of microenvironmental cues may promote MSC differentiation

Negotiating agency: Amish and ultra-Orthodox women’s responses to the Internet

This study explores how women in two devout religious communities cope with the Internet and its apparent incompatibility with their communities’ values and practices. Questionnaires containing both closed and open-ended questions were completed by 82 participants, approximately half from each community. While their discourses included similar framings of danger and threat, the two groups manifested different patterns of Internet use (and nonuse). Rigorous adherence to religious dictates is greatly admired in these communities, and the women take pride in manipulating their status in them. Their agency is reflected in how they negotiate the tension inherent in their roles as both gatekeepers and agents-of-change, which are analyzed as valuable currencies in their cultural and religious markets

Single nucleotide polymorphism-based genome-wide linkage analysis in Japanese atopic dermatitis families

<p>Abstract</p> <p>Background</p> <p>Atopic dermatitis develops as a result of complex interactions between several genetic and environmental factors. To date, 4 genome-wide linkage studies of atopic dermatitis have been performed in Caucasian populations, however, similar studies have not been done in Asian populations. The aim of this study was to identify chromosome regions linked to atopic dermatitis in a Japanese population.</p> <p>Methods</p> <p>We used a high-density, single nucleotide polymorphism genotyping assay, the Illumina BeadArray Linkage Mapping Panel (version 4) comprising 5,861 single nucleotide polymorphisms, to perform a genome-wide linkage analysis of 77 Japanese families with 111 affected sib-pairs with atopic dermatitis.</p> <p>Results</p> <p>We found suggestive evidence for linkage with 15q21 (LOD = 2.01, NPL = 2.87, <it>P </it>= .0012) and weak linkage to 1q24 (LOD = 1.26, NPL = 2.44, <it>P </it>= .008).</p> <p>Conclusion</p> <p>We report the first genome-wide linkage study of atopic dermatitis in an Asian population, and novel loci on chromosomes 15q21 and 1q24 linked to atopic dermatitis. Identification of novel causative genes for atopic dermatitis will advance our understanding of the pathogenesis of atopic dermatitis.</p