TLR3 Signaling in Human BDCA-3 Dendritic Cells Results in the Formation of Several ILT3 and ILT4 Populations

Dendritic cells (DCs) represent a population of innate immune cells that are highly efficient at promoting immune responses. DCs are capable of presenting antigens to both CD4 and CD8 T cells. DC presentation and interaction with T cells can result in either immune stimulation or tolerance. This study intends to phenotype a rare subset of DCs found in the human blood and is distinguishable by the expression of various surface markers including: lineage markers (Lin), HLADR, CD1c, and CD141 or BDCA-3. Stimulating BDCA-3 DCs with Poly I:C, a toll-like receptor (TLR) 3 agonist, resulted in the up-regulation of various canonical activation markers such as CD40, CD80, and CD86 as well as immunoglobulin-like transcript (ILT) 3 and 4 as measured by flow cytometry. ILTs are novel surface molecules with implicated inhibitory functions and are selectively expressed by APCs, such as DCs. The surface induction of ILT3 and ILT4 occurred in both time- and dose-dependent manner. The up-regulation of ILT3 and ILT4 within the BDCA-3 subset of DCs resulted in the unexpected formation of various subsets of BDCA-3 DCs expressing: ILT3- ILT4-, ILT3- ILT4+, ILT3+ ILT4-, and ILT3+ ILT4+. Due to limited numbers of cells, we focused our efforts to determine the biological differences between ILT3---ILT4- and -ILT4+ BDCA-3 DCs after Poly I:C stimulation. This study will show that these two populations of BDCA-3 DCs differ in their cytokine secretion profile, genomic signature, and their ability to prime allogenic naïve T cells

A multifaceted quality improvement project improves intraoperative redosing of surgical antimicrobial prophylaxis during pediatric surgery

BackgroundAccurate intraoperative antibiotic redosing contributes to prevention of surgical site infections in pediatric patients. Ensuring compliance with evolving national guidelines of weight‐based, intraoperative redosing of antibiotics is challenging to pediatric anesthesiologists.AimsOur primary aim was to increase compliance of antibiotic redoses at the appropriate time and appropriate weight‐based dose to 70%. Secondary aims included a subset analysis of time compliance and dose compliance individually, and compliance based on order entry method of the first dose (verbal or electronic).MethodsAt a freestanding, academic pediatric hospital, we reviewed surgical cases between May 1, 2014, and October 31, 2017 requiring antibiotic redoses. After an institutional change in cefazolin dosing in May 2015, phased interventions to improve compliance included electronic countermeasures to display previous and next dose timing, an alert 5 minutes prior to next dose, and weight‐based dose recommendation (September 2015). Physical countermeasures include badge cards, posting of guidelines, and updates to housestaff manual (September 2015). Statistical process control charts were used to assess overall antibiotic redose compliance, time compliance, and dose compliance. The chi‐square test was used to analyze group differences.ResultsA total of 3015 antibiotic redoses were administered during 2341 operative cases between May 1, 2014, and October 31, 2017. Mean monthly compliance with redosing was 4.3% (May 2014‐April 2015) and 73% (November 2015‐October 2017) (P < 0.001). Dose‐only compliance increased from 76% to 89% (P < 0.001), and time‐only compliance increased from 4.9% to 82% (P < 0.001). After implementation of countermeasures, electronic order entry compared with verbal order was associated with higher dose compliance, 90% vs 86% (P = 0.015).ConclusionThis quality improvement project, utilizing electronic and physical interventions, was effective in improving overall prophylactic antibiotic redosing compliance in accordance with institutional redosing guidelines.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150557/1/pan13651_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150557/2/pan13651.pd

FK 506 pre-treatment is associated with reduced levels of tumor necrosis factor and interleukin 6 following hepatic ischemia/reperfusion

Using a rat model, the effect of pre-treatment with FK 506 on hepatic ischemia/reperfusion injury was investigated. All control animals died within 72 h of the ischemia/reperfusion injury. Pre-treatment of the animals with FK 506 (0.3 mg/kg in 0.5 ml saline) administered intravenously improved survival. The most striking protection against fatal ischemia/reperfusion injury was achieved in rats that were given FK 506 6 and 24 h prior to the induction of the hepatic ischemic insult (70% and 80% 10-day survival rates, respectively). The hepatoprotective effect of FK 506 was assessed further in a second experiment in which the serum levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were measured. These results suggest that a 60-min period of hepatic ischemia and subsequent reperfusion triggers the release of both TNF and IL-6, and that FK 506 pre-treatment (6 h before the ischemic episode) significantly inhibits the production and/or release of these two cytokines compared to untreated controls. These data provide additional information concerning the immunosuppressive and hepatoprotective activities of FK 506. Based upon these data, it is probable that FK 506 attenuates hepatic ischemia/reperfusion injury, at least in part, by reducing TNF and IL-6 levels. © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved

Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for mucolipidosis type IV pathogenesis

The lysosomal storage disorder mucolipidosis type IV (MLIV) is caused by mutations in the transient receptor potential–mucolipin-1 (TRP-ML1) ion channel. The “biogenesis” model for MLIV pathogenesis suggests that TRP-ML1 modulates postendocytic delivery to lysosomes by regulating interactions between late endosomes and lysosomes. This model is based on observed lipid trafficking delays in MLIV patient fibroblasts. Because membrane traffic aberrations may be secondary to lipid buildup in chronically TRP-ML1–deficient cells, we depleted TRP-ML1 in HeLa cells using small interfering RNA and examined the effects on cell morphology and postendocytic traffic. TRP-ML1 knockdown induced gradual accumulation of membranous inclusions and, thus, represents a good model in which to examine the direct effects of acute TRP-ML1 deficiency on membrane traffic. Ratiometric imaging revealed decreased lysosomal pH in TRP-ML1–deficient cells, suggesting a disruption in lysosomal function. Nevertheless, we found no effect of TRP-ML1 knockdown on the kinetics of protein or lipid delivery to lysosomes. In contrast, by comparing degradation kinetics of low density lipoprotein constituents, we confirmed a selective defect in cholesterol but not apolipoprotein B hydrolysis in MLIV fibroblasts. We hypothesize that the effects of TRP-ML1 loss on hydrolytic activity have a cumulative effect on lysosome function, resulting in a lag between TRP-ML1 loss and full manifestation of MLIV

Changes in body weight and food choice in those attempting smoking cessation: a cluster randomised controlled trial

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Fear of weight gain is a barrier to smoking cessation and significant cause of relapse for many people. The provision of nutritional advice as part of a smoking cessation programme may assist some in smoking cessation and perhaps limit weight gain. The aim of this study was to determine the effect of a structured programme of dietary advice on weight change and food choice, in adults attempting smoking cessation.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; Cluster randomised controlled design. Classes randomised to intervention commenced a 24-week intervention, focussed on improving food choice and minimising weight gain. Classes randomised to control received "usual care".&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Twenty-seven classes in Greater Glasgow were randomised between January and August 2008. Analysis, including those who continued to smoke, showed that actual weight gain and percentage weight gain was similar in both groups. Examination of data for those successful at giving up smoking showed greater mean weight gain in intervention subjects (3.9 (SD 3.1) vs. 2.7 (SD 3.7) kg). Between group differences were not significant (p=0.23, 95% CI -0.9 to 3.5). In comparison to baseline improved consumption of fruit and vegetables and breakfast cereal were reported in the intervention group. A higher percentage of control participants continued smoking (74% vs. 66%).&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; The intervention was not successful at minimising weight gain in comparison to control but was successful in facilitating some sustained improvements in the dietary habits of intervention participants. Improved quit rates in the intervention group suggest that continued contact with advisors may have reduced anxieties regarding weight gain and encouraged cessation despite weight gain. Research should continue in this area as evidence suggests that the negative effects of obesity could outweigh the health benefits achieved through reductions in smoking prevalence.&lt;/p&gt

Parenting and child externalizing behaviors: Are the associations specific or diffuse?

Building upon the link between inadequate parenting and child noncompliance, aggression, and oppositionality, behavioral parent training has been identified as a well-established treatment for externalizing problems in children. Much less empirical attention has been devoted to examining whether inadequate parenting and, in turn, behavioral parent training programs, have specific effects on child externalizing problems or more diffuse effects on both internalizing and externalizing problems. As an initial attempt to examine the specificity of parenting and childhood externalizing problems, this review examines prior research on the association of three parenting behaviors (parental warmth, hostility, and control) with child externalizing versus internalizing problems. Notably, findings revealed relatively little evidence for the specificity of parenting and child externalizing behaviors in the general parenting literature or in the family context of parent depression. Clinical implications and directions for future research are discussed

Understanding the UK hospital supply chain in an era of patient choice

Author Posting © Westburn Publishers Ltd, 2011. This is a post-peer-review, pre-copy-edit version of an article which has been published in its definitive form in the Journal of Marketing Management, and has been posted by permission of Westburn Publishers Ltd for personal use, not for redistribution. The article was published in Journal of Marketing Management, 27(3-4), 401 - 423, doi:10.1080/0267257X.2011.547084 http://dx.doi.org/10.1080/0267257X.2011.547084The purpose of this paper is to investigate the UK hospital supply chain in light of recent government policy reform where patients will have, inter alia, greater choice of hospital for elective surgery. Subsequently, the hospital system should become far more competitive with supply chains having to react to these changes as patient demand becomes less predictable. Using a qualitative case study methodology, hospital managers are interviewed on a range of issues. Views on the development of the hospital supply chain in different phases are derived, and are used to develop a map of the current hospital chain. The findings show hospital managers anticipating some significant changes to the hospital supply chain and its workings as Patient Choice expands. The research also maps the various aspects of the hospital supply chain as it moves through different operational phases and highlights underlying challenges and complexities. The hospital supply chain, as discussed and mapped in this research, is original work given there are no examples in the literature that provide holistic representations of hospital activity. At the end, specific recommendations are provided that will be of interest to service to managers, researchers, and policymakers

Social democracy, embeddedness and decommodification: On the conceptual innovations and intellectual affiliations of Karl Polanyi

Of the several debates that revolve around the work of the economic historian and political economist Karl Polanyi, one that continues to exercise minds concerns his analysis of, and political attitudes toward, post-war capitalism and the welfare state. Simplified a little, it is a debate with two sides. To borrow Iván Szelényi's terms, one side constructs a ‘hard’ Karl Polanyi, the other a ‘soft’ one. The former advocated a socialist mixed economy dominated by redistributive mechanisms. He was a radical socialist for whom the market should never be the dominant mechanism of economic coordination. His ‘soft’ alter ego insisted that the market system remain essentially intact but be complemented by redistributive mechanisms. The ‘double movement’ – the central thesis of his ‘Great Transformation’ – acts, in this reading, as a self-correcting mechanism that moderates the excesses of market fundamentalism; its author was positioned within the social-democratic mainstream for which the only realistic desirable goal is a regulated form of capitalism. In terms of textual evidence there is much to be said for both interpretations. In this article I suggest a different approach, one that focuses upon the meaning of Polanyi's concepts in relation to their socio-political and intellectual environment

The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition

The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT.Oncogene advance online publication, 25 July 2016; doi:10.1038/onc.2016.260