Immunomodulation of Acellular Dermal Matrix Through Interleukin 4 Enhances Vascular Infiltration.

BACKGROUND: Acellular dermal matrix (ADM) supported implant-based reconstruction remains the most commonly performed mode of reconstruction after breast cancer. Acellular dermal matrix clinical usage has reported benefits but requires rapid and efficient vascular and cellular incorporation into the recipient to have the best outcomes. Orderly transition from M1 to M2 macrophage phenotypic profile, coordinated in part by interleukin 4 (IL-4), is an important component of vascular stabilization and remodeling. Using the ADM substrate as a delivery device for immunomodulation of macrophage phenotype holds the potential to improve integration. METHODS: Interleukin 4 was adsorbed onto ADM samples and drug elution curves were measured. Next, experimental groups of 8 C57BL/6 mice had 5-mm ADM discs surgically placed in a dorsal window chamber with a vascularized skin flap on one side and a plastic cover slip on the other in a model of implant-based breast reconstruction. Group 1 consisted of IL-4 (5 µg) adsorbed into the ADM preoperatively and group 2 consisted of an untreated ADM control. Serial gross examinations were performed with histology at day 21 for markers of vascularization, mesenchymal cell infiltration, and macrophage lineage. RESULTS: Drug elution curves showed sustained IL-4 release for 10 days after adsorption. Serial gross examination showed similar rates of superficial vascular investment of the ADM beginning at the periphery by day 14 and increasing through day 21. Interleukin-4 treatment led to significantly increased CD31 staining of vascular endothelial cells within the ADM over the control group (P < 0.05) at 21 days. Although vimentin staining did not indicate a significant increase in fibroblasts overall, IL-4 did result in a significant increase in expression of α-smooth muscle actin. The expression of macrophage phenotype markers Arginase1 and iNOS present within the ADM were not significantly affected by IL-4 treatment at the day 21 time point. CONCLUSIONS: Acellular dermal matrix has the potential to be used for immunomodulatory cytokine delivery during the timeframe of healing. Using implanted ADM as a delivery vehicle to drive IL-4 mediated angiogenesis and vascular remodeling significantly enhanced vascularity within the ADM substrate.

Internet Filtering Technology and Aversive Online Experiences in Adolescents.

OBJECTIVES: To evaluate the effectiveness of Internet filtering tools designed to shield adolescents from aversive experiences online. STUDY DESIGN: A total of 1030 in-home interviews were conducted with early adolescents aged from 12 to 15 years (M = 13.50, SD = 1.18) and their caregivers. Caregivers were asked about their use of Internet filtering and adolescent participants were interviewed about their recent online experiences. RESULTS: Contrary to our hypotheses, policy, and industry advice regarding the assumed benefits of filtering we found convincing evidence that Internet filters were not effective at shielding early adolescents from aversive online experiences. CONCLUSIONS: Preregistered prospective and randomised controlled trials are needed to determine the extent to which Internet filtering technology supports vs thwarts young people online and if their widespread use justifies their financial and informational costs.

Imparting Immunomodulatory Activity to Scaffolds via Biotin-Avidin Interactions.

Biotin-avidin interactions have been explored for decades as a technique to functionalize biomaterials, as well as for in vivo targeting, but whether changes in these interactions can be leveraged for immunomodulation remain unknown. The goal of this study was to investigate how biotin density and avidin variant can be used to deliver the immunomodulatory cytokine, interleukin 4 (IL4), from a porous gelatin scaffold, Gelfoam, to primary human macrophages in vitro. Here, we demonstrate that the degree of scaffold biotinylation controlled the binding of two different avidin variants, streptavidin and CaptAvidin. Biotinylated scaffolds were also loaded with streptavidin and biotinylated IL4 under flow, suggesting a potential use for targeting this biomaterial in vivo. While biotin-avidin interactions did not appear to influence the protein release in this system, increasing degrees of biotinylation did lead to increased M2-like polarization of primary human macrophages over time in vitro, highlighting the capability to leverage biotin-avidin interactions to modulate the macrophage phenotype. These results demonstrate a versatile and modular strategy to impart immunomodulatory activity to biomaterials.

Effects of Biotin-Avidin Interactions on Hydrogel Swelling.

Affinity interactions between the small molecule biotin and the protein avidin have been used extensively to functionalize biomaterials. More recently, researchers have leveraged the changes in biotin-avidin affinity that occur upon biotin conjugation to larger molecules to control the release of biotinylated drugs and proteins. However, the effects of biotin-avidin interactions on hydrogel properties have not been thoroughly investigated. The objective of this study was to evaluate the effect of increasing biotin and avidin concentrations on hydrogel swelling properties, as an indicator of crosslinking. Gelatin, selected as a model hydrogel material, was biotinylated at increasing fold molar excesses of biotin with a PEG linker using N-hydroxysuccinimide chemistry. Afterwards, biotinylated gelatin was formed into hydrogels and stabilized with glutaraldehyde. Swelling properties of the biotinylated hydrogels were investigated by conducting swelling studies in different avidin solutions. Increasing the degree of biotinylation caused significant decreases in swelling ratios of the hydrogels in a dose-dependent manner, suggesting increases in crosslinking of the hydrogels. However, increasing avidin concentrations in excess of biotin content did not significantly affect swelling ratios. Moving hydrogels to phosphate-buffered saline following avidin incorporation resulted in increased swelling ratios for hydrogels prepared with a lower concentration of biotin. However, hydrogels prepared with the highest concentration of biotin did not experience increased swelling ratios, implying that the stability of biotin-avidin-mediated crosslinking depends on the number of biotin molecules available for binding. Collectively, these results demonstrate that biotin-avidin interactions control hydrogel swelling properties, and that the magnitude and stability of the effects depend on the biotin concentration. These results have important implications for affinity-based controlled release of biotinylated drugs or proteins from biotin-avidin-crosslinked hydrogels.

Internet Filtering and Adolescent Exposure to Online Sexual Material.

Early adolescents are spending an increasing amount of time online, and a significant share of caregivers now use Internet filtering tools to shield this population from online sexual material. Despite wide use, the efficacy of filters is poorly understood. In this article, we present two studies: one exploratory analysis of secondary data collected in the European Union (n = 13,176), and one preregistered study focused on British adolescents and caregivers (n = 1,004) to rigorously evaluate their utility. In both studies, caregivers were asked about their use of Internet filtering, and adolescent participants were interviewed about their recent online experiences. Analyses focused on the absolute and relative risks of young people encountering online sexual material and the effectiveness of Internet filters. Results suggested that caregiver's use of Internet filtering had inconsistent and practically insignificant links with young people reports of encountering online sexual material. Our findings underscore the need for randomized controlled trials to determine the extent to which Internet filtering and related technologies support versus thwarts young people online, and if their perceived utility justifies their financial and informational costs.

The effects of grape and red wine polyphenols on gut microbiota - A systematic review.

There is a growing body of evidence implicating the gut 'microbiome' role in overall human health. Bacterial species belonging to the genera Lactobacillus and Bifidobacterium are generally considered to be beneficial and are commonly used in probiotic applications, whereas increases in some genera including Clostridum, Eubacterium and Bacteroides are implicated in negative health outcomes. Dietary polyphenols are bioactive compounds that have been found to increase the numbers of beneficial bacteria and antimicrobial actions against pathogenic bacteria, however most studies have been conducted in animal models or in-vitro colonic models. The aim of this systematic review was to provide an overview of recent trials on the effect of dietary grape and red wine polyphenols on the gut microbiota in humans. Following PRISMA guidelines, a systematic review was conducted of electronic databases (PubMed, CINAHL, Cochrane Library, Wed of Science and Scopus) to identify human intervention trials examining the effect of grape or wine polyphenols on gut microbiota. Seven trials met the inclusion criteria. One study looked at changes in gut microbiota following the ingestion of de-alcoholised red wine or red wine, and six studies referred to gut microbiota as intermediates in formation of phenolic metabolites. All studies confirmed that ingested polyphenols from grape and red wine, were modulated by gut microbiota, increasing numbers of polyphenolic metabolites which were found in blood, urine, ileal fluid and faeces. Intake of polyphenols derived from grape and red wine can modulate gut microbiota and contribute to beneficial microbial ecology that can enhance human health benefits. Additionally, grape and red wine polyphenols were modulated by the gut microbiota and there is a potential for a two-way relationship between the gut microbiota and polyphenolic compounds. Nevertheless, additional research is required to fully understand the complex relationship between gut microbiota and dietary polyphenols before any health claims can be made in relation to human health.