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Background/Aim. Cholesteatoma is characterized by progressive growth with the erosion of surrounding bone due to pressure effects, enzymatic activity and activation of osteoclasts. The aim of this study was to examine the expression levels of tumor necrosis factor (TNF)-alpha receptor 2 (TNF R2) and interleukin-1 (IL-1) in chronic otitis media (COM) with and without acquired cholesteatoma and correlate them with the degree of bone destruction. Methods. The study included 178 patients of both sexes, aged 5?75 years, who underwent microsurgical treatment for COM, with and without cholesteatoma at the Ear, Nose and Throat Department, University Clinical Center of Republika Srpska (UCC RS), Banja Luka from 2015 to 2018. Based on cholesteatoma presence, the patients with COM were divided into two groups: with cholesteatoma (CCOM) (n = 97) and without cholesteatoma (COMWC) (n = 81). Samples of cholesteatoma perimatrix in the CCOM group and tympanic cavity inflamed mucosa in the COMWC group were collected intraoperatively. Intraoperative exploration of the middle ear included the status of the ossicular chain, individual ossicles, osseous walls of the external auditory canal (EAC) and tympanic cavity. Expression levels of TNF R2 and IL-1 were investigated by immunohistochemical analysis of tissue samples obtained during ear surgery. Results. The correlation between the level of osteodestruction and the presence of cholesteatoma was significant (p < 0.01). Elevated expression levels of TNF R2 and IL-1 were most frequent in CCOM patients with osteodestruction. The probability of osteodestruction of EAC and tympanic cavity walls was significantly higher in patients with high TNF R2 expression (p < 0.05). With respect to IL-1 expression levels, no significant correlation with the described pathomorphological changes was observed. Correlation between TNF R2 and IL-1 expressions and ossicular chain destruction was significant (p < 0.01). Conclusion. Cholesteatoma presence and elevated expression levels of TNF R2 and IL-1 in COM patients are significantly correlated. Expression levels of TNF R2 and IL-1 in acquired cholesteatoma tissue have a potential clinical significance for the occurrence of bone destruction compared to expression levels in inflamed mucosa of the tympanic cavity.

Although inflammation is known to influence bone turnover and bone mineral density (BMD), less is known about role of soluble tumor necrosis factor alpha receptor 1 (sTNFα-R1) in changes in bone turnover and BMD in the year after hip fracture. We studied 245 persons (117 men and 128 women) from the Baltimore Hip Studies. Bone turnover markers of resorption (carboxy-terminal type I collagen cross-links [CTX-I]) and formation (amino-terminal propeptide type I collagen [P1NP]), BMD of the contralateral hip, and sTNFα-R1 were measured within 15 days of hospitalization and 2, 6, and 12 months later. Latent class growth modeling was used to determine sTNFα-R1 trajectories. Weighted generalized estimating equations were used to examine the association of sTNFα-R1 trajectories with serum levels of CTX-I and P1NP and BMD; standardized beta coefficients (βˆ) are reported. Higher baseline sTNFα-R1 was significantly associated with a greater rate of CTX-I change (βˆ = 0.26, p = 0.004). Four distinct sTNFα-R1 trajectories were identified. The two groups with higher sTNFα-R1 levels during the year following fracture had faster increasing levels of CTX-I compared to the group with lowest sTNFα-R1 levels (men: group 3: βˆ = 0.76, p = 0.02; group 4: βˆ = 1.4, p

BackgroundPosttraumatic stress disorder (PTSD) may contribute to heightened cardiovascular disease risk by promoting a proinflammatory state and impaired endothelial function. Previous research has demonstrated associations of PTSD with inflammatory and endothelial function biomarkers, but most work has been cross-sectional and does not separate the effects of trauma exposure from those of PTSD.MethodsWe investigated associations of trauma exposure and chronic PTSD with biomarkers of inflammation (C-reactive protein and tumor necrosis factor alpha receptor II) and endothelial function (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in 524 middle-aged women in the Nurses' Health Study II. Using linear mixed models, we examined associations of trauma/PTSD status with biomarkers measured twice, 10 to 16 years apart, in cardiovascular disease-free women, considering either average levels over time (cross-sectional) or change in levels over time (longitudinal). Biomarker levels were log-transformed. Trauma/PTSD status (based on structured diagnostic interviews) was defined as no trauma at either blood draw (n= 175), trauma at blood draw 1 but no PTSD at either draw (n= 175), and PTSD that persisted beyond blood draw 1 (chronic PTSD; n= 174). The reference group was women without trauma.ResultsIn models adjusted for known potential confounders, women with chronic PTSD had higher average C-reactive protein (B= 0.27, p < .05), tumor necrosis factor alpha receptor II (B= 0.07, p < .01), and intercellular adhesion molecule-1 (B= 0.04, p < .05) levels. Women with trauma but without PTSD had higher average tumor necrosis factor alpha receptor II levels (B= 0.05, p < .05). In addition, women with chronic PTSD had a greater increase in vascular cell adhesion molecule-1 over time (B= 0.003, p < .05).ConclusionsIncreased inflammation and impaired endothelial function may be pathways by which chronic PTSD increases cardiovascular disease risk.

Introduction: Density and co-expression of tumor necrosis factor (TNF) receptors may vary among cell populations. However, the role and potential of these changes remain unclear. This study aimed to determine the density of expression and co-expression of TNFR1/2 and the dose-dependent effect of soluble TNF on these parameters. Methods: Epithelial-like (HEp-2, K-562, MCF-7, ZR-75/1) and lymphoblast-like (MOLT-4, HL-60, Raji, RPMI-8226, IM-9) cell lines were characterized for co-expression of TNFR1/2 using a modified flow cytometry protocol. The dose-dependent effects of rhTNF on TNF receptor expression in these lines were studied. Results: This study reports a protocol for the simultaneous quantitative evaluation of the of TNF receptor number and co-expression of membrane-bound TNFR1/2. Cells within one tumor cell line were found to differ regarding their expression of type 1 and 2 TNFα receptors; simultaneously, cells with all 4 variants of co-expression may be present in culture. Conclusion: We demonstrated a dose-dependent effect of TNF on changes in the expression of TNFR1/2 by the percentage of positive cells and by the number of receptors, which may be used to control TNF-mediated processes in target cells.

Background: The aim of the study is to evaluate in vivo and in vitro effects of etanercept, a soluble tumor necrosis factor receptor, on the contractile responses of superior mesenteric artery in an experimental mesenteric ischemia and reperfusion model. Material and methods: After obtaining animal ethics committee approval, 24 Sprague eDawley rats were allocated to three groups. Control group (Gr C, n = 6) underwent a sham operation, whereas ischemia/reperfusion and treatment groups underwent 90 min ischemia and 24- h reperfusion (Gr I/R, n = 12; Gr I/RthornE, n = 6). The treatment group received 5 mg/kg etanercept intravenously at the beginning of reperfusion. At the end of reperfusion, all animals were sacrificed, and third branch of superior mesenteric artery was dissected for evaluation of contractile responses. In vitro effects of etanercept on vasocontractile responses were also evaluated. The excised ileums were analyzed under light microscope. Two- way analysis of variance following Bonferroni post hoc test was used for evaluation of contractile responses. Results: Endothelin- 1 and phenylephrine- mediated vasocontractile sensitivity were found increased in Gr I/R when compared with Gr C. Both intravenous administration and organ bath incubation of etanercept decreased the sensitivity of contractile agents for Gr I/R. Mucosal injury, lamina propria disintegration, and denuded villous tips were observed in Gr I/R, whereas the epithelial injury and the subepithelial edema were found to be milder in Gr I/RthornE. Conclusions: Etanercept can be a promising agent in mesenteric ischemic reperfusion injury as it does not only inhibit inflammation by blocking tumor necrosis factor- a in circulation but also restores vascular contractility during reflow. These findings support an unexplained recuperative effect of drug beyond its anti- inflammatory effects. (C) 2018 Elsevier Inc. All rights reserved.

Osteoprotegerin (OPG) is a member of the tumor necrosis factor alpha receptor family and has recently emerged as key factor in atherosclerosis development. It is also associated with the development and extent of coronary artery disease (CAD). We evaluate the prognostic ability of serum OPG levels

Purpose: The purpose of this study was to examine the influence of narrowband ultraviolet (NB-UVB) therapy on the serum concentration of soluble tumor necrosis factor receptor type 1 (sTNF-R1) in psoriasis patients. Methods: Twenty-seven patients received NB-UVB therapy three to five times a week for 4 weeks. The assessment of skin lesions using psoriasis area and severity index (PASI) and serum concentration of sTNF-R1 was performed at the baseline, at 2, 4 and 4 weeks after treatment cessation. The sera of healthy subject were used as controls. Results: The baseline PASI was 13.56±5.71, sTNF-R1 concentration was 1.89±0.43 ng/ml in patients and 1.48±0.30 ng/ml in controls (P

Tumor necrosis factor-alpha (TNF-alpha) is a highly pleiotropic cytokine produced mainly by activated macrophages. This cytokine has been found to mediate the growth of certain tumors, the replication of HIV-1, septic shock, cachexia, graft-versus-host disease, and autoimmune diseases. The binding of TNF-alpha to the p55 tumor necrosis factor receptor type I (TNFRI) is considered one of the initial steps responsible for the multiple physiologic effects mediated by TNF-alpha. The role of TNF-alpha as an inflammatory mediator through TNFRI makes both of these genes attractive targets for intervention in both acute and chronic inflammatory diseases. We have designed antisense oligodeoxynucleotides (ODNs) containing chemically modified purine and pyrimidine bases that specifically inhibit TNFRI expression and functions. These ODNs were designed to hybridize to the 3'-polyadenylation signal region of the TNFRI gene. In cell-based assays, gene-specific antisense inhibition occurred in a dose-dependent fashion at submicromolar concentrations in the presence of cellular uptake enhancing agents. Within ODN sets with a common pattern of stabilizing backbone substitution, the inhibition of the gene expression is found to be correlated with the affinity of the ODNs for their cognate mRNA target sites, providing direct evidence for an antisense mechanism of action. In addition, events triggered by the binding of TNF-alpha to TNFRI, such as the production of IL-6 and IL-8, were significantly reduced by treatment of cells with the anti-TNFRI ODN. Therefore, antisense ODNs can be used to control biologic processes mediated by TNF-alpha and may be useful as therapeutic agents to treat conditions resulting from overproduction of TNF-alpha.

Kinetics of regulation of membrane receptors for tumor necrosis factor-alpha (TNF) in human breast adenocarcinoma MCF-7 cells was investigated. When MCF-7 cells were incubated with radioiodinated human recombinant TNF, they bound TNF specifically and accumulated it intracellularly. Preincubation of cells with native TNF up to 1 x 10(-9) M for 12 h stimulated specific binding of TNF, indicating that concentrations of membrane receptors for TNF were regulated by the ligand. Accumulation of radioactivity in cells incubated with [125I]TNF proceeded at a constant rate for up to 24 h. Kinetics of binding and internalization of TNF were similar in the presence and absence of protein synthesis for at least 1 h, suggesting that the TNF receptor was either replenished from an intracellular pool of receptors or was recycled (reutilized) during the course of TNF internalization. Data were analyzed kinetically by fitting equations of compartmental models of ligand-cell interactions with and without the term for receptor recycling. Fits were obtained only for the model with receptor recycling; absence of the term for receptor recycling resulted in physically impossible best-fit parameter values. Analysis of the best-fit parameters indicated that both internalization and recycling of the receptor were stimulated by the ligand.

Background: The aim of the study is to evaluate in vivo and in vitro effects of etanercept, a soluble tumor necrosis factor receptor, on the contractile responses of superior mesenteric artery in an experimental mesenteric ischemia and reperfusion model. Material and methods: After obtaining animal ethics committee approval, 24 Sprague eDawley rats were allocated to three groups. Control group (Gr C, n = 6) underwent a sham operation, whereas ischemia/reperfusion and treatment groups underwent 90 min ischemia and 24- h reperfusion (Gr I/R, n = 12; Gr I/RthornE, n = 6). The treatment group received 5 mg/kg etanercept intravenously at the beginning of reperfusion. At the end of reperfusion, all animals were sacrificed, and third branch of superior mesenteric artery was dissected for evaluation of contractile responses. In vitro effects of etanercept on vasocontractile responses were also evaluated. The excised ileums were analyzed under light microscope. Two- way analysis of variance following Bonferroni post hoc test was used for evaluation of contractile responses. Results: Endothelin- 1 and phenylephrine- mediated vasocontractile sensitivity were found increased in Gr I/R when compared with Gr C. Both intravenous administration and organ bath incubation of etanercept decreased the sensitivity of contractile agents for Gr I/R. Mucosal injury, lamina propria disintegration, and denuded villous tips were observed in Gr I/R, whereas the epithelial injury and the subepithelial edema were found to be milder in Gr I/RthornE. Conclusions: Etanercept can be a promising agent in mesenteric ischemic reperfusion injury as it does not only inhibit inflammation by blocking tumor necrosis factor- a in circulation but also restores vascular contractility during reflow. These findings support an unexplained recuperative effect of drug beyond its anti- inflammatory effects. (C) 2018 Elsevier Inc. All rights reserved.