Dermatophagoides farinae is a frequent allergen in canine atopic dermatitis despite its reported scarcity in the UK, and the aim of this study was to determine whether dogs were uniquely exposed to this species. Der f 1 and Der p 1 in dust collected from living room carpets, bedroom carpets and dog beds of 13 houses with no dogs, 13 with healthy dogs, and 16 with Dermatophagoides-sensitized atopic dogs were quantified by ELISA. Der p 1 levels (microg g(-1) house dust) were significantly higher than Der f 1 in living rooms (Der p 1 median = 1.9, 95% CI = 2.05-6.32, n = 42; Der f 1 median = 0.07, 95% CI = 0.01-0.06, n = 42), bedrooms (Der p 1 median = 4.35, SD = 5.52; Der f 1 median = 0.01, 95% CI = 0.001-0.1, n = 42) and dog beds (Der p 1 median = 1.04, 95% CI = 1.4-8.1, n = 29; Der f 1 median = 0.008, 95% CI = 0.01-0.04, n = 29) (P < 0.0001). Living rooms in houses without dogs had significantly greater Der p 1 levels (median = 7.0, 95% CI = 3.53-15.8, n = 13) than houses with healthy (median = 1.19, 95% CI = 0.44-3.49, n = 13) or atopic dogs (median = 0.78, 95% CI = 0.63-2.42, n = 16) (P = 0.0004). Environmental flea control in living rooms and washing dog beds was associated with significantly reduced Der p 1 levels. This confirms that D. pteronyssinus is common but D. farinae is rare in the sampling area. Apparent sensitization to D. farinae is probably due to cross-reaction. A combination of environmental measures could reduce allergen exposure.
Background: There is no validated way of measuring diagnostic delay in cancer, especially covering patient and primary care delays. An instrument is needed in order to determine the effect of potential interventions to reduce delay and improve cancer morbidity and mortality.
These findings are of policy importance in that there is no evidence from this study that general practice excisions are managed poorly or have a worse prognosis.
Abnormal wear of cobalt-containing metal-on-metal joints is associated with inflammatory pseudotumours. Cobalt ions activate human toll-like receptor 4 (TLR4), which normally responds to bacterial lipopolysaccharide (LPS) in sepsis. Activation of TLR4 by LPS increases the expression of chemokines IL-8 and CXCL10, which recruit leukocytes and activated T-cells, respectively. This study was designed to determine whether cobalt induces a similar inflammatory response to LPS by promoting the expression of IL-8 and CXCL10. A human monocytic cell line, derived from acute monocytic leukaemia, was treated with cobalt ions and expression of IL-8 and CXCL10 measured at mRNA and protein levels. Cobalt-treated macrophages showed a 60-fold increase in IL-8 mRNA, and an eightfold increase in production of the mature chemokine (both p < 0.001); expression of the CXCL10 gene and protein was also significantly increased by cobalt (both p < 0.001). Experiments were also performed in the presence of CLI-095, a TLR4-specific antagonist which abrogated the cobalt-mediated increase in IL-8 and CXCL10 expression. These findings suggest that cobalt ions induce inflammation similar to that observed during sepsis by the simultaneous activation of two TLR4-mediated signalling pathways. These pathways result in increased production of IL-8 and CXCL10, and may be implicated in pseudotumour formation following metal-on-metal replacement.
Metal-on-metal (MoM) hip replacements, often manufactured from a cobalt-chrome alloy, are associated with adverse reactions including soft tissue necrosis and osteolysis. Histopathological analysis of MoM peri-implant tissues reveals an inflammatory cell infiltrate that includes macrophages, monocytes and neutrophils.Toll-like receptor 4 (TLR4) is an innate immune receptor activated by bacterial lipopolysaccharide. Recent studies have demonstrated that cobalt ions from metal-on-metal joints also activate human TLR4, increasing cellular secretion of inflammatory chemokines including interleukin-8 (IL-8, CXCL8) and CCL2. Chemokines recruit immune cells to the site of inflammation, and their overall effect depends on the chemokine profile produced.This study investigated the effect of cobalt on the secretion of inflammatory cytokines CCL20 and IL-6. The chemotactic potential of conditioned media from a cobalt-stimulated human monocyte cell line on primary monocytes and neutrophils was investigated using an in vitro transwell migration assay. The role of TLR4 in observed effects was studied using a small molecule TLR4-specific antagonist.Cobalt ions significantly increased release of CCL2 and IL-6 by MonoMac 6 cells (P<0.001). Conditioned media from cobalt-stimulated cells significantly increased monocyte and neutrophil chemotaxis in vitro (P<0.001). These effects were abrogated by the TLR4 antagonist (P<0.001) suggesting that they occur through cobalt activation of TLR4.This study demonstrates the role of TLR4 in cobalt-mediated immune cell chemotaxis and provides a potential mechanism by which cobalt ions may contribute to the immune cell infiltrate surrounding failed metal hip replacements. It also highlights the TLR4 signalling pathway as a potential therapeutic target in preventing cobalt-mediated inflammation.
Cobalt-containing metal-on-metal hip replacements are associated with adverse reactions to metal debris (ARMD), including inflammatory pseudotumours, osteolysis, and aseptic implant loosening. The exact cellular and molecular mechanisms leading to these responses are unknown. Cobaltions (Co2+) activate human Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to Gram negative bacterial lipopolysaccharide (LPS).We investigated the effect of Co2+-mediated TLR4 activation on human microvascular endothelial cells (HMEC-1), focusing on the secretion of key inflammatory cytokines and expression of adhesion molecules. We also studied the role of TLR4 in Co2+-mediated adhesion molecule expression in MonoMac 6 macrophages.We show that Co2+ increases secretion of inflammatory cytokines, including IL-6 and IL-8, in HMEC-1. The effects are TLR4-dependent as they can be prevented with a small molecule TLR4 antagonist. Increased TLR4-dependent expression of intercellular adhesion molecule 1 (ICAM1) was also observed in endothelial cells and macrophages. Furthermore, we demonstrate for the first time that Co2+ activation of TLR4 upregulates secretion of a soluble adhesion molecule, sICAM-1, in both endothelial cells and macrophages. Although sICAM-1 can be generated through activity of matrix metalloproteinase-9 (MMP-9), we did not find any changes in MMP9 expression following Co2+ stimulation.In summary we show that Co2+ can induce endothelial inflammation via activation of TLR4. We also identify a role for TLR4 in Co2+-mediated changes in adhesion molecule expression. Finally, sICAM-1 is a novel target for further investigation in ARMD studies.
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