Good to excellent long-term survival of a single-design condylar constrained knee arthroplasty for primary and revision surgery.

PURPOSE: The purpose of the study was to determine the long-term survivorship, functional outcomes of a single-design condylar constrained (CCK) TKA in primary and revision cases as well as to assess specific risk factors for failure. It was hypothesized that primary CCK TKA had a better survival than revision knees. METHODS: One hundred and forty three patients who underwent revision TKA (n = 119) or complex primary TKA (n = 24) using a single-design condylar constrained knee system (Genesis CCK, Smith & Nephew) performed at a single institution between 1999 and 2008 were retrospectively included. The median follow-up amounted to 11.8 years (IQR 10.3-14.4). Implant survivorship was analyzed using Kaplan-Meier survival estimates and multivariate Cox regression analysis to identify risk factors for failure. Function was determined using the Oxford Knee Score (OKS). RESULTS: The implant survival was 86.4% after five, 85.5% after ten and 79.8% at 15 years. A reduced implant survivorship was found in males (HR 5.16, p = 0.001), smokers (HR 6.53, p = 0.004) and in obese patients (HR 2.26, p = 0.095). Patients who underwent primary TKA had a higher revision-free implant survivorship compared to revision TKA at 15 years (100% vs. 76%, p = 0.036). The main cause for re-revision was infection in 10% of all revision TKA performed with the CCK design included, while no case was revised for instability. The median OKS was 39 (IQR 35-44) in 102 patients available for long-term functional outcome. CONCLUSION: CCK implants are associated with excellent long-term survival when used in primary TKA; however, survival was worse when used during revision TKA. Males, smokers, obese patients and are at higher risk for revision. While instability and aseptic loosening were rare, infection remains a major concern. LEVEL OF EVIDENCE: Level IV, retrospective observational study.

Long-term stimulation of Toll-like receptor 3 in primary human hepatocytes leads to sensitization for antiviral responses induced by poly I:C treatment.

Chronic hepatitis C infection is associated with increased expression of interferon-sensitive genes (ISGs) in the liver, which is, paradoxically, correlated with the nonresponse to interferon (IFN)-based therapies. In the present study PHHs were isolated from HCV-infected or uninfected patients and stimulated with the TLR1-9 ligands for 6-24 h. Expression of cytokines and ISGs was determined by ELISA and qRT-PCR. A comparative analysis was performed for TLR3 signalling, which was also correlated with single nucleotide polymorphisms (SNPs) related to HCV pathogenesis. TLR-activated PHHs produced pro-inflammatory and anti-inflammatory cytokines, whereas IFNs were exclusively induced by TLR3 stimulation. Here, IL-29 and IL-28A were significantly highly expressed than IFN-α and IFN-ß. TLR3-induced IFN response was enhanced in hepatocytes isolated from patients with HCV infection. This hyper-responsiveness could be mimicked in naïve PHHs consistently stimulated with low dose of poly I:C, but not Guardiquimod. The higher responsiveness in PHH isolated from HCV-infected patients could be partially explained by higher frequencies of unfavourable SNP alleles of different SNPs associated with HCV progression and treatment outcome. These data suggest that durable activation of TLR3 but not TLR7, by low doses of viral replicative intermediates, increases the sensitivity to viral invasion. These findings shed new light on the relevance of TLR3 in the pathogenesis of HCV and may provide a possible explanation for the increased ISG expression during chronic HCV infection, the so-called IFN paradox.

Toll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigen.

It has been recently shown that Toll-like receptor (TLR) signalling in murine nonparenchymal liver cells (NPCs) is suppressed in the presence of Hepatitis B virus surface antigen (HBsAg). It is not clear, however, whether this is also relevant for the adaptive immune responses and how this effect is mediated. Peripheral blood mononuclear cells (PBMCs) from Hepatitis B virus (HBV) patients and controls were stimulated by TLR ligands in the absence or presence of autologous serum. Interestingly, TLR-mediated cytokine expression (Interleukin-6 and -10) as well as TLR3-induced interferon (IFN) expression in PBMCs of HBV patients was significantly higher than in the healthy volunteers, showing a negative correlation with the levels of HBsAg. In addition, TLR3-mediated IFN-γ production was inhibited in the presence of HBV-containing serum. To mechanistically analyse this observation, murine Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) were stimulated with TLR3 ligands in the presence or absence of HBsAg. Mixed lymphocyte reactions were performed to study T-cell activation induced by TLR-stimulated NPCs. Gene expression of cytokines and TLR3 was analysed by quantitative rt-PCR, and activation of transcription factors was assessed by Western blot or reporter gene assays. TLR-induced expression of interferon γ, interferon sensitive genes and proinflammatory cytokines in murine KCs and LSECs was efficiently suppressed in the presence of HBsAg, whereas the expression of anti-inflammatory cytokines was enhanced. Activation of NFκB, IRF-3 and MAPKs in these liver cells was potently suppressed by HBsAg. T-cell activation mediated through TLR3-stimulated KCs or LSECs was suppressed by HBsAg which could be reverted by anti-IL-10 antibodies. These findings may, at least in part, explain how HBV evades innate and adaptive immune responses to maintain a persistent infection.