TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis.

TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.

Primary total hip arthroplasty with an uncemented femoral component five- to nine-year results.

This study reports the outcome of total hip arthroplasty with use of an uncemented, tapered stem with a 5- to 9-year follow-up. The first 200 consecutive patients (214 hips) undergoing total hip arthroplasty with the Accolade TMZF stem (Stryker Orthopaedics, Mahwah, NJ) were enrolled prospectively. Follow-up for these patients averaged 7.6 years and encompassed review of clinical records as well as review of serial anteroposterior and lateral radiographs. There were 5 revision surgeries for aseptic loosening, 2 cases of infection, instability, and polyethylene wear. Our failure rate, defined as hips needing revision, was 2.6%, and the failure rate due to aseptic loosening of the femoral component was 0.6%. These results demonstrate the high success rate of this implant providing support for its continued use.

Stiffness after revision total knee arthroplasty.

Stiffness after a revision total knee arthroplasty (TKA) is a disabling complication that has largely been overlooked in the literature. This study attempts to define the prevalence of stiffness after revision TKA and to determine the risk factors that may lead to its development. Thirty-two knees (4.0%) presented with stiffness that we defined as a range of motion less than 90 degrees . Risk factors were found to be poor preoperative range of motion, stiffness as primary indication for revision, younger age, shorter interval between index primary and revision TKA, presence of well-fixed components at the time of revision, postoperative wound drainage, and lower Charlson index. Because of the challenges of treating stiffness, efforts should be invested in preventing this complication.

Revision for stiffness following TKA: a predictable procedure?

BACKGROUND: Stiffness is a known complication following total knee arthroplasty. Multiple options are available to address this problem but revision TKA has been reported to be an effective treatment especially in the presence of technical issues such as oversized or loose components. However, it is not clearly known what factors may affect the outcome of revision TKA for stiffness. The purpose of this study was to evaluate the results of TKA revision for stiffness and to determine which potential factors may predict the outcome. MATERIALS AND METHODS: Between 1999 and 2006, 39 patients (24 females and 15 males) were revised for stiffness following their primary TKA. The average age was 60.8 years with an average BMI of 30.7. The mean follow up was 74.4 months. RESULTS: Following revision TKA, the overall range of motion and flexion contracture improved significantly from 68 to 90 (p=0.001) and from 14 to 5 (p<0.0001), respectively. Although the KSS were significantly improved from 45.72 to 77.10 (p<0.0001), the functional score did not improve significantly. Of the 39 knees which had stiffness, 10 (25.6%) required a second revision. We could not find any demographic or operative characteristics as a predictor failure. CONCLUSION: Our study shows that TKA revision is a viable option, still unpredictable, to improve the ROM in patients with prolonged stiffness after TKA. Although revision for stiffness is not always successful in terms of achieving functional range of motion, it could improve pain in presence of less than functional range of motion. LEVEL OF EVIDENCE: Prognostic Level II.

Morphology of the proximal femur differs widely with age and sex: relevance to design and selection of femoral prostheses.

The ability of uncemented femoral stems to osseointegrate properly depends largely on their fit in the proximal femur. We evaluated the topography of the proximal femur and determined differences based on age and sex. Retrospectively, anteroposterior radiographs from 312 (168 male, 144 female) pre-operative total hip arthroplasty (THA) patients (age of 21-85 years) were collected. Radiographic measurements were taken at 10 mm intervals along the length of the femur. Variables including canal flare index (CFI) and cortical index (CI) were calculated. Data were binned into three age groups and separated by sex for comparison. Measurements showed that CFI decreased with age for both sexes; however, females demonstrated a greater decrease. Decrease in flare occurred primarily on the lateral side. CI also decreased with age, the most pronounced drop occurring in older females. A clear difference exists between male and female proximal femoral geometry. This decrease is most likely attributed to the loss of cortical bone. The medial component likely demonstrates less loss of flare due to strong compressive forces that are transmitted through this portion of the femur. These results demonstrate the necessity of considering age and sex when selecting a proper prosthesis.

TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL.

The adapter protein TRAF6 is critical for mediating signal transduction from members of the IL-1R/TLR and TNFR superfamilies. The TRAF6 RING finger domain functions as an ubiquitin E3 ligase capable of generating non-degradative K63-linked ubiquitin chains. It is believed that these chains serve as docking sites for formation of signaling complexes, and that K63-linked autoubiquitination of TRAF6 is essential for formation and activation of a complex involving the kinase TAK1 and its adapters, TAB1 and TAB2. In order to assess independently the E3 ligase and ubiquitin substrate functions of TRAF6, we generated, respectively, RING domain and complete lysine-deficient TRAF6 mutants. We found that while the TRAF6 RING domain is required for activation of TAK1, it is dispensable for interaction between TRAF6 and the TAK1-TAB1-TAB2 complex. Likewise, lysine-deficient TRAF6 was found to interact with the TAK1-TAB1-TAB2 complex, but surprisingly was also found to be fully competent to activate TAK1, as well as NFkappaB and AP-1 reporters. Furthermore, lysine-deficient TRAF6 rescued IL-1-mediated NFkappaB and MAPK activation, as well as IL-6 elaboration in retrovirally-rescued TRAF6-deficient fibroblasts. Lysine-deficient TRAF6 also rescued RANKL-mediated NFkappaB and MAPK activation, and osteoclastogenesis in retrovirally-rescued TRAF6-deficient bone marrow macrophages. While incapable of being ubiquitinated itself, we demonstrate that lysine-deficient TRAF6 remains competent to induce ubiquitination of IKKgamma/NEMO. Further, this NEMO modification contributes to TRAF6-mediated activation of NFkappaB. Collectively, our results suggest that while TRAF6 autoubiquitination may serve as a marker of activation, it is unlikely to underpin RING finger-dependent TRAF6 function.