Valgus instability and related factors beyond 2 years following unlinked total elbow arthroplasty.

HYPOTHESIS AND BACKGROUND: Total elbow arthroplasty (TEA), categorized into linked and unlinked types, is a commonly reported treatment for rheumatoid arthritis of the elbow. Although unlinked TEA preserves bone, it may result in instability. This study aimed to assess the outcomes of unlinked TEA in rheumatoid arthritis of the elbow beyond 2 years and to identify factors correlating with postoperative valgus instability of unlinked TEA. METHODS: This study included patients who underwent TEA for rheumatoid arthritis of the elbow at our department between August 2009 and January 2017, with a follow-up period exceeding 2 years. Elbow joint range of motion (ROM) and clinical scores were evaluated preoperatively and at the final follow-up. Factors contributing to valgus instability, such as the Larsen grade, sex, age, side, preoperative ROM, postoperative ROM, implant placement, preoperative carrying angle, and the use of biological disease-modifying antirheumatic drugs (bDMARDs), were also assessed. RESULTS: This study encompassed 26 elbows from 23 patients, with a mean patient age at surgery of 64.8 years and a mean follow-up duration of 92.4 months. Significant improvements were observed in the ROM (extension: from -31° preoperatively to -21° postoperatively [P = .02], flexion: from 116° to137° [P < .001]), Japanese Orthopaedic Association-Japan Elbow Society Elbow Function Score (from 45.9 to 86.3 points [P < .001]), and Mayo Elbow Performance Score (from 43.6 to 91.7 points [P < .001]). At the last follow-up, 2 elbows exhibited radiolucent lines around the humeral stem, whereas 7 had valgus instability. Factors correlated with valgus instability included total arc at the final follow-up, preoperative carrying angle, and the use of bDMARDs. DISCUSSION AND CONCLUSION: Unlinked TEA demonstrated favorable midterm outcomes for rheumatoid arthritis of the elbow, albeit with occasional valgus instability. Surgeons should consider preoperative carrying angle and bDMARD use, and exercise caution regarding intraoperative extensions.

Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development.

Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and ßTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

Postoperative Infection Related with the Total Elbow Arthroplasty (Kudo's Prosthesis) in Rheumatoid Arthritis.

BACKGROUND: Total Elbow Arthroplasty (TEA) for the rheumatoid arthritis (RA) has been popularized since 1980s. The outcomes of TEA using any type of implant design for RA has been satisfactory. On the other hand, many orthopedicians experience several postoperative complications. Among them, postoperative infection has still being the most troublesome and difficult to treat. This study is to clarify the causes of postoperative infection of TEA using Kudo's prosthesis for RA and discuss how to manage and prevent infection. METHODS: 421 TEAs were performed for 405 cases with RA at the authors' institute during the period between 1982 and 2007. They were followed up for 1~25 years (Av. 12.3 years). The authors examined pain, the range of motion, roentgenograms and complications postoperatively. We were able to start treatment within 4 weeks after occurrence of infection. For surgical management of infected TEAs, debridement of the synovium and removal of the prosthesis with loosening were performed for all cases. In addition, all cases have been regularly and strictly followed-up with the elbow protector to prevent recurrence of infection since 2008. RESULTS: There were 98 TEAs with the postoperative complications (23.3%). Eight out of 98 TEAs were infected (1.9%). Five of eight infected TEAs were primarily at the surgical scar site infection (SSSI) (60%), unknown causes in two, hematogenous course in 1. It's obvious that surgical scar site infection (SSSI) was the leading cause of postoperative infection in this study. Thus, the authors made the elbow proctor to avoid injuries of the skin around surgical scar site (SSS). Since 2008, all of the TEAs and revised TEAs have been applied with this protector. CONCLUSIONS: The authors reported 8 infected TEAs: 5 cases were revised, 2 with the brace, 1 had above the elbow amputated. The regular and meticulous follow up and application of the elbow protector were useful to prevent infection of post-TEAs using Kudo's prosthesis in RA. Since 2008, there have been no infection of post TEAs and revised TEAs.

Effect of low-intensity pulsed ultrasound on bone healing at osteotomy sites after forearm bone shortening.

PURPOSE: To test the hypothesis that low-intensity pulsed ultrasound (LIPUS) may accelerate healing at osteotomy sites after forearm bone shortening osteotomies. METHODS: In this prospective study, we enrolled 27 patients who underwent ulnar shortening osteotomy for ulnar impaction syndrome or radial shortening osteotomy for Kienböck disease. We randomized limbs to be treated with LIPUS (14 osteotomies, LIPUS group) or without LIPUS (13 osteotomies, control group). At 1 week postoperatively, patients in the LIPUS group received once-daily 20-minute LIPUS treatments that continued until at least 12 weeks postoperatively. At 2, 4, 6, 8, 12, 16, and 24 weeks postoperatively, we assessed union of the osteotomy site to determine the time to union using 4 projections of x-rays. RESULTS: In this study, all osteotomies achieved complete union. The mean times to complete cortical union were 57 days in the LIPUS group and 76 days in the control group. Regarding endosteal union, the mean times were 121 days in the LIPUS group and 148 days in the control group. The LIPUS group had significantly reduced times for both types of union. CONCLUSIONS: Application of LIPUS shortened the time to cortical union by 27%, and to endosteal union by 18%. Our results indicate that LIPUS accelerated bone healing after we performed forearm bone shortening osteotomies. This may provide earlier return to activity and work for patients undergoing forearm osteotomies.

Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery.

Tendon reconstruction using grafts often results in adhesions that limit joint flexion. These adhesions are precipitated by inflammation, fibrosis, and the paucity of tendon differentiation signals during healing. In order to study this problem, we developed a mouse model in which the flexor digitorum longus (FDL) tendon is reconstructed using a live autograft or a freeze-dried allograft, and identified growth and differentiation factor 5 (Gdf5) as a therapeutic target. In this study we have investigated the potential of rAAV-Gdf5 -loaded freeze-dried tendon allografts as "therapeutically endowed" tissue-engineering scaffolds to reduce adhesions. In reporter gene studies we have demonstrated that recombinant adeno-associated virus (rAAV)-loaded tendon allografts mediate efficient transduction of adjacent soft tissues, with expression peaking at 7 days. We have also demonstrated that the rAAV-Gdf5 vector significantly accelerates wound healing in an in vitro fibroblast scratch model and, when loaded onto freeze-dried FDL tendon allografts, improves the metatarsophalangeal (MTP) joint flexion to a significantly greater extent than the rAAV-lacZ controls do. Collectively, our data demonstrate the feasibility and efficacy of therapeutic tendon allograft processing as a novel paradigm in tissue engineering in order to address difficult clinical problems such as tendon adhesions.

Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene.

The zinc finger transcription factor Osterix (Osx) regulates bone formation and osteoblast differentiation in vitro and in vivo. We investigated the transcriptional mechanisms underlying the mouse Osx expression by isolating and characterizing its 5' upstream region. We performed 5' RACE on mRNA isolated from murine chondroprogenitor cells and determined a cap site of Osx approximately -99 nucleotides upstream of the initiation codon. Sequence analysis of this TATA-less promoter shows several putative response elements for Sox9, VDRE, Runx and Sp1. Transfection of the Osx promoter driving the luciferase reporter gene into C3H10T1/2 and ATDC5 cells shows a strong basal promoter activity between 565 bp and 2 kb. Deletion mutant analyses show that the most proximal 852 kb of the Osx promoter contains the highest activating domains, while strong repressive domains were identified between 1.8 and 2 kb. Over-expression experiments indicate that Runx2 significantly transactivates the Osx promoter by at least 2 fold indicating that Osx is downstream of Runx2 in mesenchymal cells. This up-regulation was abrogated when the Runx2 responsive element on the Osx promoter was mutated. Finally, we show that Runx2 specifically binds to this DNA element in the Osx promoter. Thus our results show for the first time Osx transcriptional regulation through the bone and cartilage related transcription factor Runx2.

Role of macrophage migration inhibitory factor (MIF) in peripheral nerve regeneration: anti-MIF antibody induces delay of nerve regeneration and the apoptosis of Schwann cells.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine involved in inflammation and immune responses as well as in cell growth. Although we previously demonstrated the presence of MIF in peripheral nerves, and MIF mRNA expression was up-regulated after axotomy, the role of MIF in nerve injury and regeneration has not been evaluated. MATERIALS AND METHODS: To examine the potential role of MIF in nerve regeneration, we locally administered an anti-MIF polyclonal antibody into regenerating rat sciatic nerves using the silicone chamber model. The effect of the anti-MIF antibody on nerve regeneration was evaluated using an axonal reflex test. In addition, we carried out a terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay and immunohistochemical analysis of the damaged nerve segments with regard to apoptosis-related proteins such as p53 to evaluate the effects of anti- MIF antibodies on apoptosis during the regeneration process. RESULTS: The regeneration length of the nerve in the anti-MIF antibody-treated group was significantly shorter than that in the non-immune rabbit IgG-treated group at weeks 2, 4 and 6 after surgery. TUNEL assay showed that a large number of apoptotic cells, mostly Schwann cells, were observed in the intratubal and distal nerve segments at weeks 4 and 6 after surgery by the anti-MIF antibody treatment. Consistent with these results, Ki-67-positive cells were significantly decreased by the anti-MIF antibody treatment. Immunohistochemical analyses revealed that p53 and, to a lesser extent, Fas were more up-regulated in the anti-MIF antibody-treated nerves than in the controls. CONCLUSION: Taken together, these results suggest that MIF plays an important role in acceleration of peripheral nerve regeneration and in prevention of Schwann cell apoptosis, mainly through overcoming the apoptotic effect of p53.