Background
The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration.
Hypothesis
After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers.
Study Design
Controlled laboratory study.
Methods
Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses.
Results
Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibro-cartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51 % increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%.
Conclusion
The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development of a stable bone-tendon interface, although decreases in muscle fiber specific force production were observed, and force production in fact declined.
Clinical Relevance
This study demonstrates that the inhibition of 5-LOX, COX-1, and COX-2 modulates the healing process of repaired rotator cuff tendons. Although further studies are necessary, the treatment of patients with licofelone after cuff repair may improve the development of a stable enthesis and enhance postoperative outcomes.
The transcription factor CCAAT/enhancer-binding protein ␣ (C/EBP␣) is required during adipogenesis for development of insulin-stimulated glucose uptake. Modes for regulating this function of C/EBP␣ have yet to be determined. Phosphorylation of C/EBP␣ on Ser-21 has been implicated in the regulation of granulopoiesis and hepatic gene expression. To explore the role of Ser-21 phosphorylation on C/EBP␣ function during adipogenesis, we developed constructs in which Ser-21 was mutated to alanine (S21A) to model dephosphorylation. In two cell culture models deficient in endogenous C/EBP␣, enforced expression of S21A-C/EBP␣ resulted in normal lipid accumulation and expression of many adipogenic markers. However, S21A-C/ EBP␣ had impaired ability to activate the Glut4 promoter specifically, and S21A-C/EBP␣ expression resulted in diminished GLUT4 and adiponectin expression, as well as reduced insulinstimulated glucose uptake. No defects in insulin signaling or GLUT4 vesicle trafficking were identified with S21A-C/EBP␣ expression, and when exogenous GLUT4 expression was enforced to normalize expression in S21A-C/EBP␣ cells, insulin-responsive glucose transport was reconstituted, suggesting that the primary defect was a deficit in GLUT4 levels. Mice in which endogenous C/EBP␣ was replaced with S21A-C/EBP␣ displayed reduced GLUT4 and adiponectin protein expression in epididymal adipose tissue and increased blood glucose compared with wild-type littermates. These results suggest that phosphorylation of C/EBP␣ on Ser-21 may regulate adipocyte gene expression and whole body glucose homeostasis.Although adipocytes were initially thought to be passive storage vessels for caloric excess, it is now known that adipose tissue acts as an important metabolic and endocrine organ (1-4). One of the major regulatory hormones for fat cell function is insulin, which regulates whole body energy balance by increasing glucose uptake into muscle and adipose tissue via translocation of the glucose transporter GLUT4 to the cell surface and by inhibiting hepatic gluconeogenesis (4 -7). Several studies have identified C/EBP␣ 2 as a critical factor for development of insulin-sensitive glucose uptake in developing adipocytes (8 -11).Adipogenesis is a coordinated transcriptional cascade of gene expression regulated by many transcription factors, including PPAR␥ and members of the C/EBP and KLF families of transcription factors (12-17). Mouse models suggest that C/EBP␣ and PPAR␥ are each required for complete development of adipose tissue in vivo (18 -20). In vitro cell culture studies determined that although constitutive expression of either PPAR␥ or C/EBP␣ is sufficient to convert fibroblasts into fatladen, adipocyte-like cells (21), C/EBP␣ is required for the establishment of insulin-stimulated glucose uptake in adipocytes (10, 11). In both C/EBP␣ Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) and NIH-3T3 fibroblasts, which are also deficient in C/EBP␣, overexpression of PPAR␥ is sufficient to induce lipid accumulation, but these "adipocytes" do not transpo...
Background Nonadherence to postoperative therapy protocols can adversely affect the outcome after flexor tendon surgery. In this study, we hypothesize that patients with partial or no insurance coverage for their aftercare are less likely to attend postoperative therapy sessions and have a higher incidence of a poorer outcome than those who have full insurance coverage. Methods We analyzed 159 patients with flexor tendon injuries at a level 1 trauma center. Demographic variables along with the clinical outcome data were collected and cross-tabulated. Associations among descriptive and clinical variables were assessed using Fisher's Exact tests and chi-square analyses. Comparisons for continuous variables were performed using the Kruskal-Wallis Test. Results Eighteen patients (11.3 %) had an injury in zone 1, followed by 68 (42.8 %) in zone 2, 15 (9.4 %) in zone 3, 9 (5.7 %) in zone 4, 38 (23.9 %) in zone 5, and 11 (6.9 %) in zone 6. Patients completed 8.2 therapy sessions on average. Patients had state assistance program (40.3 %), private insurance (35.2 %), Medicaid/Medicare (11.3 %), worker's compensation (8.8 %) insurance, or paid themselves (13.2 %). Fifty-three (33.3 %) patients had excellent outcomes, 46 (29 %) had good, 40 (25 %) had fair, and 20 (12.5 %) had a poor outcome. Patients responsible to pay for their aftercare were significantly less likely to be adherent to therapy and had poorer outcomes than those with full coverage. Conclusion Patients responsible for the pay of their postoperative rehabilitation are less likely to participate in therapy and may be at a higher risk of having a poor outcome.
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