Effects of Isometric Quadriceps Muscle Exercise with Visual and Auditory Feedback at 1 Year after Total Knee Arthroplasty.

OBJECTIVE: To examine the effect of isometric quadriceps exercises with visual and auditory feedback after total knee arthroplasty (TKA). METHODS: The sample included 41 patients from our previous study who could be followed up for 1 year after TKA. Patients in the intervention group performed isometric quadriceps exercises with visual and auditory feedback using the quadriceps training machine from the 2nd to the 14th day after TKA, whereas those in the control group underwent standard postoperative rehabilitation (without visual or auditory feedback during isometric quadriceps exercises) in the hospital. Patients were evaluated for pain intensity, timed up and go test (TUG) score, 10-m gait speed, 6-minute walking distance (6MWD), and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score 1 year after TKA. Additionally, exercise habits and responses to the International Physical Activity Questionnaire (IPAQ) were investigated. RESULTS: Pain intensity was significantly lower in the intervention group than in the control group. Greater improvements in the TUG test scores, 10-m gait speed, 6MWD, and WOMAC scores were observed in the intervention group. Walking activity, as recorded by the IPAQ, and the proportion of patients with exercise habits were significantly higher in the intervention group than in the control group. CONCLUSIONS: These results suggest that performing isometric quadriceps exercise with visual and auditory feedback using the quadriceps training machine has good effects, such as pain reduction, physical function improvement, exercise tolerance, and increased physical activity at 1 year after TKA.

Short-Term Effects of Isometric Quadriceps Muscle Exercise with Auditory and Visual Feedback on Pain, Physical Function, and Performance after Total Knee Arthroplasty: A Randomized Controlled Trial.

Severe acute pain after total knee arthroplasty (TKA) may cause delay in muscle strength and functional recovery, and it is a risk factor for chronic postoperative pain. Although pharmacological approaches are the typical firstline to treat acute pain; recently, nonpharmacological approaches such as exercise have been increasingly applied. The purpose of this investigation was to evaluate the effects of a rehabilitation program involving isometric quadriceps exercise with auditory and visual feedback to improve the short-term outcome after TKA. Sixty-two patients, planning a primary unilateral TKA, were randomly assigned to either an intervention group (n = 31) involving isometric quadriceps exercise with auditory and visual feedback in usual rehabilitation after TKA or a control group (n = 31) involving a standardized program for TKA. Patients in the intervention group performed the isometric quadriceps muscle exercise using the Quadriceps Training Machine from 2 to 14 days after TKA instead of the traditional quadriceps sets. Pain intensity, isometric knee extension strength, range of motion, timed up and go test (TUG), 10-m gait speed, 6-minute walking distance, the Western Ontario and McMaster University Osteoarthritis index (WOMAC), the hospital anxiety and depression scale, and the pain catastrophizing scale were assessed before TKA (baseline) and 1 to 3 weeks after TKA. Pain intensity significantly decreased in the intervention group than in the control group at 1 (p = 0.005), 2 (p = 0.002), and 3 (p = 0.010) weeks after TKA. Greater improvements in TUG (p = 0.036), 10-m gait speed (p = 0.047), WOMAC total score (p = 0.017), pain (p = 0.010), and function (p = 0.028) 3 weeks after TKA were observed in the intervention group. These results suggest that isometric quadriceps exercises with auditory and visual feedback provided early knee pain relief, possibly leading to better improvements in physical performance, and patient's perception of physical function in the early stages of postoperative TKA. Further studies should investigate whether this short-term effect is sustainable.

Autocrine/paracrine role of the angiopoietin-1 and -2/Tie2 system in cell proliferation and chemotaxis of cultured fibroblastic synoviocytes in rheumatoid arthritis.

Hypervascularity is a characteristic synovial feature of rheumatoid arthritis (RA). We previously reported that Tie1 and Tie2, endothelium-specific tyrosine kinase receptors essential for angiogenesis, are expressed not only by vascular cells, but also by a subpopulation of synovial lining and stromal cells in the inflamed RA synovium. The present study used immunohistochemistry and in situ hybridization to examine whether angiopoietin-1 and -2 (Ang1 and Ang2), ligands for Tie2, are also expressed in the RA synovium. Ang1 and Ang2 were expressed in all of 15 RA synovial samples, and their distribution pattern was similar to that of Tie2. Intense staining was noted in synovial lining and stromal cells, as well as in small vessels in areas of papillary projection and high cell density. Double immunohistochemistry revealed coexpression of Ang1, Ang2, and Tie2 in synovial components exhibiting proliferating cell nuclear antigen immunoreactivity. In addition, Ang1 and Ang2 were preferentially expressed in vimentin-positive fibroblastic cells. To address the functional role of Ang/Tie signaling in RA pathophysiology, we carried out [(3)H]thymidine incorporation and transwell chemotaxis assays using cultured fibroblastic synoviocytes obtained from 2 RA patients. Incubation with various concentrations of recombinant Ang1 or Ang2 did not alter DNA synthesis, but the ligands enhanced chemotactic migration of RA fibroblastic synoviocytes. Our results suggest that the autocrine/paracrine signaling of the Ang/Tie2 system is important for the up-regulated angiogenesis in the RA synovium, as well as for synoviocyte behavior, by regulating chemotactic cell movement.

P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain.

UNLABELLED: The paired-like homeoprotein, Cart1, is involved in skeletal development. We describe here that the general coactivator p300/CBP controls the transcription activity of Cart1 through acetylation of a lysine residue that is highly conserved in other homeoproteins. Acetylation of this residue increases the interaction between p300/CBP and Cart1 and enhances its transcriptional activation. INTRODUCTION: Cart1 encodes a paired-like homeoprotein expressed selectively in chondrocyte lineage during embryonic development. Although its target gene remains unknown, gene disruption studies have revealed that Cart1 plays an important role for craniofacial bone formation as well as limb development by cooperating with another homeoprotein, Alx4. In this report, we study the functional involvement of p300/CBP, coactivators with intrinsic histone acetyltransferase (HAT) activity, in the transcriptional control of Cart1. METHODS: To study the transcription activity of Cart1, a reporter construct containing a putative Cart1 binding site was transiently transfected with the expression vectors of each protein. The interaction between p300/CBP and Cart1 was investigated by glutathione S-transferase (GST) pull-down, yeast two-hybrid, and immunoprecipitation assays. In vitro acetylation assay was performed with the recombinant p300-HAT domain and Cart1 in the presence of acetyl-CoA. RESULTS AND CONCLUSIONS: p300 and CBP stimulate Cart1-dependent transcription activity, and this transactivation is inhibited by E1A and Tax, oncoproteins that suppress the activity of p300/CBP. Cart1 binds to p300 in vivo and in vitro, and this requires the homeodomain of Cart 1 and N-terminal 139 amino acids of p300. Confocal microscopy analysis shows that Cart1 recruits overexpressed and endogenous p300 to a Cart1-specific subnuclear compartment. Cart1 is acetylated in vivo and sodium butyrate and trichostatin A, histone deacetylase inhibitors, markedly enhance the transcription activity of Cart1. Deletion and mutagenesis analysis identifies the 131st lysine that locates immediately adjacent to the homeodomain as a target of p300-HAT, and a point mutation to this residue attenuates the binding affinity to p300 as well as p300-dependent transcription activity. Together, these results indicate that p300/CBP acts as a cotransactivator to Cart1 through a direct interaction and specific lysine acetylation. In addition, because 131st lysine is highly conserved in other types of homeoprotein, this lysine may be a common target for HAT of p300/CBP for these proteins.

A histone deacetylase inhibitor enhances killing of undifferentiated thyroid carcinoma cells by p53 gene therapy.

Mutation of the p53 tumor suppressor gene is recognized to be a key event in the development of the highly aggressive behavior of undifferentiated or anaplastic thyroid carcinomas. Attempts to treat these carcinomas with p53 gene therapy have, however, been largely unsuccessful. Since epigenetic changes such as histone deacetylation are associated with loss of thyroid differentiation, we have evaluated the potential of combining p53 gene therapy with exposure to the histone deacetylase inhibitor (HDAC-1), depsipeptide. We used two carcinoma cell lines: FRO cells that express very low levels of p53 and WRO cells producing a dominant negative p53. A p53 response element luciferase assay showed that stimulation of p53 transcriptional activity by the combined treatment with the HDAC-1 and p53 was 10 to 100 times greater than with p53 alone. Western blot analysis demonstrated that the HDAC-1 increased the expression of acetylated histones, as well as of p21(cip1/waf1), but did not affect levels of total histone and endogenous p53. The combined treatment was much more effective than either treatment alone in inhibiting the growth of both cell lines, and flow cytometric analysis suggested that this was due to an increase in the sub-G1 apoptotic population. Our findings indicate that HDAC-1 enhances apoptotic killing by p53 transfer, and suggest that this combination strategy may be useful in treating undifferentiated thyroid carcinomas.

Functional domains of paired-like homeoprotein Cart1 and the relationship between dimerization and transcription activity.

BACKGROUND: Cart1 encodes the paired-like homeodomain in the central portion of the gene, and plays a crucial role in the developmental lineage of bone and cartilage, especially in head formation. However, its transactivation mechanism is still poorly understood, including the target gene. Here, we report biochemical dissections of Cart1 functional domains and a relationship between dimerization and transcription activity. RESULTS: Deletion studies of GAL4-fused Cart1 indicated that the transactivation domain is located in the middle portion of the C-terminal domain, but the N-terminal is also required for a full activation of the consensus palindromic binding site (TAATNNNATTA). Analysis of the basic amino acid residues at both ends of the homeodomain revealed that both sides act as nuclear localization signals, and are necessary for the cooperative binding to the palindromic sequence. In this study, two additional Cart1 isoforms that behave as dominant negatives were identified from rat chondrosarcoma cells. These isoforms suppressed the transcription activity of the wild-type, despite loss of DNA binding ability, and could interact with the wild-type in yeast. Finally, we demonstrated that wild-type Cart1 forms a DNA-independent homodimer in in vivo conditions, and that the transactivation of wild-type Cart1 was suppressed by the N- or C-terminal domain which was expressed in the nucleus. CONCLUSION: These results revealed that homodimerization through direct interaction is necessary for the potent transcription activity of Cart1.