Differential matrix degradation and turnover in early cartilage lesions of human knee and ankle joints

OBJECTIVE: To determine whether there are differences in matrix turnover within early cartilage lesions of the ankle (talocrural) joint compared with the knee (tibiofemoral) joint that may help explain differences in the prevalence of osteoarthritis in these 2 joints. METHODS: Cartilage removed from lesions of the tali and femoral condyles was analyzed for type IIB collagen messenger RNA, C-terminal type II procollagen propeptide (CPII), the collagenase cleavage neoepitope (Col2-3/4C(short)), and the denaturation epitope (Col2-3/4m). The content of collagen, glycosaminoglycan, and epitope 846 of aggrecan was quantitated. RESULTS: In ankle lesions, there was an up-regulation of markers of synthesis (CPII [P = 0.07]; epitope 846 [P < or = 0.0001]), but these were down-regulated in the knee (CPII [P = 0.1]; epitope 846 [P = 0.004]). In lesions of the knee, but not the ankle, there was an up-regulation of collagen degradation markers (P = 0.008). On a molar basis, there was 24 times more cleavage epitope than denaturation epitope in knee lesions compared with ankle lesions. CONCLUSION: The up-regulation of matrix turnover that is seen in early cartilage lesions of the ankle would appear to represent an attempt to repair the damaged matrix. The increase in collagen synthesis and aggrecan turnover seen in ankle lesions is absent from knee lesions. Instead, there is an increase in type II collagen cleavage. Together with the differences in collagen denaturation, these changes point to an emphasis on matrix assembly during early lesion development in the ankle and to degradation in the knee, resulting in fundamental differences in matrix turnover in these lesions.     

Effectiveness of a pedometer-based program using a socio-cognitive intervention on physical activity and quality of life in a setting of cardiac rehabilitation

Background

Physical activity contributes to improve health and quality of life. However, the prevalence of sedentary lifestyle is elevated after an acute coronary syndrome.

Methods

A randomized controlled trial was performed to evaluate the impact of a pedometer-based program associated with a socio-cognitive intervention on physical activity behaviour, cardiovascular risk factors, and quality of life during the year after an acute coronary syndrome event. During hospitalization, we randomized 32 patients to an experimental group and 33 patients to a usual care group. The experimental intervention included 6 consultations with a clinical nurse specialist during 12 months.

Results

Groups characteristics were comparable. At baseline, the percentage of participants considered in the active range category was similar between groups (31% vs 41%; P = 0.915). However, the proportion of participants who were still active was greater in the experimental group than in the usual care group at 6, 9, and 12 months follow-up (75% vs 41%; 68% vs 36%, and 83% vs 55%, respectively; P < 0.05). After 12 months, changes in overall quality of life and in health and the functioning scores were different between groups (interaction effects [groups by time] P = 0.048 and P = 0.036, respectively).

Conclusions

The use of a pedometer concomitantly with a socio-cognitive intervention improves adherence to physical activity and quality of life during the year after an acute coronary syndrome event. This finding is relevant because physical activity and quality of life are a great concern in preventive cardiology. These results support applying this innovative approach in cardiac rehabilitation programs.     

Effects of tenidap on canine experimental osteoarthritis i. morphologic and metalloprotease analysis

Objective. To examine the effects of tenidap and diclofenac on osteoarthritic lesions and metalloprotease activity in experimental osteoarthritis (OA). Methods. The anterior cruciate ligament of the right stifle joint of 25 mongrel dogs was sectioned by a stab wound. Seven dogs received no treatment, 6 were treated with oral omeprazole (20 mg/day), another 6 were treated with diclofenac (0.25 mg/kg/twice daily) plus omeprazole (20 mg/day), and 6 received oral tenidap (3 mg/kg/twice daily) plus omeprazole (20 mg/day). The dogs received medication for 8 weeks; all dogs were killed at the end of this period. Eight normal dogs were used as controls. Lesions were evaluated macroscopically for the incidence and size of osteophytes and the area and grade of cartilage erosions on the condyles and plateaus, along with histologic evaluation of the severity of the cartilage lesions and synovial inflammation. Stromelysin and collagenase activities and the collagenase messenger RNA (mRNA) level were measured in cartilage and synovial membrane. Results. Compared with the untreated or omeprazole-treated OA groups, the dogs treated with tenidap exhibited significant reduction in the incidence (P < 0.001) and size (P < 0.0001) of osteophytes. Tenidap also significantly decreased the size and grade of cartilage macroscopic lesions, as well as the histologic severity of cartilage lesions on both condyles and plateaus. The histologic severity of synovial inflammatory reaction was also significantly reduced (P < 0.003) in the tenidap group. Tenidap markedly decreased stromelysin and collagenase activity in both cartilage (stromelysin P < 0.003; collagenase P < 0.01) and synovial membrane (stromelysin P < 0.003; collagenase P < 0.005). Moreover, tenidap also decreased the collagenase mRNA level in cartilage (P < 0.005) and synovial membrane (P < 0.002). Diclofenac slightly reduced the incidence and size of osteophytes and cartilage lesions, but these changes were not statistically significant. Diclofenac had no effect on the severity of synovial inflammation, metalloprotease activity, or collagenase expression. Conclusion. This study showed that tenidap had a more potent anti-osteoarthritic effect than diclofenac in this model. The effect of the drug in suppressing metalloprotease synthesis, a process known to play a major role in the pathophysiology of osteoarthritic lesions, may explain its mechanism of action.     

Improvement in rejection of human decay accelerating factor transgenic pig-to-primate renal xenografts with administration of rabbit antithymocyte serum

BACKGROUND: Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressive regimen. METHODS: Nine baboons received life-supporting heterotopic single-kidney transplants from human decay accelerating factor transgenic pigs. Immunosuppression consisted of GAS (a galactosyl alpha-1,3-galactose analog), cyclosporine, and steroids. Group 1 (n=2) was also treated with CyP and a rapamycin derivative (RAD), group 2 (n=4) received RATS and RAD, and group 3 (n=3) received only RATS. Animals were maintained until death or sacrifice because of uncontrollable rejection or other complications. Graft histopathology was assessed at the study endpoint. RESULTS: Mean survival was 28+/-11.3 days, 23+/-2.5 days, and 20+/-2.5 days for groups 1, 2, and 3 (not significant). Graft rejection was the cause of death in both CyP-treated animals. One RATS-treated animal died of rejection; the others died of infections or bleeding. Two RATS-treated animals developed posttransplant lymphoproliferative disorder, and one died of cytomegalovirus pneumonitis. Histopathology revealed severe AHXR in group 1 kidneys, involving 100+/-0% of the tissue examined. In contrast, AHXR was reduced in groups 2 and 3, involving 21+/-14% and 18+/-28%, respectively, of the tissue examined (P<0.01). CONCLUSIONS: Substitution of RATS for CyP was well tolerated and resulted in reduced severity of AHXR in this model. Complications seen in RATS-treated animals may be preventable through the use of standard prophylaxis for infections. Our data suggest that further studies are warranted to explore the use of antilymphocyte agents in xenotransplantation.     

Expression of N-terminally truncated isoforms of CDP/CUX is increased in human uterine leiomyomas

Genetic analyses and mRNA expression studies have implicated CUTL1 as a candidate tumor-suppressor gene in uterine leiomyomas and breast cancers. However, modulation of CDP/Cux, the protein encoded by CUTL1, does not agree with this notion. The activity of CDP/Cux, which is the DNA binding subunit of HiNF-D, was upregulated as normal cells progressed into S phase and constitutively elevated in several tumor cell lines. Activation of CDP/Cux at the G(1)/S transition involved the proteolytic processing of the protein to generate a shorter isoform. Uterine leiomyomas represent a unique reagent for molecular analysis because they are resected as homogeneous tumor tissue together with the adjacent normal myometrium and they are often very large. In the present study, proteins were isolated from 16 pairs of matched tumors and adjacent myometrium and analyzed by Western blot and electrophoretic mobility shift assays. Strikingly, in 11/16 tumors, the steady-state level of small CDP/Cux isoforms was increased compared to normal control tissue. Where tested, a corresponding increase in CDP/Cux stable DNA binding activity was observed. DNA sequencing analysis of CUTL1 cDNAs from 6 leiomyomas, including 4 with LOH of CUTL1, did not reveal any gross rearrangement or point mutations. Altogether these findings suggest that CUTL1 is probably not the tumor suppressor on 7q22. Moreover, the frequent increase in smaller CDP/Cux isoforms indicates that molecular events associated with the truncation of CDP/Cux proteins may be selected in uterine leiomyomas.