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Purpose: Exercise therapy with a focus on muscle strengthening has proven to be effective for the management of knee osteoarthritis (OA). Yet it is not known whether high-intensity resistance training (RT) is more effective in improving upper leg muscle strength and physical performance than low-intensity RT. Still, there is some controversy regarding the effectiveness of high-intensity RT and whether or not it is harmful, for instance by accelerating cartilage degeneration, osteophyte formation, or increasing synovitis. Any catabolic or anabolic response of musculoskeletal tissue to RT might first be visible on a biochemical level before changes in clinical symptoms are measurable. Serum biomarkers can objectively measure early biochemical changes and assess whether RT leads to a more anabolic or catabolic response. The aim of this study is to assess (i) whether high-intensity RT elicits a different response (e.g. catabolic) on systemic inflammation and musculoskeletal tissues in and surrounding the joint, including bone, cartilage, muscle, and synovial tissue compared to low-intensity RT; and (ii) whether there is an association between changes in serum levels of inflammatory and musculoskeletal tissue-derived biomarkers and improvements in clinical outcomes (performance-based tests and self-reported outcomes on pain and activity limitations).Methods: In a randomized controlled trial, 177 participants with knee OA conducted a high-intensity (70%-80% of the Repetition Maximum (1RM)) or low-intensity (40%-50% 1RM) RT program 3 times a week for 12 weeks. Measures of clinical outcomes and serum samples were collected at the start of RT (pre-intervention), after 3 months at the end of RT (post-intervention), and 6 months after RT (follow-up). As a reflection of systemic inflammation (CRP), synovitis (CRPM, C3M), bone turnover (OC, CTX-I), cartilage turnover (PRO-C2, C2M, huARGS), muscle turnover (PRO-C3, PRO-C6), and cell behaviour (col10neo) a total of eleven serum biomarkers were analysed. With the exception of CRP, which was determined with an immunoturbidimetric assay, ELISA assays were used to quantify serum levels of the other 10 serum biomarkers. The primary outcome measures are the changes in serum biomarker levels. Other outcome measures include upper leg muscle strength, performance-based tests, and self-reported outcomes on pain and activity limitations.Results: High-intensity RT resulted in greater improvements in muscle strength compared to low-intensity RT when measured by the estimated 1RM. No significant differences between groups were found for upper leg muscle strength (Nm/kg) when measured with an isokinetic dynamometer. Both groups showed similar improvements in pain and physical functioning. Although there is no difference between groups in clinical outcomes, except for the estimated 1RM, we expect that participants in the high-intensity RT group are more likely to have enhanced serum levels of catabolic biomarkers than participants in the low-intensity RT group. Since both the high-intensity RT group and low-intensity RT group improved over time, we expect that changes in serum biomarker levels are associated with overall improvements in clinical outcomes. Almost all participants had normal CRP values (Conclusions: The work to date on CRP serum levels suggests that RT did not influence CRP levels. This result may be explained by the high percentage of participants with normal CRP levels (

OBJECTIVE: To investigate whether an exercise program, initially focusing on knee stabilization and subsequently on muscle strength and performance of daily activities is more effective than an exercise program focusing on muscle strength and performance of daily activities only, in reducing activity limitations in patients with knee osteoarthritis (OA) and instability of the knee joint.DESIGN: A single-blind, randomized, controlled trial involving 159 knee OA patients with self-reported and/or biomechanically assessed knee instability, randomly assigned to two treatment groups. Both groups received a supervised exercise program for 12 weeks, consisting of muscle strengthening exercises and training of daily activities, but only in the experimental group specific knee joint stabilization training was provided. Outcome measures included activity limitations (Western Ontario and McMaster Universities Osteoarthritis Index - WOMAC physical function, primary outcome), pain, global perceived effect and knee stability.RESULTS: Both treatment groups demonstrated large (∼20-40%) and clinically relevant reductions in activity limitations, pain and knee instability, which were sustained 6 months post-treatment. No differences in effectiveness between experimental and control treatment were found on WOMAC physical function (B (95% confidence interval - CI) = -0.01 (-2.58 to 2.57)) or secondary outcome measures, except for a higher global perceived effect in the experimental group (P = 0.04).CONCLUSIONS: Both exercise programs were highly effective in reducing activity limitations and pain and restoring knee stability in knee OA patients with instability of the knee. In knee OA patients suffering from knee instability, specific knee joint stabilization training, in addition to muscle strengthening and functional exercises, does not seem to have any additional value. Dutch Trial Register (NTR) registration number: NTR1475.

Purpose: To explore associations between tissue abnormalities (bone marrow lesions, effusion, synovitis, cartilage loss and osteophytes) visualised by MRI, with both biomechanical impairments (proprioceptive inaccuracy, laxity, quadriceps and hamstrings weakness) and clinical symptoms (pain, stiffness, activity limitations and crepitus) in a cohort of patients with knee osteoarthritis (OA). Methods: Cross-sectional study in 105 patients with knee OA from the Amsterdam Osteoarthritis cohort. Multivariable regression analyses were used to explore associations between MRI features in each compartment with OA symptoms. Results: Associations were found between presence of synovitis with quadriceps weakness (p1⁄4.004) and between severity of cartilage loss in the patellafemoral compartment with quadriceps weakness (p1⁄4.035). No associations were found for proprioceptive inaccuracy, laxity and hamstrings weakness. Medial tibiofemoral cartilage loss was the only MRI feature associated with pain and activity limitations. In contrary, all MRI features, except for synovitis, were found to be associated with the presence of crepitus. Conclusions: As we far as we know, this is the first study to find a significant association between synovitis and quadriceps weakness. This relationship was independent of pain severity. It may imply that strategies that decrease inflammation might be valuable to prevent clinical deterioration in OA patients. Since inflammation had not been identified by physical examination in most cases with MRI-assessed synovitis, MRI can play an important role in clinical assessment of knee OA patients.

Purpose: Although a number of bioreductive agents are substrates for purified DT-diaphorase the role of this enzyme in either activation or detoxification of these agents in the whole cell is unclear. The aim of this study was to determine the role of DT-diaphorase in the metabolic activation of E09 under both aerobic and hypoxic conditions. Methods and Materials: A panel of lung cancer cell lines was used and drug sensitivity was determined by clonogenic or tetrazolium-dye-based assays. Activities of DT-diaphorase, cytochrome P450 and cytochrome b5 reductase were determined spectrophotometrically by following the reduction of cytochrome c. Results: Small-cell lung cancer cell lines showed a 600-fold range in DT-diaphorase activities but levels were much higher in three of the four non-small-cell lines. Activities of cytochromes P450 and b5 reductase were much lower than those of DT-diaphorase and showed much less variation between cell lines. There was no relationship between the activities of any of the enzymes and aerobic sensitivity to SR 4233, BCNU and cis-platin. Under aerobic conditions there was a clear correlation between DT-diaphorase activity and sensitivity to E09. The small-cell lines were much more resistant to E09 than the DT-diaphorase rich non-small-cell lines. A doxorubicin resistant variant of one of the small-cell lines (H69LX10) did not show cross resistance to E09 but did show a small degree (3-fold) of cross resistance to SR 4233. Under hypoxic conditions, cell lines with high levels of DT-diaphorase showed only a small increase in sensitivity to E09 (1.5-7 fold); cell lines with low levels of activity showed a 10- 37-fold increase in sensitivity. Conclusion: These results suggest that under hypoxic conditions, E09 is metabolized by 1-electron reducing enzymes to a toxic species. This reduction product is oxygen sensitive but a similar degree of activation is obtained under aerobic conditions in cell lines with high levels of 2-electron reducing DT-diaphorase.