Osteochondral angiogenesis and increased protease inhibitor expression in OA

SummaryObjectiveNormal cartilage is resistant to vascular invasion and anti-angiogenic protease inhibitors may contribute to its avascular status. We hypothesized that dysregulated expression of four key anti-angiogenic protease inhibitors may contribute to increased osteochondral vascularity in osteoarthritis (OA).DesignMedial tibial plateaux from OA patients (n=40) were compared with those from non-arthritic controls collected post-mortem (PM, n=10). Immunohistochemistry was performed for protease inhibitors TIMP-1, TIMP-3, PAI-1 and SLPI and the pro-angiogenic factor vascular endothelial growth factor (VEGF). Immunoreactivity in articular chondrocytes was scored. Chondropathy was measured as a modified Mankin score, and osteochondral vascular density as number of channels crossing each mm of tidemark. Non-parametric analyses were used for all data.ResultsAll protease inhibitors and VEGF were localised to chondrocytes near the articular surface, less often in the middle zone, and rarely to deep chondrocytes. Scores for VEGF, TIMP-1, TIMP-3, SLPI and PAI-1 were all increased in OA compared with PM, and higher scores were associated with greater chondropathy. Chondrocyte expression of VEGF was associated with higher osteochondral vascular density (r=0.32, P<0.05), whereas protease inhibitors were not.ConclusionsThe resistance of normal articular cartilage to vascular invasion may be more due to its matrix environment than ongoing protease inhibitor expression. Upregulation of protease inhibitors by superficial chondrocytes in OA may moderate the angiogenic effects of growth factors such as VEGF. However, failure of deep chondrocytes to express anti-angiogenic protease inhibitors may permit vascular invasion into the articular cartilage

Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis

SummaryObjectivesWe hypothesised that osteochondral and synovial angiogenesis in osteoarthritis (OA) are independent processes. We investigated whether indices of osteochondral and synovial angiogenesis display different relationships with synovitis, disease severity and chondrocalcinosis in patients with OA.DesignSynovium and medial tibial plateaux were obtained from 62 patients undergoing total knee joint replacement for OA (18 [29%] had chondrocalcinosis) and from 31 recently deceased people with no evidence of joint pathology post-mortem (PM). Vascular endothelium, proliferating endothelial cells (ECs) and macrophages were quantified by immunohistochemistry for CD34, CD31/Ki67 and CD14, respectively. Grades were assigned for radiographic and histological OA disease severity, clinical disease activity and histological synovitis (based on cellular content of the synovium).ResultsBlood vessels breached the tidemark in 60% of patients with OA and 20% of PM controls. Osteochondral vascular density increased with increasing cartilage severity and clinical disease activity scores, but not with synovitis. Synovial EC proliferation, inflammation and macrophage infiltration were higher in OA than in PM controls. Synovial angiogenesis indices increased with increasing histological synovitis, but were not related to osteochondral vascular density or other indices of OA disease severity. OA changes were more severe in patients with concurrent chondrocalcinosis. Chondrocalcinosis was not associated with increased angiogenesis or histological synovitis beyond that seen in OA alone.ConclusionOsteochondral and synovial angiogenesis appear to be independent processes. Osteochondral vascularity is associated with the severity of OA cartilage changes and clinical disease activity, whereas synovial angiogenesis is associated with histological synovitis. Modulation of osteochondral and synovial angiogenesis may differentially affect OA disease

Central pain mechanisms predict physical inactivity at 1-year in individuals with knee pain

Purpose: Pain is the primary clinical manifestation in individuals with osteoarthritis (OA). It is an unpleasant and distressing experience, particularly during weight-bearing activities, inhibiting activity, and reducing quality of life. Two groups of mechanisms cause OA pain: peripheral (local joint pain from joint pathology) and central (severely worsened pain due to brain and spinal cord processing of peripheral nociceptive inputs). Each contributes to varying extents at different times to an individual’s OA pain. Pain and physical inactivity are often treated by discrete interventions, but in reality are tightly integrated. Several traits linked to central pain processing, such as catastrophising, depression and fatigue, have been independently linked to physical inactivity. This study aimed to explore cross sectional and longitudinal associations between central pain mechanisms and physical inactivity in individuals with knee pain.Methods: This study is an analysis of the first 5,000 participants with validated questionnaire data, aged ≥40 who completed FRAIL in the Investigating Musculoskeletal Health and Wellbeing (IMH&W) cohort (n= >8,570), based in the East Midlands region of the UK. Participants completed a questionnaire at baseline and 1-year later, including participant characteristics and 0 to 10 numerical rating scale (NRS) of pain in the most troublesome joint in the past 4-weeks. Central pain Mechanisms Trait (CMT) was measured using the Central Aspects of Pain in the Knee (CAP-Knee) questionnaire, comprising 8-items addressing anxiety, depression, catastrophising, neuropathic-like pain, fatigue, sleep disturbance, pain distribution and cognitive impact, giving a maximum total score of 16. Self-reported physical activity was measured using the FiND questionnaire item, through which participants report their level of physical activity as either regular (at least 2-4 hours a week) or none/mainly sedentary. Associations were explored using logistic regression models. Data are presented as median (interquartile range), odds ratios (OR), and 95% confidence intervals.Results: 2473 participants completed the FRAIL, of whom 722 participants reported knee as their most troublesome joint and an NRS pain ≥1, of whom 407 participants had self-reported physical activity data also at 1-year. The 722 participants had a median (IQR) age 72 (65-77), with a BMI of 28.08 (24.82-31.64), 55% were female, and 70% reported being regularly physically active at baseline. Median (IQR) CAP-Knee was 8 (5-11) and NRS pain was 6 (4-8). Individuals who did not complete follow-up data had significantly higher baseline NRS pain, CAP-Knee, lower BMI, and were more sedentary. For each unit increase in NRS pain or CAP-Knee at baseline, participants were more likely to be sedentary at baseline (NRS OR=1.25 (95%CI 1.16, 1.36), P<0.001; CAP-Knee OR=1.20 (95%CI 1.14, 1.26), P<0.001) and follow-up (NRS OR=1.17 (95%CI 1.05, 1.30), P=0.004; CAP-Knee OR=1.15 (95%CI 1.08, 0.93), P<0.001). When adjusted for potential confounders age, sex, BMI, knee replacement the association between baseline CAP-Knee and baseline physical activity remained significant (aOR=1.19 (95%CI 1.13, 1.25) P<0.001, Table 1), and significantly predicted 1-year physical inactivity (aOR=1.13, (95%CI 1.06, 1.21) P<0.001, Table 2). The depression item was the only CAP-Knee item significantly associated with physical activity levels in both cross-sectional and longitudinal analyses. Baseline fatigue was significantly associated with baseline physical activity.Conclusions: Higher scores for baseline central pain mechanisms were associated with lower baseline physical activity and predicted 1-year physical inactivity. Our data highlight the integration between pain and physical activity. The observed associations between central pain mechanisms and physical activity might indicate shared neurological mechanisms, and central pain mechanisms might also act as barriers to increasing activity. Specific central mechanisms, particularly depression and fatigue, might be important targets to help improve physical activity in people with knee pain

Environment-Induced Decoherence and the Transition From Quantum to Classical

We study dynamics of quantum open systems, paying special attention to those aspects of their evolution which are relevant to the transition from quantum to classical. We begin with a discussion of the conditional dynamics of simple systems. The resulting models are straightforward but suffice to illustrate basic physical ideas behind quantum measurements and decoherence. To discuss decoherence and environment-induced superselection einselection in a more general setting, we sketch perturbative as well as exact derivations of several master equations valid for various systems. Using these equations we study einselection employing the general strategy of the predictability sieve. Assumptions that are usually made in the discussion of decoherence are critically reexamined along with the ``standard lore'' to which they lead. Restoration of quantum-classical correspondence in systems that are classically chaotic is discussed. The dynamical second law -it is shown- can be traced to the same phenomena that allow for the restoration of the correspondence principle in decohering chaotic systems (where it is otherwise lost on a very short time-scale). Quantum error correction is discussed as an example of an anti-decoherence strategy. Implications of decoherence and einselection for the interpretation of quantum theory are briefly pointed out.Comment: 80 pages, 7 figures included, Lectures given by both authors at the 72nd Les Houches Summer School on "Coherent Matter Waves", July-August 199

A clinical assessment tool to improve the use of pain relieving treatments in knee osteoarthritis

Purpose: Approximately 1 in 4 individuals in the UK over the age of 55 experience knee pain (KP), predominantly due to osteoarthritis (OA). Following treatment targeted at the affected knee, pain relief is reported in only 60%–80% of individuals with painful knee OA. This suggests that mechanisms occurring within the central nervous system (central mechanisms) also influence the KP experience. Although reduced pressure pain detection thresholds (PPTs) at sites distal to the affected joint can indicate central mechanisms, application of PPTs to clinical practice and population-based studies is limited. A feasible, validated questionnaire-based tool to help identify people with KP who may benefit more from centrally acting treatments could prove useful. This study aimed to develop a self-report scale which represents traits associated with central mechanisms in people with KP.Methods: Participants: 9506 individuals completed the Knee Pain and related health In the Community (KPIC) baseline survey. 2152 participants reporting KP were included in this study. 322 individuals with current KP and 98 with no pain undertook PPT assessment at the proximal tibia, distal to the index knee. Questionnaires: The KPIC baseline survey included self-report questionnaires for pain catastrophizing (Pain Catastrophizing Scale), pain patterns (ICOAP), neuropathic-like pain (modified pain DETECT), quality of life (SF-12), and mental health (Hospital Anxiety and Depression Scale). Also included were individual questions addressing the presence and onset of KP, pain severity, risk factors for KP and/or OA, fatigue, cognitive impact, pain distribution (Manikin), sleep. Item Selection: Items related to central mechanisms were selected according to predefined criteria (See Fig. 1): (i) strength of association to constructs measured by the host scale, using exploratory structural equation modelling (ESEM); (ii) expert opinion on relevance to central mechanisms (inter-rater agreement k* ≥ 0.60); (iii) adequate targeting indicated b