Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures

The basic mechanisms by which strontium ranelate acts on bone are still unclear. We show that an important action of strontium salts is to block calcification in cultures of osteoblasts, the bone-forming cells. These results suggest that strontium treatment could have previously overlooked effects on bone

Sedentary behaviour is associated with increased long-term cardiovascular risk in patients with rheumatoid arthritis independently of moderate-to-vigorous physical activity

Background Rheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). The physical dysfunction symptomatic of RA means people living with this disease spend large periods of the day sedentary, which may further elevate their risk of CVD. The primary aim of this study was to investigate relationships between objectively assessed sedentary behaviour patterns and light physical activity (LPA) with 10-year risk of CVD. Secondary aims were to explore the role of sedentary behaviour patterns and LPA for individual CVD risk factors and functional disability in RA. The extent to which associations were independent of moderate-to-vigorous physical activity (MVPA) engagement was also examined. Methods Baseline data from a subsample of participants recruited to the Physical Activity in Rheumatoid Arthritis (PARA) study were used to answer current research questions. Sixty-one patients with RA (mean age (± SD) = 54.92 ± 12.39 years) provided a fasted blood sample and underwent physical assessments to evaluate factors associated with their cardiovascular health. Sedentary behaviour patterns (sedentary time, sedentary bouts, sedentary breaks), LPA and MVPA were measured via 7-days of accelerometry. Ten-year CVD risk was computed (Q-risk-score2), and functional disability determined via questionnaire. Results Regressions revealed significant positive associations between sedentary time and the number of sedentary bouts per day ≥20 min with 10-year CVD risk, with the reverse true for LPA participation. Associations were independent of MVPA engagement. Conclusions Promoting LPA participation and restricting sedentary bouts to <20 min may attenuate long-term CVD risk in RA, independent of MVPA engagement

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions

Binary systems and their nuclear explosions

Peer ReviewedPreprin

Acupuncture in the treatment of rheumatoid arthritis: a double-blind controlled pilot study

<p>Abstract</p> <p>Background</p> <p>In planning a randomized controlled trial of acupuncture, we conducted a pilot study using validated outcome measures to assess the feasibility of the protocol, and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis (RA).</p> <p>Methods</p> <p>The study employs a randomized, prospective, double-blind, placebo-controlled trial to evaluate the effect of electroacupuncture (EA), traditional Chinese acupuncture (TCA) and sham acupuncture (Sham) in patients with RA. All patients received 20 sessions over a period of 10 weeks. Six acupuncture points were chosen. Primary outcome is the changes in the pain score. Secondary outcomes included the changes in the ACR core disease measures, DAS 28 score and the number of patients who achieved ACR 20 at week 10.</p> <p>Results</p> <p>From 80 eligible patients, 36 patients with mean age of 58 ± 10 years and disease duration of 9.3 ± 6.4 years were recruited. Twelve patients were randomized to each group. Twelve, 10 and 7 patients from the EA, TCA and Sham group respectively completed the study at 20 weeks (p < 0.03); all except one of the premature dropouts were due to lack of efficacy. At week 10, the pain score remained unchanged in all 3 groups. The number of tender joints was significantly reduced for the EA and TCA groups. Physician's global score was significantly reduced for the EA group and patient's global score was significantly reduced for the TCA group. All the outcomes except patient's global score remained unchanged in the Sham group.</p> <p>Conclusion</p> <p>This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for RA.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00404443</p

Monocyte Scintigraphy in Rheumatoid Arthritis: The Dynamics of Monocyte Migration in Immune-Mediated Inflammatory Disease

Background: Macrophages are principal drivers of synovial inflammation in rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disease. Conceivably, synovial macrophages are continuously replaced by circulating monocytes in RA. Animal studies from the 1960s suggested that macrophage replacement by monocytes is a slow process in chronic inflammatory lesions. Translation of these data into the human condition has been hampered by the lack of available techniques to analyze monocyte migration in man. Methods/Principal Findings: We developed a technique that enabled us to analyze the migration of labelled autologous monocytes in RA patients using single photon emission computer tomography (SPECT). We isolated CD14+ monocytes by CliniMACS in 8 patients and labeled these with technetium-99m (99m-Tc-HMPAO). Monocytes were re-infused into the same patient. Using SPECT we calculated that a very small but specific fraction of 3.4x10(-3) (0.95-5.1x10(-3)) % of re-infused monocytes migrated to the inflamed joints, being detectable within one hour after re-infusion. Conclusions/Significance: The results indicate monocytes migrate continuously into the inflamed synovial tissue of RA patients, but at a slow macrophage-replacement rate. This suggests that the rapid decrease in synovial macrophages that occurs after antirheumatic treatment might rather be explained by an alteration in macrophage retention than in monocyte influx and that RA might be particularly sensitive to treatments targeting inflammatory cell retention

Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways

Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through -3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis

Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA