Lessons from animal models of arthritis over the past decade

This review summarizes the major developments in animal models of arthritis in the past decade. It focuses on novel transgenic models, addresses the involvement of cytokines and discusses novel findings in cartilage and bone erosion. It is clear that interest has been raised in the direct arthritogenic role of autoantibodies, apart from T cell involvement, and their interaction with cells through Fcgamma receptors. In addition, a role for IL-6 and IL-17 and Th17 cells seems apparent in most T cell-driven arthritis models, with environmental triggering through Toll-like receptors contributing to this process. Further insights into enzymes involved in cartilage proteoglycan loss in arthritis, as well as mediators regulating bone erosion and bone apposition, have been gained

Evapotranspiration Derived from Satellite Observed Surface Temperatures

Evapotranspiration is calculated from surface temperatures using an energy balance method. This method is sensitive to the temperature difference between the surface and the air above, and somewhat to the windspeed. In this study we consider the influence of the spatial variability of air temperature on the interpretation of surface temperatures. It is argued that small-scale atmospheric variations can be corrected by using temperature and wind data at a height of 50 m. Three models have been used to calculate these 50 m data from standard weather observations. The first model uses a very simple concept of constant temperature and wind over the test area (zero-dimensional). In the second model windspeed is also taken constant, but air temperature is evaluated from the initial vertical temperature in the atmosphere with a one-dimensional slab layer model. The third model is a two-dimensional primitive equations model in which wind velocity is calculated from the geostrophic wind and air temperature similar to model 2. A homogeneous grassland area was selected in the north of the Netherlands close to the sea. Several days in the summer of 1983 with clear skies and winds from the sea were selected. Surface temperatures were derived from the NOAA-7 satellite overpass in the early afternoon using the split-window technique. On most days an almost linear increase of both surface and air temperature is found with increasing distance to the sea. This study reveals that model 1 results in an unrealistic decrease of the calculated evapotranspiration with increasing distance to the coast. Furthermore evapotranspiration is underestimated. The evapotranspiration as calculated with models 2 and 3 is almost constant in the test area and agrees well with measurements. Model 3 gave more scatter, probably due to the fact that uncalibrated wind velocities were used. For practical calculation of evapotranspiration the Priestley-Taylor parameter α is often used. This study shows how this parameter can be derived from satellite observations of surface temperature

Immunocytokines: the long awaited therapeutic magic bullet in rheumatoid arthritis?

Modulatory cytokines such as IL-4 and IL-10 looked promising biologicals, but suffered from poor exposure at the inflamed joints when administered via the patient-friendly subcutaneous route. Immunocytokines have now been engineered with tissue targeting potential and are a possible solution to this problem, although challenges still exist. Local inflammatory processes cause destruction of extracellular matrix (ECM) components, leading to neo-eptitopes, and/or elicit the synthesis of new ECM components. This makes ECM elements interesting targets for antibody-mediated recognition and retention, to achieve higher levels of immunocytokines at the site of therapeutic interference. The study presented by Schwager and colleagues shows that targeted delivery of IL-10 is more efficacious in experimental arthritis. Clinical studies are warranted to show whether this strategy works for all rheumatoid arthritis patients or is better for subgroups with a defined ECM phenotype. In principle, the scFv-targeting system is plastic enough to allow for personalized strategies

Waardebepaling bij financiële herstructurering en de nieuwe WHOA

Geïnspireerd op de Engelse Scheme of Arrangement en het Amerikaanse Chapter 11, is door de regering op 5 juli 2019 het wetsvoorstel voor de Wet homologatie onderhands akkoord ("WHOA") ingediend bij de Tweede Kamer. De WHOA beoogt een regeling voor een gerechtelijk dwangakkoord buiten faillissement te introduceren, hetgeen het reorganiserend vermogen van ondernemingen dient te versterken en onnodige faillissementen te voorkomen. In dit artikel beschouwen de auteurs de belangrijke rol die waardebepaling bij financiële herstructureringen speelt. Ze gaan eerst in op financiële herstructureringen in het algemeen en het doel en de opzet van de WHOA. Vervolgens wordt de rol van waardebepaling binnen het kader van de WHOA uiteengezet en bespreken de auteurs welke vraagstukken zich daarbij in de praktijk kunnen voordoen

Trapped in a vicious loop: Toll-like receptors sustain the spontaneous cytokine production by rheumatoid synovium

Synovial tissue of patients with rheumatoid arthritis (RA) spontaneously produces several cytokines, of which a fundamental role in joint inflammation and destruction has been established. However, the factors sustaining this phenomenon remain poorly understood. In a recent report, blockade of Toll-like receptor 2 (TLR2) was found to inhibit the spontaneous release of inflammatory cytokines by intact RA synovial explant cultures. Adding to the recent evidence implicating other TLRs (in particular, TLR4), this observation highlights the potential of TLRs as therapeutic targets to suppress the local production of multiple cytokines and to control the chronic inflammatory loop in RA

Gene therapy in animal models of rheumatoid arthritis: are we ready for the patients?

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints, with progressive destruction of cartilage and bone. Anti-tumour necrosis factor-α therapies (e.g. soluble tumour necrosis factor receptors) ameliorate disease in 60–70% of patients with RA. However, the need for repeated systemic administration of relatively high doses in order to achieve constant therapeutic levels in the joints, and the reported side effects are downsides to this systemic approach. Several gene therapeutic approaches have been developed to ameliorate disease in animal models of arthritis either by restoring the cytokine balance or by genetic synovectomy. In this review we summarize strategies to improve transduction of synovial cells, to achieve stable transgene expression using integrating viruses such as adeno-associated viruses, and to achieve transcriptionally regulated expression so that drug release can meet the variable demands imposed by the intermittent course of RA. Evidence from animal models convincingly supports the application of gene therapy in RA, and the feasibility of gene therapy was recently demonstrated in phase I clinical trials

IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis

The origin and role of IL-17, a T-cell derived cytokine, in cartilage and bone destruction during rheumatoid arthritis (RA) remain to be clarified. In human ex vivo models, addition of IL-17 enhanced IL-6 production and collagen destruction, and inhibited collagen synthesis by RA synovium explants. On mouse cartilage, IL-17 enhanced cartilage proteoglycan loss and inhibited its synthesis. On human RA bone explants, IL-17 also increased bone resorption and decreased formation. Addition of IL-1 in these conditions increased the effect of IL-17. Blocking of bone-derived endogenous IL-17 with specific inhibitors resulted in a protective inhibition of bone destruction. Conversely, intra-articular administration of IL-17 into a normal mouse joint induced cartilage degradation. In conclusion, the contribution of IL-17 derived from synovium and bone marrow T cells to joint destruction suggests the control of IL-17 for the treatment of RA