IL-15 and its role in rheumatoid arthritis

Background: IL-15 is involved in all phases of rheumatoid arthritis. Recently we have shown that rheumatoid arthritis synovial fibroblasts (RASF) express both IL-15 and functional IL-15 receptor [1]. Objective: The aim of present study was to identify pathways that are regulated by autocrine IL-15 (IL-15R) in RASF. Methods: RASF were transfected with plasmid encoding IL-15R antagonist (CRB-15, Cardion AG) or control constructs. RNA from transient transfectants were used for Microarray analysis. The differential expression of genes obtained by microarray analysis was verified by SYBR Green real-time PCR. The expression of IL-15Rα, cell proliferation and the expression of p16 and p21 were evaluated in stably transfected cells. Results: The IL-15R antagonist produced by transfected RASF blocked the endogenous IL-15/IL-15Rα interaction, which resulted in an inhibition of cell proliferation (45 ± 10%) via an increase of the expression of p16. In addition, we found that inhibition of IL-15Rα induced the expression of mRNA for FGFR-3. Since two isoforms of FGFR-3 have been identified (FGFR-3b and FGFR-3c) [2], we tested the effect of IL-15Rα inhibition on their expression. In contrast to FGFR-3b, the level of mRNA for FGFR-3c was strongly increased in cells transfected with the IL-15R antagonist (4.71 ± 2.5 in transient transfectants and 6.1 ± 1 fold in stable transfectants). FGFR-3c isoform binds specifically FGF-9, but also FGF-2 [2]. Besides FGFR-3, FGF-2 that is abundant in RA joints binds to FGFR-1. In vitro studies revealed that FGFR-1 transmits a potent mitogenic signal, whereas FGFR-3 usually has no stimulatory effect or inhibits cell proliferation. In contrast to FGFR-3c, blocking of IL-15Rα did not change the mRNA expression for FGFR-1 in RASF. Moreover, we checked whether FGF-2 affects the expression of IL-15Rα. Indeed, FGF-2 strongly decreased the spontaneous and tumor necrosis factor alpha-triggered expression of IL-15Rα at the mRNA and protein levels. Conclusion: Our findings raise the possibility of a negative loop between FGF-2/FGFR-3c and IL-15/IL-15R signaling in RASF. Moreover, the activation of RASF by FGFs could depend on the ratio of FGFR-1/FGFR-3 expression, which is controlled by the endogenous IL-15/IL-15R system

Arresting bubble coarsening: A two-bubble experiment to investigate grain growth in presence of surface elasticity

Many two-phase materials suffer from grain-growth due to the energy cost which is associated with the interface that separates both phases. While our understanding of the driving forces and the dynamics of grain growth in different materials is well advanced by now, current research efforts address the question of how this process may be slowed down, or, ideally, arrested. We use a model system of two bubbles to explore how the presence of a finite surface elasticity may interfere with the coarsening process and the final grain size distribution. Combining experiments and modelling in the analysis of the evolution of two bubbles, we show that clear relationships can be predicted between the surface tension, the surface elasticity and the initial/final size ratio of the bubbles. We rationalise these relationships by the introduction of a modified Gibbs criterion. Besides their general interest, the present results have direct implications for our understanding of foam stability

Kardiovaskuläre Manifestationen bei Rheumatoider Arthritis

Zusammenfassung : Die Rheumatoide Arthritis (RA) ist eine systemische Erkrankung des Bindegewebes, die durch eine polyartikuläre Entzündung mit synovialer Hyperplasie und progredienter Gelenkzerstörung, aber auch durch extraartikuläre Manifestationen und systemische pathologische Immunphänomene charakterisiert ist. Eine erhöhte Mortalität innerhalb der RA-Patientenpopulation ist seit langem bekannt und vor allem auf ein erhöhtes kardiovaskuläres Risiko zurückzuführen. Die Korrelation der kardiovaskulären Morbidität und Mortalität mit der Erkrankungsaktivität sowie dem Ausmaß extraartikulärer Manifestationen war der Ausgangspunkt für die Suche nach entzündungs- und erkrankungsassoziierten Pathomechanismen. Endothelzelldysfunktion und vaskuläre Inflammation konnten als zentrale Mechanismen der Atheroskleroseinduktion und deren Progression charakterisiert werden. Beide Phänomene stellen eine uniforme Reaktionsweise von Gefäßen unter dem Einfluss klassischer Risikofaktoren sowie einer systemischen-Entzündung dar. Für die akzelerierte Atherosklerose von RA-Patienten sind neben den klassischen Risikofaktoren erkrankungsbedingte Faktoren wie Immobilität, medikamentöse Therapie sowie Entzündungsmediatoren zu berücksichtigen. Bei den beschriebenen entzündungsvermittelten Mechanismen der Gefäßschädigung kommt vor allem den bei RA-Patienten als Folge der Synovialitis exzessiv gebildeten pro-inflammatorischen Zytokinen eine Bedeutung zu. Die Frage, ob der Entzündungsmarker CRP gleichzeitig einen kardiovaskulären Risikoindikator und einen Mediator atherosklerotischer Gefäßschädigung darstellt, bedarf noch endgültiger Beantwortung durch weitere Studien. Neben diesen unspezifischen entzündungsassoziierten Mechanismen können bei der Rheumatoiden Arthritis zusätzlich krankheitsspezifische Immunphänomene, wie die klonal expandierten autoreaktiven T-Zellen für die kardiovaskuläre Morbidität und Mortalität von Bedeutung sein. Die neueren TNFα-hemmenden Basistherapeutika interferieren auf unterschiedlichen Ebenen mit pro-atherosklerotischen Prozessen. Die Zukunft wird zeigen, wie sich diese Medikamente auf die kardiovaskuläre Morbidität und Mortalität auswirke

Preparing potential teachers for the transition from employment to teacher training: an evaluative case study of a Maths Enhancement Course

In response to a UK government drive to improve maths teaching in schools, the South West London Maths Enhancement Course (MEC) has been set up though collaboration between three Higher Education institutions (HEIs) to provide an efficient route for non maths graduates in employment to upgrade their subject knowledge and give a smooth transition into teacher training (PGCE). An evaluation of the scheme, measured against Teacher Development Agency (TDA) objectives and success criteria agreed by university staff, involved thematic analysis of focus group discussions and interviews with students and staff during both the MEC and PGCE courses. This has revealed a high level of satisfaction and success related to a number of underlying issues, particularly around student recruitment, curriculum design, peer support and staff collaboration. The model offers an example of practice transferable to a range of programmes aimed at supporting students in the transition between levels and institutions

Evaluation of a measles vaccine campaign by oral-fluid surveys in a rural Kenyan district: interpretation of antibody prevalence data using mixture models

We evaluated the effectiveness of a measles vaccine campaign in rural Kenya, based on oral-fluid surveys and mixture-modelling analysis. Specimens were collected from 886 children aged 9 months to 14 years pre-campaign and from a comparison sample of 598 children aged 6 months post-campaign. Quantitative measles-specific antibody data were obtained by commercial kit. The estimated proportions of measles-specific antibody negative in children aged 0–4, 5–9 and 10–14 years were 51%, 42% and 27%, respectively, pre- campaign and 18%, 14% and 6%, respectively, post-campaign. We estimate a reduction in the proportion susceptible of 65–78%, with ~85% of the population recorded to have received vaccine. The proportion of ‘weak’ positive individuals rose from 35% pre-campaign to 54% post-campaign. Our results confirm the effectiveness of the campaign in reducing susceptibility to measles and demonstrate the potential of oral-fluid studies to monitor the impact of measles vaccination campaigns

The inhibitor of differentiation-2 promotes synovial fibroblast-dependent osteoclastogenesis in rheumatoid arthritis

Objectives: Despite indirect evidence suggesting that low oxygen levels might occur in the rheumatoid arthritis (RA) synovium, direct proof of the presence of hypoxia in the arthritic synovium as well as the relevance of low oxygen levels for joint destruction is lacking. The aim of this study was to analyse the distribution of hypoxia in arthritic joints and to evaluate the molecular effects of the hypoxic environment on the phenotype of RA synovial fibroblasts (SF).<p></p> Methods: The hypoxia marker EF-5 was applied in mice with the collagen-induced arthritis (CIA). Expression profile analysis with hypoxic and normoxic SF was performed using subtractive hybridization and microarray. The expression of the inhibitor of differentiation-2 (Id-2), CD68 (macrophage marker) and prolyl hydroxylase (fibroblast marker) was evaluated by immunohistochemistry on synovial tissues from RA, osteoarthritis patients and CIA mice. To evaluate the function of Id-2 in SF, cells were transfected with the pcDNA3.1 containing cDNA for Id-2 or Id-2-specific siRNA or mock controls. The expression of Id-2 and genes regulated by Id-2 in transfected SF was evaluated by SYBR Green real-time PCR and western blot. SF stably transfected with Id-2 were cocultured with bone marrow cells in a transwell system. The expression of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin were measured by real-time PCR. The development of osteoclasts was evaluated by visualization of the activity of tartrate-resistant acid phosphatase.<p></p> Results: Using the hypoxia marker EF-5 we found that in mice with CIA, synovial cells invading bone and cartilage are exposed to reduced oxygen levels. Expression profile studies identified Id-2 as being upregulated under low oxygen conditions. In addition, IL-1beta stimulation increased the expression of Id-2 in these cells. Histological studies of RA synovium and CIA synovium showed strong expression of Id-2 in SF at sites of synovial invasion into bone. Overproduction of Id-2 in SF by stable transfection triggered the expression of several genes promoting osteoclastogenesis, including BMP-2, PTHrP, Wnt5a and vascular endothelial growth factor. Conversely, the suppression of endogenous Id-2 led to the downregulation of the expression of these molecules. Consistent with these findings coculture of Id-2 transfected SF with bone marrow cells increased the expression of the osteoclast differentiation factor RANKL, and decreased the expression of the osteoclast inhibitory factor osteoprotegerin in bone marrow stromal cells, which was followed by an increase in the number of osteoclasts.<p></p> Conclusion: Taken together, our data provide evidence that hypoxia is present at sites of synovial invasion in RA and that Id-2 induced by hypoxia contributes at these sites to joint destruction by promoting SF-dependent osteoclastogenesis

Formal Analysis of Quantum Systems using Process Calculus

Quantum communication and cryptographic protocols are well on the way to becoming an important practical technology. Although a large amount of successful research has been done on proving their correctness, most of this work does not make use of familiar techniques from formal methods, such as formal logics for specification, formal modelling languages, separation of levels of abstraction, and compositional analysis. We argue that these techniques will be necessary for the analysis of large-scale systems that combine quantum and classical components, and summarize the results of initial investigation using behavioural equivalence in process calculus. This paper is a summary of Simon Gay's invited talk at ICE'11.Comment: In Proceedings ICE 2011, arXiv:1108.014