A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes

SummaryObjectiveRecent studies revealed a close connection between adipose tissue, adipokines and articular degenerative inflammatory diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). The goal of this work was to investigate the activity of adiponectin in human and murine chondrocytes and to study its functional role in the modulation of nitric oxide synthase type II (NOS2). For completeness, interleukin (IL)-6, IL-1β, matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, prostaglandin E2 (PGE2), leukotriene B4 (LTB4), tumor necrosis factor alpha (TNF)-α and monocyte chemoattractant protein-1 (MCP-1) accumulation have been evaluated in adiponectin-stimulated chondrocytes cell culture supernatants.MethodsMurine ATDC5 cell line, C28/I2, C20A4, TC28a2 human immortalized chondrocytes, and human cultured chondrocytes were used. Nitrite accumulation was determined by Griess reaction. Adiponectin receptors (AdipoRs) expression was evaluated by immunofluorescence microscopy and confirmed by reverse transcriptase-polymerase chain reaction. NOS2 expression was evaluated by Western blot analysis whereas cytokines, prostanoids and metalloproteinases production was evaluated by specific enzyme-linked immunosorbent assays.ResultsHuman and murine chondrocytes express functional AdipoRs. Adiponectin induces NOS2. This effect is inhibited by aminoguanidine, dexamethasone and by a selective inhibitor of phosphatidylinositol 3-kinase. In addition, adiponectin is able to increase IL-6, MMP-3, MMP-9 and MCP-1 by murine cultured chondrocytes whereas it was unable to modulate TNF-α, IL-1β, MMP-2, TIMP-1, PGE2 and LTB4 release.ConclusionsThese results bind more closely the interactions between fat-derived adipokines and articular inflammatory diseases, and suggest that adiponectin is a novel key element in the maintenance of cartilage homeostasis which might be considered as a potential therapeutical target in joint degenerative diseases

Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab

<p>Objective To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA).</p> <p>Methods GO–REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14.</p> <p>Results Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1α) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor α). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone.</p> <p>Conclusions This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment.</p&gt

On supersymmetric Minkowski vacua in IIB orientifolds

Supersymmetric Minkowski vacua in IIB orientifold compactifications based on orbifolds with background fluxes and non-perturbative superpotentials are investigated. Especially, microscopic requirements and difficulties to obtain such vacua are discussed. We show that orbifold models with one and two complex structure moduli and supersymmetric 2-form flux can be successfully stabilized to such vacua. By taking additional gaugino condensation on fixed space-time filling D3-branes into account also models without complex structure can be consistently stabilized to Minkowski vacua.Comment: 17 pages, 2 figures; More detailed proof for absence of complex flat directions in susy AdS vacua given; Footnotes and reference adde

Inflation with racetrack superpotential and matter field

Several models of inflation with the racetrack superpotential for the volume modulus coupled to a matter field are investigated. In particular, it is shown that two classes of racetrack inflation models, saddle point and inflection point ones, can be constructed in a fully supersymmetric framework with the matter field F-term as a source of supersymmetry breaking and uplifting. Two models of F-term supersymmetry breaking are considered: the Polonyi model and the quantum corrected O'Raifeartaigh model. In the former case, both classes of racetrack inflation models differ significantly from the corresponding models with non-supersymmetric uplifting. The main difference is a quite strong dominance of the inflaton by the matter field. In addition, fine-tuning of the parameters is relaxed as compared to the original racetrack models. In the case of the racetrack inflation models coupled to the O'Raifeartaigh model, the matter field is approximately decoupled from the inflationary dynamics. In all of the above models the gravitino mass is larger than the Hubble scale during inflation. The possibility of having the gravitino much lighter than the Hubble scale is also investigated. It is very hard to construct models with light gravitino in which the volume modulus dominates inflation. On the other hand, models in which the inflationary dynamics is dominated by the matter field are relatively simple and seem to be more natural.Comment: 40 pages, 13 figures, references added, typos corrected, version to be publishe

Clinical characteristics and patient-reported outcomes in patients with inadequately controlled rheumatoid arthritis despite ongoing treatment

Background Despite the wide array of treatments available for rheumatoid arthritis (RA), some patients continue to report unmet clinical needs. We investigated the extent of inadequate disease control in patients with RA. Methods Data were drawn from the Adelphi 2014 RA Disease-Specific Program in France, Germany, Italy, Spain and the UK. Rheumatologists provided patient demographics, comorbidities, satisfaction with RA control and other clinical details. Patients reported their level of satisfaction and completed the EuroQoL 5-Dimensions Health Questionnaire and Work Productivity and Activity Impairment Questionnaire. Patients had been on their current therapy 653 months and had 28-joint disease activity scores (DAS28) reported. Adequately controlled (DAS28 643.2) and inadequately controlled (DAS28 >3.2) patient cohorts were compared using univariate tests. Results Of 1147 patients, 74% were women, the mean age was 52 years and the mean time since RA diagnosis was 7 years. Twenty-seven percent of patients had inadequately controlled RA, whereas 73% had adequately controlled RA. Inadequately controlled patients were more affected clinically versus adequately controlled patients; 69% vs 13% had moderate/severe RA, the current level of pain was 4.6 vs 2.3, and 67% vs 41% experienced flares, respectively (all p<0.0001). Inadequately controlled patients had higher rates of depression (16% vs 5%; p<0.0001), worse health state, greater work and activity impairment, and lower satisfaction rates among the patients and their physicians than the adequately controlled cohort. Conclusion RA was insufficiently controlled in over a quarter of patients despite their current therapy and this had a negative impact on the patients

High sodium intake is associated with self-reported rheumatoid arthritis: a cross sectional and case control analysis within the SUN cohort

Sodium intake is a potential environmental factor for immune-mediated inflammatory diseases. The aim of this study is to investigate the association of sodium intake with rheumatoid arthritis. We performed a cross-sectional study nested in a highly educated cohort investigating dietary habits as determinants of disease. Daily sodium intake in grams per day was estimated from a validated food frequency questionnaire. We identified prevalent self-reported cases of rheumatoid arthritis. Logistic regressionmodelswere used to estimate the odds ratio for rheumatoid arthritis by sodium intake adjusting for confounders. Linear trend tests and interactions between variables were explored. Sensitivity analyses included age- and sex-matched case–control study, logistic multivariate model adjusted by residuals, and analysis excluding individuals with prevalent diabetes or cardiovascular disease. The effective sample size was 18,555 individuals (mean age 38-years old, 60% women) including 392 self-reported rheumatoid arthritis. Median daily sodium intake (estimated from foods plus added salt) was 3.47 (P25–75: 2.63–4.55) grams. Total sodium intake in the fourth quartile showed a significant association with rheumatoid arthritis (fully adjusted odds ratio 1.5; 95% CI 1.1–2.1, P for trend¼0.02). Never smokers with high sodium intake had higher association than ever smokers with high sodium intake (P for interaction¼0.007). Dosedependent association was replicated in the case–control study. High sodiumintakemay be associated with a diagnosis of rheumatoid arthritis. This confirms previous clinical and experimental research

Metastable SUSY Breaking, de Sitter Moduli Stabilisation and K\"ahler Moduli Inflation

We study the influence of anomalous U(1) symmetries and their associated D-terms on the vacuum structure of global field theories once they are coupled to N=1 supergravity and in the context of string compactifications with moduli stabilisation. In particular, we focus on a IIB string motivated construction of the ISS scenario and examine the influence of one additional U(1) symmetry on the vacuum structure. We point out that in the simplest one-Kahler modulus compactification, the original ISS vacuum gets generically destabilised by a runaway behaviour of the potential in the modulus direction. In more general compactifications with several Kahler moduli, we find a novel realisation of the LARGE volume scenario with D-term uplifting to de Sitter space and both D-term and F-term supersymmetry breaking. The structure of soft supersymmetry breaking terms is determined in the preferred scenario where the standard model cycle is not stabilised non-perturbatively and found to be flavour universal. Our scenario also provides a purely supersymmetric realisation of Kahler moduli (blow-up and fibre) inflation, with similar observational properties as the original proposals but without the need to include an extra (non-SUSY) uplifting term.Comment: 38 pages, 8 figures. v2: references added, minor correction

Gauge vs. Gravity mediation in models with anomalous U(1)'s

In an attempt to implement gauge mediation in string theory, we study string effective supergravity models of supersymmetry breaking, containing anomalous gauge factors. We discuss subtleties related to gauge invariance and the stabilization of the Green-Schwarz moduli, which set non-trivial constraints on the transmission of supersymmetry breaking to MSSM via gauge interactions. Given those constraints, it is difficult to obtain the dominance of gauge mediation over gravity mediation. Furthermore, generically the gauge contributions to soft terms contain additional non-standard terms coming from D-term contributions. Motivated by this, we study the phenomenology of recently proposed hybrid models, where gravity and gauge mediations compete at the GUT scale, and show that such a scenario can respect WMAP constraints and would be easily testable at LHC.Comment: 40 pages, 5 figure

DBI Inflation in the Tip Region of a Warped Throat

Previous work on DBI inflation, which achieves inflation through the motion of a $D3$ brane as it moves through a warped throat compactification, has focused on the region far from the tip of the throat. Since reheating and other observable effects typically occur near the tip, a more detailed study of this region is required. To investigate these effects we consider a generalized warp throat where the warp factor becomes nearly constant near the tip. We find that it is possible to obtain 60 or more e-folds in the constant region, however large non-gaussianities are typically produced due to the small sound speed of fluctuations. For a particular well-studied throat, the Klebanov-Strassler solution, we find that inflation near the tip may be generic and it is difficult to satisfy current bounds on non-gaussianity, but other throat solutions may evade these difficulties.Comment: 26 pages, 1 figure. v1. references added, typos corrected v2. clarifications mad