Role of Interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression

Background: The use of TNF inhibitors has been a major progress in the treatment of chronic inflammation. However, not all patients respond. In addition, response will be often lost when treatment is stopped. These clinical aspects indicate that other cytokines might be involved and we focus here on the role of IL-17. In addition, the chronic nature of joint inflammation may contribute to reduced response and enhanced chronicity. Therefore we studied the capacity of IL-17 to regulate synoviolin, an E3 ubiquitin ligase implicated in synovial hyperplasia in human rheumatoid arthritis (RA) FLS and in chronic reactivated streptococcal cell wall (SCW)-induced arthritis.<p></p> Methodology/Principal Findings: Chronic reactivated SCW-induced arthritis was examined in IL-17R deficient and wild-type mice. Synoviolin expression was analysed by real-time RT-PCR, Western Blot or immunostaining in RA FLS and tissue, and p53 assessed by Western Blot. Apoptosis was detected by annexin V/propidium iodide staining, SS DNA apoptosis ELISA kit or TUNEL staining and proliferation by PCNA staining. IL-17 receptor A (IL-17RA), IL-17 receptor C (IL-17-RC) or synoviolin inhibition were achieved by small interfering RNA (siRNA) or neutralizing antibodies. IL-17 induced sustained synoviolin expression in RA FLS. Sodium nitroprusside (SNP)-induced RA FLS apoptosis was associated with reduced synoviolin expression and was rescued by IL-17 treatment with a corresponding increase in synoviolin expression. IL-17RC or IL-17RA RNA interference increased SNP-induced apoptosis, and decreased IL-17-induced synoviolin. IL-17 rescued RA FLS from apoptosis induced by synoviolin knockdown. IL-17 and TNF had additive effects on synoviolin expression and protection against apoptosis induced by synoviolin knowndown. In IL-17R deficient mice, a decrease in arthritis severity was characterized by increased synovial apoptosis, reduced proliferation and a marked reduction in synoviolin expression. A distinct absence of synoviolin expressing germinal centres in IL-17R deficient mice contrasted with synoviolin positive B cells and Th17 cells in synovial germinal centre-like structures.<p></p> Conclusion/Significance: IL-17 induction of synoviolin may contribute at least in part to RA chronicity by prolonging the survival of RA FLS and immune cells in germinal centre reactions. These results extend the role of IL-17 to synovial hyperplasia.<p></p&gt

Stabilized Kuramoto-Sivashinsky system

A model consisting of a mixed Kuramoto - Sivashinsky - KdV equation, linearly coupled to an extra linear dissipative equation, is proposed. The model applies to the description of surface waves on multilayered liquid films. The extra equation makes its possible to stabilize the zero solution in the model, opening way to the existence of stable solitary pulses (SPs). Treating the dissipation and instability-generating gain in the model as small perturbations, we demonstrate that balance between them selects two steady-state solitons from their continuous family existing in the absence of the dissipation and gain. The may be stable, provided that the zero solution is stable. The prediction is completely confirmed by direct simulations. If the integration domain is not very large, some pulses are stable even when the zero background is unstable. Stable bound states of two and three pulses are found too. The work was supported, in a part, by a joint grant from the Israeli Minsitry of Science and Technology and Japan Society for Promotion of Science.Comment: A text file in the latex format and 20 eps files with figures. Physical Review E, in pres

Stable periodic waves in coupled Kuramoto-Sivashinsky - Korteweg-de Vries equations

Periodic waves are investigated in a system composed of a Kuramoto-Sivashinsky - Korteweg-de Vries (KS-KdV) equation, which is linearly coupled to an extra linear dissipative equation. The model describes, e.g., a two-layer liquid film flowing down an inclined plane. It has been recently shown that the system supports stable solitary pulses. We demonstrate that a perturbation analysis, based on the balance equation for the field momentum, predicts the existence of stable cnoidal waves (CnWs) in the same system. It is found that the mean value U of the wave field u in the main subsystem, but not the mean value of the extra field, affects the stability of the periodic waves. Three different areas can be distinguished inside the stability region in the parameter plane (L,U), where L is the wave's period. In these areas, stable are, respectively, CnWs with positive velocity, constant solutions, and CnWs with negative velocity. Multistability, i.e., the coexistence of several attractors, including the waves with several maxima per period, appears at large value of L. The analytical predictions are completely confirmed by direct simulations. Stable waves are also found numerically in the limit of vanishing dispersion, when the KS-KdV equation goes over into the KS one.Comment: a latex text file and 16 eps files with figures. Journal of the Physical Society of Japan, in pres

Lowering the recommended maximal wall thickness threshold improves diagnostic sensitivity in Asians with hypertrophic cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined as left ventricular end-diastolic maximal wall thickness (WTMax) ≥15.0 mm, without accounting for ethnicity, sex, and body size. It is well-established that Asians have smaller hearts than do Caucasians. OBJECTIVES: This study aims to examine the implications of this single absolute WTMax threshold on the diagnosis of HCM in Asians. METHODS: The study consisted of 360 healthy volunteers (male: n = 174; age: 50 ± 12 years) and 114 genetically characterized patients with HCM (male: n = 83; age: 52 ± 13 years; genotype-positive, n = 39). All participants underwent cardiovascular magnetic resonance. WTMax was measured semiautomatically at end-diastole according to the standard 16 myocardial segments. RESULTS: Healthy male volunteers had increased WTMax compared with that of female volunteers (8.4 ± 1.2 mm vs 6.6 ± 1.1 mm, respectively; P 15.0 mm (specificity of 100% and sensitivity of 51%). Lowering WTMax thresholds to 10.0 mm in female patients and 12.0 mm in male patients did not affect specificity (100%) but significantly improved sensitivity (84%). Despite lower left ventricular mass, female patients with HCM demonstrated more features of adverse cardiac remodeling than did male patients: increased myocardial fibrosis, higher asymmetric ratio, and disproportionately worse myocardial strain. CONCLUSIONS: The study highlights cautious application of guideline-recommended WTMax to diagnose HCM in Asians. Lowering WTMax to account for ethnicity and sex improves diagnostic sensitivity without compromising specificity

Studies of Phase Turbulence in the One Dimensional Complex Ginzburg-Landau Equation

The phase-turbulent (PT) regime for the one dimensional complex Ginzburg-Landau equation (CGLE) is carefully studied, in the limit of large systems and long integration times, using an efficient new integration scheme. Particular attention is paid to solutions with a non-zero phase gradient. For fixed control parameters, solutions with conserved average phase gradient $\nu$ exist only for $|\nu|$ less than some upper limit. The transition from phase to defect-turbulence happens when this limit becomes zero. A Lyapunov analysis shows that the system becomes less and less chaotic for increasing values of the phase gradient. For high values of the phase gradient a family of non-chaotic solutions of the CGLE is found. These solutions consist of spatially periodic or aperiodic waves travelling with constant velocity. They typically have incommensurate velocities for phase and amplitude propagation, showing thereby a novel type of quasiperiodic behavior. The main features of these travelling wave solutions can be explained through a modified Kuramoto-Sivashinsky equation that rules the phase dynamics of the CGLE in the PT phase. The latter explains also the behavior of the maximal Lyapunov exponents of chaotic solutions.Comment: 16 pages, LaTeX (Version 2.09), 10 Postscript-figures included, submitted to Phys. Rev.

A Simple Model for Anisotropic Step Growth

We consider a simple model for the growth of isolated steps on a vicinal crystal surface. It incorporates diffusion and drift of adatoms on the terrace, and strong step and kink edge barriers. Using a combination of analytic methods and Monte Carlo simulations, we study the morphology of growing steps in detail. In particular, under typical Molecular Beam Epitaxy conditions the step morphology is linearly unstable in the model and develops fingers separated by deep cracks. The vertical roughness of the step grows linearly in time, while horizontally the fingers coarsen proportional to $t^{0.33}$. We develop scaling arguments to study the saturation of the ledge morphology for a finite width and length of the terrace.Comment: 20 pages, 12 figures; [email protected]