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

Mutually Penetrating Motion of Self-Organized 2D Patterns of Soliton-Like Structures

Results of numerical simulations of a recently derived most general dissipative-dispersive PDE describing evolution of a film flowing down an inclined plane are presented. They indicate that a novel complex type of spatiotemporal patterns can exist for strange attractors of nonequilibrium systems. It is suggested that real-life experiments satisfying the validity conditions of the theory are possible: the required sufficiently viscous liquids are readily available.Comment: minor corrections, 4 pages, LaTeX, 6 figures, mpeg simulations available upon or reques

Effects of reverberation on perceptual segregation of competing voices

Two experiments investigated the effect of reverberation on listeners’ ability to perceptually segregate two competing voices. Culling et al. [Speech Commun. 14, 71–96 (1994)] found that for competing synthetic vowels, masked identification thresholds were increased by reverberation only when combined with modulation of fundamental frequency (F0). The present investigation extended this finding to running speech. Speech reception thresholds (SRTs) were measured for a male voice against a single interfering female voice within a virtual room with controlled reverberation. The two voices were either (1) co-located in virtual space at 0° azimuth or (2) separately located at ±60° azimuth. In experiment 1, target and interfering voices were either normally intonated or resynthesized with a fixed F0. In anechoic conditions, SRTs were lower for normally intonated and for spatially separated sources, while, in reverberant conditions, the SRTs were all the same. In experiment 2, additional conditions employed inverted F0 contours. Inverted F0 contours yielded higher SRTs in all conditions, regardless of reverberation. The results suggest that reverberation can seriously impair listeners’ ability to exploit differences in F0 and spatial location between competing voices. The levels of reverberation employed had no effect on speech intelligibility in quiet. © 2003 Acoustical Society of America

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]

Laboratory evidence of disseminated intravascular coagulation is associated with a fatal outcome in children with cerebral malaria despite an absence of clinically evident thrombosis or bleeding

Background A procoagulant state is implicated in cerebral malaria (CM ) pathogenesis, but whether disseminated intravascular coagulation (DIC ) is present or associated with a fatal outcome is unclear. Objectives To determine the frequency of overt DIC , according to ISTH criteria, in children with fatal and non‐fatal CM . Methods/patients Malawian children were recruited into a prospective cohort study in the following diagnostic groups: retinopathy‐positive CM (n = 140), retinopathy‐negative CM (n = 36), non‐malarial coma (n = 14), uncomplicated malaria (UM ), (n = 91), mild non‐malarial febrile illness (n = 85), and healthy controls (n = 36). Assays in the ISTH DIC criteria were performed, and three fibrin‐related markers, i.e. protein C, antithrombin, and soluble thrombomodulin, were measured. Results and conclusions Data enabling assignment of the presence or absence of ‘overt DIC ’ were available for 98 of 140 children with retinopathy‐positive CM . Overt DIC was present in 19 (19%), and was associated with a fatal outcome (odds ratio [OR] 3.068; 95% confidence interval [CI] 1.085–8.609; P = 0.035]. The levels of the three fibrin‐related markers and soluble thrombomodulin were higher in CM patients than in UM patients (all P < 0.001). The mean fibrin degradation product level was higher in fatal CM patients (71.3 μg mL−1 [95% CI 49.0–93.6]) than in non‐fatal CM patients (48.0 μg mL−1 [95% CI 37.7–58.2]; P = 0.032), but, in multivariate logistic regression, thrombomodulin was the only coagulation‐related marker that was independently associated with a fatal outcome (OR 1.084 for each ng mL−1 increase [95% CI 1.017–1.156]; P = 0.014). Despite these laboratory derangements, no child in the study had clinically evident bleeding or thrombosis. An overt DIC score and high thrombomodulin levels are associated with a fatal outcome in CM , but infrequently indicate a consumptive coagulopathy

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

Auditory verbal hallucinations and childhood trauma subtypes across the psychosis continuum:a cluster analysis

Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters. Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses. Results: The total sample (n = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma (n = 299); (2) emotion-focused trauma (n = 71); (3) multi-trauma (n = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly. Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches

P137 Supporting patients to get the best from their osteoporosis treatment; what works for whom, why and in what circumstance: a rapid realist review

Abstract Background/Aims For two decades, clinicians and academics have been writing about the problem of poor adherence in osteoporosis, while people with osteoporosis have identified a need for more follow up and information about medicines. We aimed to understand what works in supporting people with osteoporosis to get the best from their medicines, and specifically, to understand what mechanisms enable components of interventions to support osteoporosis medication optimisation and the underlying contextual conditions that enabled these mechanisms. Methods We conducted a Rapid Realist Review. The scope was informed by a workshop of the Effectiveness Working Group of the Royal Osteoporosis Society Osteoporosis and Bone Research Academy and the approach informed by background syntheses of qualitative literature and the Perceptions and Practicalities Approach as an underpinning conceptual framework. A primary search identified observational or interventional studies which aimed to improve medicines adherence or optimisation. Included studies were assessed for quality and data extracted relating to context, mechanism and outcomes. A supplementary second search was conducted to gain additional insight on included key papers and emerging mechanisms. Extracted data were interrogated by authors independently for patterns of context-mechanism-outcome configurations and further discussed in weekly team meetings. Recommendations for research and clinical practice were co-developed with clinical and lay stakeholders. Results 41 papers were included. We identified five contextual timepoints for the person with osteoporosis (identifying a problem; starting medicine; continuing medicine) and the practitioner and healthcare system (making a diagnosis and giving a treatment recommendation; reviewing medicine) and mechanisms relating to patient informed decision making, treatment burden, supporting routinisation and memory, supporting clinical decision making, targeting support, and approaches which were integrated and sustainable. Interventions which support patient informed decision making, improve patient knowledge and understanding, have potential to influence long-term commitment to treatment, although few studies explicitly addressed patients’ perceptions of illness and treatment as recommended in NICE guidelines. During treatment, targeting additional consultations to those most in need may be a cost and clinically effective approach to enable this. Supporting primary care clinician decision making and integration of primary and secondary care services also appears to be important, in improving rates of treatment initiation and adherence. Supporting patients’ ability to adhere (eg by lowering treatment burden and issuing reminders) may be helpful to address practical difficulties but there is little evidence to support the use of reminders alone. Conclusion For medicines optimisation for people with osteoporosis, we suggest a need for more patient-centred interventions to address patients’ perceptions of illness and treatment, and reduce treatment burden. Specialist services should consider the extent to which they integrate with, and support primary care clinical decision-making, in order to impact long-term clinical outcomes. Specific research recommendations have been co-developed, to address these knowledge gaps. Disclosure Z. Paskins: Grants/research support; NIHR, Versus Arthritis, Royal Osteoporosis Society. O. Babatunde: None. A. Sturrock: None. L. Toh: None. R. Horne: None. I. Maidment: None. </jats:sec