The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis which impacts significantly on the quality of life and work capacity of affected individuals. Recent evidence has shown that early control of inflammation in PsA leads to improved long-term outcomes. It is postulated that prompt intervention after diagnosis using a remission-induction treatment strategy will lead to improved outcomes and optimal disease control of PsA. The aim of the present study was to compare the clinical efficacy of a treatment strategy in newly diagnosed, treatment naïve PsA subjects, using the combination of golimumab (GOL), methotrexate (MTX) and steroids versus standard care (MTX monotherapy plus steroids). Methods/design: GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel-group, imaging-supplemented study. Eighty-eight PsA patients, diagnosed within 24 months prior to screening and treatment naïve, will be randomised at baseline to receive: (arm 1) the combination of intramuscular/intra-articular prednisolone, MTX and GOL or (arm 2) the combination of intramuscular/intra-articular prednisolone, MTX and placebo for 24 weeks (interventional period). Primary outcome measure is clinical improvement (at least 1 unit difference) in the Psoriatic ArthritiS Disease Activity Score (PASDAS) composite index. Reflecting a “step down” therapeutic approach, all participants successfully completing the interventional period will be followed up for a further 28 weeks. During this observational period, stable maintenance MTX monotherapy will continue for both arms, unless in case of intolerance or PsA relapse. In the latter case, additional treatment will be provided. Overall, the GOLMePsA study length is planned to be 52 weeks. Discussion: The hypothesis underlining this study is that very early treatment with first-line GOL reduces disease activity in PsA, in comparison to conventional therapy. Trial registration: EudraCT 2013–004122-28. 24/09/2013

Autocatalytic nitration of prostaglandin endoperoxide synthase-2 by nitrite inhibits prostanoid formation in rat alveolar macrophages

Aims: Prostaglandin endoperoxide H2 synthase (PGHS) is a well-known target for peroxynitrite-mediated nitration. In several experimental macrophage models, however, the relatively late onset of nitration failed to coincide with the early peak of endogenous peroxynitrite formation. In the present work,weaimed to identify an alternative, peroxynitrite-independent mechanism, responsible for the observed nitration and inactivation of PGHS-2 in an inflammatory cell model. Results: In primary rat alveolar macrophages stimulated with lipopolysaccharide (LPS), PGHS-2 activity was suppressed after 12 h, although the prostaglandin endoperoxide H2 synthase (PGHS-2) protein was still present. This coincided with a nitration of the enzyme. Coincubation with a nitric oxide synthase-2 (NOS - 2) inhibitor preserved PGHS-2 nitration and at the same time restored thromboxane A 2 (TxA 2) synthesis in the cells. Formation of reactive oxygen species (ROS) was maximal at 4 h and then returned to baseline levels. Nitrite (NO 2 -) production occurred later than ROS generation. This rendered generation of peroxynitrite and the nitration of PGHS-2 unlikely. We found that the nitrating agent was formed from NO2-, independent from superoxide (•O 2 - ). Purified PGHS-2 treated with NO 2 - was selectively nitrated on the active site Tyr371, as identified by mass spectrometry (MS). Exposure to peroxynitrite resulted in the nitration not only of Tyr 371, but also of other tyrosines (Tyr). Innovation and Conclusion: The data presented here point to an autocatalytic nitration of PGHS-2 byNO 2 - , catalyzed by the enzyme's endogenous peroxidase activity and indicate a potential involvement of this mechanism in the termination of prostanoid formation under inflammatory conditions. © 2012 Mary Ann Liebert, Inc

The promotion of self-regulation through parenting interventions

The capacity for a parent to self-regulate their own performance is argued to be a fundamental process underpinning the maintenance of positive, nurturing, non-abusive parenting practices that promote good developmental and health outcomes in children. Deficits in self-regulatory capacity, which have their origins in early childhood, are common in many psychological disorders, and strengthening self-regulation skills is widely recognised as an important goal in many psychological therapies and is a fundamental goal in preventive interventions. Attainment of enhanced self-regulation skills enables individuals to gain a greater sense of personal control and mastery over their life. This paper illustrates how the self-regulatory principles can be applied to parenting and family-based interventions at the level of the child, parent, practitioner and organisation. The Triple P-Positive Parenting Program, which uses a self-regulatory model of intervention, is used as an example to illustrate the robustness and versatility of the self-regulation approach to all phases of the parent consultation process

The effects of parenting on emotion and self-regulation

The capacity to regulate one’s own arousal, attention, emotion, and cognition to manage goal-directed behaviors is a crucial skill that impacts on almost every area of one’s life. The development of such self-regulatory skills during childhood is considered an early indicator for later life successes, as effective self-regulation is predictive of a multitude of short and long-term outcomes including school-readiness, relationships with peers and family, academic achievement, feelings of higher self-worth, ability to cope with stress, less substance abuse and law breaking, and better mental health. Children’s self-regulatory capacities are greatly influenced by environmental experiences, such as the quality of parenting they receive. This chapter considers ways in which parenting facilitates self-regulation in children. Following a brief overview of the normative development of self-regulation during childhood, the chapter specifically examines the impact of parenting on the development of children’s executive functions, effortful control, compliance, and emotion regulation. A range of classic theoretical models are reviewed and empirical studies showcased. As self-regulation is a broad and multidimensional construct, the chapter also discusses some of the related conceptual and methodological issues