GILZ regulates type I interferon release and sequesters STAT1.

Glucocorticoids remain a mainstay of modern medicine due to their ability to broadly suppress immune activation. However, they cause severe adverse effects that warrant urgent development of a safer alternative. The glucocorticoid-induced leucine zipper (GILZ) gene, TSC22D3, is one of the most highly upregulated genes in response to glucocorticoid treatment, and reduced GILZ mRNA and protein levels are associated with increased severity of inflammation in systemic lupus erythematosus (SLE), Ulcerative Colitis, Psoriasis, and other autoimmune/autoinflammatory diseases. Here, we demonstrate that low GILZ permits expression of a type I interferon (IFN) signature, which is exacerbated in response to TLR7 and TLR9 stimulation. Conversely, overexpression of GILZ prevents IFN-stimulated gene (ISG) up-regulation in response to IFNα. Moreover, GILZ directly binds STAT1 and prevents its nuclear translocation, thereby negatively regulating IFN-induced gene expression and the auto-amplification loop of the IFN response. Thus, GILZ powerfully regulates both the expression and action of type I IFN, suggesting restoration of GILZ as an attractive therapeutic strategy for reducing reliance on glucocorticoids.

The evolving demographics of participants in psoriatic arthritis phase III randomised controlled trials of b/tsDMARDs: A systematic review.

OBJECTIVES: To characterize the evolving demographics of participants recruited to phase III randomised controlled trials (RCTs) of biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in peripheral psoriatic arthritis (PsA). METHODS: We conducted a systematic review of EMBASE, MEDLINE, and the Cochrane Database of Clinical Trials (CENTRAL) to identify all placebo-controlled phase III RCTs of b/tsDMARDs in peripheral PsA published up to 1 June 2022. Data extracted included inclusion criteria, date of initiation, countries in which studies were conducted, age, sex, race, disease duration, swollen joint count, tender joint count, Health Assessment Questionnaire - Disability Index, Psoriasis Area and Severity Index, and radiographic damage scores. Trends over time were evaluated using descriptive statistics. RESULTS: 34 eligible RCTs from 33 reports were included. The proportion of female participants increased over time with females representing 29.0-43.7% of participants in studies initiated in 2000-2004 which increased to 46.0-58.8% in 2015-2019. While the number of countries included in RCTs increased significantly from 1-8 countries (2000-2004) to 2-46 (2015-2019), the proportion of white participants changed marginally from 90.0-98.0% (2000-2004) to 80.9-97.3% (2015-2019). The SJC and TJC decreased from 13.9 to 24.6 respectively (2000-2004), to 7.0-13.9 and 12.9-24.9 (2015-2019). Baseline CRP and HAQ-DI remained stable. CONCLUSION: Despite the expansion of countries from which PsA RCT participants were recruited from, non-white participants continue to be under-represented. Improving diversity in patient representation is imperative to further our understanding of PsA phenotypes, proteogenomics, socioeconomic determinants, and treatment effects, to advance the care of all patients with psoriatic disease.

Breaking the chain of transmission within a tertiary health service: An approach to contact tracing during the COVID-19 pandemic.

BACKGROUND: Tertiary referral health service. INTERVENTION(S): An approach to hospital based contact tracing is described along with tools employed to streamline the process and including the development of an outbreak management team (OMT) for each contact trace. RESULTS: Forty-one OMTs occurred, involving 23 HCW and 18 patient index cases. The total furloughed HCWs arising from these contact traces was 383, with individual contact traces furloughing a mean (range) of 10 (0-80) HCWs. Importantly, 15 furloughed HCWs subsequently became COVID-19 positive during their 14-day isolation period, showing the importance of the contact tracing process and the ability to remove workers from the workplace before they become infectious. CONCLUSIONS: A standardised, streamlined contact tracing procedure in healthcare settings ensures any impacts of COVID-19 positive cases are consistently managed. This response framework may be of use to other health services and help reduce the transmission of COVID-19 in the workplace.

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus.

Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn-/-) mice in which GILZ expression was genetically ablated. In Lyn-/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A, and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18. This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE.

Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase.

The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating "Go" responses upon exposure to reward-related stimuli and "NoGo" responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson's disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.

Alcohol sponsorship of a summer of sport: a frequency analysis of alcohol marketing during major sports events on New Zealand television.

AIMS: This research aims to assess the nature and extent of alcohol marketing through sport sponsorship over a summer of televised sport in New Zealand. METHODS: Frequency analysis of New Zealand television broadcasts of five international sporting events during the summer of 2014-2015. Broadcasts were analysed to identify the percentage of time when alcohol brands were visible during game-play. The number of independent alcohol brand exposures was recorded. RESULTS: Alcohol brands were observed during every televised event. Audiences were exposed to between 1.6 and 3.8 alcohol brand exposures per minute. Alcohol brands were visible between 42 and 777 times across the games examined. For three out of the five events alcohol brands were visible for almost half of the game. CONCLUSION: Alcohol sponsorship was prevalent in international sport on New Zealand television. Given the popularity of broadcast sport, especially with children, there is an urgent need for regulation of alcohol sponsorship of sport. There are viable models of alcohol sponsorship replacement but their implementation requires the will of both sporting organisations and politicians. This research adds weight to arguments to implement recommendations to remove all alcohol sponsorship of sport.

Comparison of initial cell retention and clearance kinetics after subendocardial or subepicardial injections of endothelial progenitor cells in a canine myocardial infarction model.

UNLABELLED: Neither intravenous nor intracoronary routes provide targeted stem cell delivery to recently infarcted myocardium in sufficient quantities. Direct routes appear preferable. However, most prior studies have used epicardial injections, which are not practical for routine clinical use. The objective of this study was to compare cell retention and clearance kinetics between a subepicardial and a subendocardial technique. METHODS: We evaluated 7 dogs with each technique, using (111)In-tropolone-labeled endothelial progenitor cells and serial SPECT/CT for 15 d after injection. RESULTS: In vivo indium imaging demonstrated comparable degrees of retention: 57% +/- 15% for the subepicardial injections and 54% +/- 26% for the subendocardial injections. Clearance half-lives were also similar at 69 +/- 26 and 60 +/- 21 h, respectively. CONCLUSION: This study demonstrates that subendocardial injections, clinically more practical, show clearance kinetics comparable to those of subepicardial injections and will facilitate the ultimate clinical use of this treatment modality.