Augmenting Endogenous Levels of Retinal Annexin A1 Suppresses Uveitis in Mice

PURPOSE: The purpose of this study was to examine the expression of the anti-inflammatory protein Annexin A1 (AnxA1) in mice and human retinae during uveitis and to determine whether local administration of human recombinant AnxA1 (hrAnxA1) can suppress uveitis in mice. METHODS: Retinal sections from mice (healthy normal and uveitis) and postmortem human (no history of eye disease (n = 5) and uveitis (n = 7)) were stained for AnxA1 expression and imaged by immunofluorescence microscopy. AnxA1 cellular expression was determined by colabeling with CD45, glial fibrillary acidic protein (GFAP), and Iba-1 cells, with additional staining of AnxA1 receptors formyl peptide receptor 1 (FPR1) and FPRL1/FPR2. Mice with acute endotoxin-induced uveitis and chronic experimental autoimmune uveitis were treated locally by intravitreal injection with hrAnxA1, and disease was assessed by clinical scoring and quantification of leukocyte infiltrate via flow cytometry. RESULTS: Constitutive expression of AnxA1 was observed in both healthy mouse and human retinae, and its expression increased during uveitis compared to healthy controls. AnxA1 colocalizes predominantly with CD45(+) cells, GFAP(+) macroglia, and to a lesser extent, Iba-1(+) myeloid cells. We also demonstrate that local treatment with hrAnxA1 attenuates the severity of uveitis in mice. CONCLUSIONS: These data indicate that locally expressed AnxA1 is elevated in the retina during intraocular inflammation. We demonstrate that local administration of hrAnxA1 to augment levels results in suppression of uveitis in mice. TRANSLATIONAL RELEVANCE: Our data suggest that elevated expression of retinal AnxA1 in human uveitis may be immunoregulatory and that local supplementation with hrAnxA1 may provide a potential novel treatment for inflammatory eye diseases such as noninfectious uveitis

Unravelling the therapeutic potential of IL-33 for atrophic AMD

Age-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases “wet” or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD

Soluble CD200 Correlates With Interleukin-6 Levels in Sera of COPD Patients: Potential Implication of the CD200/CD200R Axis in the Disease Course

BACKGROUND: COPD represents a multifactorial lung disorder with high morbidity and mortality. Despite intensive research concerning the underlying disease mechanisms, the involvement of the CD200/CD200R axis in supporting or preventing the onset of COPD has not yet been addressed. Since the CD200/CD200R axis is crucially implicated in the maintenance of pulmonary immune homeostasis, we hypothesized that it might be involved in controlling the onset of COPD. METHODS: To address this, we analyzed the serum samples from COPD patients and normal controls for soluble (s) CD200 and correlated the data to COPD-relevant clinical parameters. In addition, basic studies were conducted in CD200-deficient and wild-type mice in which COPD-like inflammation was induced with elastase/LPS followed by lung and serum component analysis. RESULTS: We observed a positive correlation between serum sCD200 and IL-6 levels as well as a trend toward a negative correlation of sCD200 with vitamin D3 in COPD patients. Further investigations in mice revealed that despite elevated serum concentration of MMP-9 in CD200KO mice, the early onset of COPD-like lung inflammation was similar in CD200-deficient and wild-type animals in terms of immune cell infiltration, emphysematous changes, and mucus overproduction. CONCLUSIONS: While our murine studies suggest that the co-inhibitory molecule CD200 does not appear to play a prominent role in the early onset of COPD-like features, correlation of sCD200 serum levels with COPD-related parameters in humans with established disease revealed that the CD200/CD200R axis may be mechanistically linked to the disease course in COPD patients

Infliximab in chronic non-infectious paediatric uveitis refractory to previous biologic therapy

OBJECTIVES: To examine the outcome of infliximab treatment in patients with non-infectious paediatric uveitis who have previously failed biologic treatment. METHODS: A retrospective cohort study was performed at Bristol Eye Hospital, UK. Paediatric patients with chronic non-infectious uveitis who had been switched to infliximab due to inadequate uveitis control were identified. Two separate groups were evaluated: group 1 consisted of 20 children (36 eyes) who had been switched to infliximab following treatment failure with adalimumab (=in-class switching), while group 2 (5 patients; 9 eyes) included those who had been switched to infliximab from a non-TNF antagonist after failing several biologics (=across-class switching). The change in anterior chamber (AC) activity between baseline and 6- and 24-months follow-up was the primary outcome measure. RESULTS: A statistically significant reduction in AC activity was found between baseline and 6-months follow-up (RE: p = 0.002; LE: p < 0.001) and between baseline and 24-months follow-up (RE: p = 0.016; LE: p = 0.011) in group 1. No statistically significant difference was found for either eye in the number of steroid eye drops needed between time points or the difference in visual acuity in time. In group 2, analysis of change of AC activity, number of steroid eye drops and visual acuity failed to reach statistical significance. Treatment failure occurred in four patients (20% of group 1) and adverse events developed in six patients including three patients with acute infusion reactions. CONCLUSIONS: This study supports the efficacy and safety of infliximab in adalimumab-refractory patients with paediatric non-infectious uveitis

Portugal e o Porto de Sines na grande estratégia geoeconómica chinesa:a Belt and Road Initiative

Dissertação de Mestrado em EstratégiaEm 1978, com as reformas implementadas por Deng Xiaoping, a República Popular da China iniciou uma Grande Estratégia Geoeconómica que fez com que se encontre, em menos de quatro décadas, a disputar a liderança mundial com os EUA. A sua reemergência, num mundo pautado pela globalização, depende cada vez mais das relações comerciais internacionais. A Belt and Road Initiative é, assim, um meio desta projectar globalmente o seu poder económico, de modo a conseguir exportar o excesso da sua capacidade produtiva, ao mesmo tempo que garante o fornecimento dos recursos que necessita para a sustentabilidade da sua economia e consequentemente da manutenção do seu sistema político. Neste contexto, a presente dissertação visa compreender o potencial que a integração de Portugal terá na interconectividade desta Iniciativa chinesa a nível mundial. Em particular, pretende averiguar como a localização do Porto de Sines no ponto mais ocidental da Eurásia, a par com a excepcionalidade das suas características técnicas aumentam a possibilidade de Portugal vir ser incluído nos documentos oficiais chineses como parte da Belt and Road Initiative.In 1978, with the reforms implemented by Deng Xiaoping, the People's Republic of China began a new cycle focused on economic development that made it compete for world leadership with the United States of America in less than four decades. Its reemergence, in a world dominated by globalization, depends more and more on international trade relations. The Belt and Road Initiative is, in a way, a means of projecting its economic power globally, so as to be able to export the excess of its productive capacity, while guaranteeing the supply of resources that it needs for the sustainability of its economy and consequently the maintenance of its political system. In this context, the present dissertation aims to understand the potential that the integration of Portugal will have in the interconnectivity of this Chinese initiative worldwide. In particular, it seeks to ascertain how the location of the Port of Sines at the westernmost point of Eurasia, along with the exceptional technical characteristics of the port increases the possibility of Portugal being included in the Chinese official documents as part of the Belt and Road Initiative.N/

Assessment and in vivo scoring of murine experimental autoimmune uveoretinitis using optical coherence tomography

Despite advances in clinical imaging and grading our understanding of retinal immune responses and their morphological correlates in experimental autoimmune uveoretinitis (EAU), has been hindered by the requirement for post-mortem histology. To date, monitoring changes occurring during EAU disease progression and evaluating the effect of therapeutic intervention in real time has not been possible. We wanted to establish whether optical coherence tomography (OCT) could detect intraretinal changes during inflammation and to determine its utility as a tool for accurate scoring of EAU. EAU was induced in C57BL/6J mice and animals evaluated after 15, 26, 36 and 60 days. At each time-point, contemporaneous Spectralis-OCT scanning, topical endoscopic fundal imaging (TEFI), fundus fluorescein angiography (FFA) and CD45-immunolabelled histology were performed. OCT features were further characterised on retinal flat-mounts using immunohistochemistry and 3D reconstruction. Optic disc swelling and vitreous opacities detected by OCT corresponded to CD45+ cell infiltration on histology. Vasculitis identified by FFA and OCT matched perivascular myeloid and T-cell infiltrates and could be differentiated from unaffected vessels. Evolution of these changes could be followed over time in the same eye. Retinal folds were visible and found to encapsulate mixed populations of activated myeloid cells, T-cells and microglia. Using these features, an OCT-based EAU scoring system was developed, with significant correlation to validated histological (Pearson r(2) = 0.6392, P<0.0001, n = 31 eyes) and TEFI based scoring systems (r(2) = 0.6784, P<0.0001). OCT distinguishes the fundamental features of murine EAU in vivo, permits dynamic assessment of intraretinal changes and can be used to score disease severity. As a result, it allows tissue synchronisation with subsequent cellular and functional assessment and greater efficiency of animal usage. By relating OCT signals with immunohistochemistry in EAU, our findings offer the opportunity to inform the interpretation of OCT changes in human uveitis

Uveitis Associated with Monogenic Autoinflammatory Syndromes in Children

Monogenic autoinflammatory syndromes (MAISs), are caused by pathogenic genetic variants in the innate immune system, leading to dysregulation and aberrant inflammasome activation spontaneously or with minimal triggering. The diagnosis and treatment of MAISs can be intricate, relying on an increased recognition of potential differential diagnoses. This review examines the clinical features of MAIS, with a special focus on uveitis. It also evaluates treatment options and assesses the effects of activating molecular and cytokine pathways

Cross sectional, qualitative thematic analysis of patient perspectives of disease impact in juvenile idiopathic arthritis-associated uveitis

BACKGROUND: Chronic health conditions in children can have a significant impact on their quality of life. The aim of this study was to explore the subjective experience of children and young people being treated for chronic, non-infectious uveitis associated with a systemic disease such as juvenile idiopathic arthritis. METHODS: A semi-structured interview was conducted with 10 children and young people aged between 6 and 18 years of age and their parents. RESULTS: Preliminary thematic analysis indicated that both the treatment and complications of the disorder have a significant impact on the quality of life and emotional well-being of patients, not only in terms of the discomfort experienced but also in perceptions of social isolation, anxiety and sense of injustice. CONCLUSION: This study shows that themes including "impact on school", "social factors" and "emotional reactions" are important domains influencing health-related quality of life (HRQoL) in children with chronic uveitis. Inclusion of questions relating to these domains should be considered in future uveitis-specific tools examining HRQoL in these patients

Resonances in rotationally inelastic scattering of OH(X2ΠX^2\Pi) with helium and neon

We present detailed calculations on resonances in rotationally and spin-orbit inelastic scattering of OH (X\,^2\Pi, j=3/2, F_1, f) radicals with He and Ne atoms. We calculate new \emph{ab initio} potential energy surfaces for OH-He, and the cross sections derived from these surfaces compare favorably with the recent crossed beam scattering experiment of Kirste \emph{et al.} [Phys. Rev. A \textbf{82}, 042717 (2010)]. We identify both shape and Feshbach resonances in the integral and differential state-to-state scattering cross sections, and we discuss the prospects for experimentally observing scattering resonances using Stark decelerated beams of OH radicals.Comment: 14 pages, 15 Figure