Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress.

Endothelial microparticles (EMPs) are endothelium-derived submicron vesicles that are released in response to diverse stimuli and are elevated in cardiovascular disease, which is correlated with risk factors. This study investigates the effect of EMPs on endothelial cell function and dysfunction in a model of free fatty acid (FFA) palmitate-induced oxidative stress. EMPs were generated from TNF-α-stimulated HUVECs and quantified by using flow cytometry. HUVECs were treated with and without palmitate in the presence or absence of EMPs. EMPs were found to carry functional eNOS and to protect against oxidative stress by positively regulating eNOS/Akt signaling, which restored NO production, increased superoxide dismutase and catalase, and suppressed NADPH oxidase and reactive oxygen species (ROS) production, with the involvement of NF-erythroid 2-related factor 2 and heme oxygenase-1. Conversely, under normal conditions, EMPs reduced NO release and increased ROS and redox-sensitive marker expression. In addition, functional assays using EMP-treated mouse aortic rings that were performed under homeostatic conditions demonstrated a decline in endothelium-dependent vasodilatation, but restored the functional response under lipid-induced oxidative stress. These data indicate that EMPs harbor functional eNOS and potentially play a role in the feedback loop of damage and repair during homeostasis, but are also effective in protecting against FFA-induced oxidative stress; thus, EMP function is reflected by the microenvironment.-Mahmoud, A. M., Wilkinson, F. L., McCarthy, E. M., Moreno-Martinez, D., Langford-Smith, A., Romero, M., Duarte, J., Alexander, M. Y. Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress

Obstetric Outcomes in Women with Rheumatic Disease and COVID-19 in the Context of Vaccination Status

OBJECTIVE: To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy. METHODS: Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020-25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi -square or Fisher's exact test. RESULTS: There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2%(n = 2). CONCLUSION: In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy

Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: results from the British Isles Lupus Assessment Group Biologics Register.

OBJECTIVES: To describe the baseline characteristics of SLE patients requiring biologic therapy in the UK and to explore short term efficacy and infection rates associated with rituximab (RTX) use. METHODS: Patients commencing biologic therapy for refractory SLE and who consented to join BILAG-BR were analysed. Baseline characteristics, disease activity (BILAG 2004/SLEDAI-2K) and rates of infection over follow-up were analysed. Response was defined as loss of all A and B BILAG scores to ⩽ 1 B score with no new A/B scores in other organ systems at 6 months. RESULTS: Two hundred and seventy SLE patients commenced biologic therapy from September 2010 to September 2015, most commonly RTX (n = 261). Two hundred and fifty (93%) patients were taking glucocorticoids at baseline at a median [interquartile range (IQR)] oral dose of 10 mg (5-20 mg) daily. Response rates at 6 months were available for 68% of patients. The median (IQR) BILAG score was 15 (10-23) at baseline and 3 (2-12) at 6 months (P < 0.0001). The median (IQR) SLEDAI-2K reduced from 8 (5-12) to 4 (0-7) (P < 0.001). Response was achieved in 49% of patients. There was also a reduction in glucocorticoid use to a median (IQR) dose of 7.5 mg (5-12 mg) at 6 months (P < 0.001). Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. A higher proportion of early infections were non-respiratory (odds ratio = 1.98, 95% CI: 0.99, 3.9; P = 0.049). CONCLUSION: RTX is safe and is associated with improvement in disease activity in refractory SLE patients with concomitant reductions in glucocorticoid use. Early vigilance for infection post-infusion is important to further improve treatment risks and benefits

Dysregulation of cytokine and monocyte function in systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterised by the presence of antibodies that recognise and target both protein and nucleic acid autoantigens. Elevated levels of a number of cytokines are a hallmark feature of disease, with B Lymphocyte Stimulator (BLyS) in particular showing an association with disease activity in prospective studies. Indeed an anti-BLyS targeted therapy, belimumab, has been successfully introduced for the treatment of SLE. In addition to cytokines the role that the innate immune system plays in disease pathogenesis is increasingly recognised with aberrant monocyte/macrophage function having been identified in SLE patients. Given the pivotal role that both monocytes and cytokines play in SLE we sought to investigate the role these may play in an Irish SLE cohort. We identified BLyS as the pro-inflammatory cytokine that appears to have the strongest association with both disease activity, damage accrual as well as clinical phenotypes in SLE in Irish patients. In addition we investigated the effect of BLyS on monocyte function in SLE. Results demonstrated that BLyS promotes aberrant activation of multiple signalling pathways in healthy and SLE patient monocytes resulting in increased expression of a number of genes such a IL-6, IFN-a and BLyS itself, all of which play significant roles in SLE. We have also shown that BLyS stimulation results in enhanced activation and antigen presenting capacity of SLE patient monocytes with a consequential enhancement of T cell activation also observed on co-culture experiments. Finally we investigated the effect of BLyS on monocyte subset differentiation and microRNA expression. These investigations highlighted a role for BLyS in inducing a mixed monocyte population in SLE whilst at the same time identifying a number of microRNAs such mir-155-5p, mir-1246, mir- 132-3p and mir-125a-5p that a differentially expressed in SLE patients when compared to controls. Overall these preliminary findings highlight potential novel mechanisms that may be used to regulate BLyS production. Thus our findings have not only contributed to the understanding behind the molecular pathogenesis of SLE but also underlined the therapeutic potential in manipulating BLyS levels fo r the tre a tm e n t o f SLE.</p

The major autolysin is redundant forstaphylococcus aureususa300 lac je2 virulence in a murine device-related infection model

The major Staphylococcus aureus autolysin, Atl, has been implicated in attachment to surfaces and release of extracellular DNA during biofilm formation under laboratory conditions. Consistent with this, polyclonal antibodies to the amidase and glucosaminidase domains of Atl inhibited in vitro biofilm formation. However, in a murine model of device-related infection the community-associated S. aureus strain USA300 LAC JE2 established a successful infection in the absence of atl. These data indicate that Atl activity is not required for biofilm production in this infection model and reveal the importance of characterizing the contribution of biofilm phenotypes to virulence under in vivo conditions

PROTOCOL: Enhancing men's awareness of testicular diseases (E-MAT) feasibility trial: Protocol for a mixed method process evaluation

Background: Testicular cancer (TC) is the most common malignancy in men under 50 years. Athletes are particularly at risk of testicular trauma and diseases. Experiencing negative testicular symptoms does not necessarily imply that men seek help. Men’s awareness of testicular diseases is often lacking and their intention to seek help for testicular symptoms is sub-optimal. The use of virtual reality (VR) may be effective in promoting men’s awareness of testicular diseases. The Enhancing Men's Awareness of Testicular diseases (E-MAT) feasibility trial aims to test the effect of E-MATVR (intervention; interactive experience using virtual reality [VR]) compared to information delivered Electronically E-MATE (control; same information as E-MATVR delivered as plain text and images) on testicular knowledge, and testicular self-examination among male athletes affiliated with a national sports organisation. The overall aim of this mixed method process evaluation will be to describe (i) the experiences of participants and key stakeholders (e.g., researchers); (ii) the perceived effectiveness of intervention components; (iii) acceptability of the feasibility trial and intervention procedures; (iv) the relationship between implementation, mechanisms, and context; and (v) the barriers and facilitators to support effective conduct of a future definitive trial.   Methods: This mixed method process evaluation will use a descriptive realist evaluation. Quantitative data will be gathered using a usability and satisfaction survey, in addition to fidelity checks during intervention delivery. Quantitative data will be analysed using descriptive and inferential statistics. Qualitative data will be gathered from semi-structured interviews and focus groups with participants and key stakeholders to investigate their experiences of E-MATVR and E-MATE, and explore areas for improvement. Thematic analysis of transcripts will be conducted. Conclusions: This process evaluation will provide an in-depth understanding of how the interventions worked within this cohort and lessons for a future definitive trial

The major autolysin is redundant forstaphylococcus aureususa300 lac je2 virulence in a murine device-related infection model

The major Staphylococcus aureus autolysin, Atl, has been implicated in attachment to surfaces and release of extracellular DNA during biofilm formation under laboratory conditions. Consistent with this, polyclonal antibodies to the amidase and glucosaminidase domains of Atl inhibited in vitro biofilm formation. However, in a murine model of device-related infection the community-associated S. aureus strain USA300 LAC JE2 established a successful infection in the absence of atl. These data indicate that Atl activity is not required for biofilm production in this infection model and reveal the importance of characterizing the contribution of biofilm phenotypes to virulence under in vivo conditions