The Role of Immunometabolism in the Pathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder in which pathogenic abnormalities within both the innate and adaptive immune response have been described. In order to activated, proliferate and maintain this immunological response a drastic upregulation in energy metabolism is required. Recently, a greater understanding of these changes in cellular bioenergetics have provided new insight into the links between immune response and the pathogenesis of a number of diseases, ranging from cancer to diabetes and multiple sclerosis. In this review, we highlight the latest understanding of the role of immunometabolism in SLE with particular focus on the role of abnormal mitochondrial function, lipid metabolism, and mTOR signaling in the immunological phenomenon observed in the SLE. We also consider what implications this has for future therapeutic options in the management of the disease in future

Association of treatments for acute myocardial infarction and survival for seven common comorbidity states : a nationwide cohort study

BACKGROUND: Comorbidity is common and has a substantial negative impact on the prognosis of patients with acute myocardial infarction (AMI). Whilst receipt of guideline-indicated treatment for AMI is associated with improved prognosis, the extent to which comorbidities influence treatment provision its efficacy is unknown. Therefore, we investigated the association between treatment provision for AMI and survival for seven common comorbidities. METHODS: We used data of 693,388 AMI patients recorded in the Myocardial Ischaemia National Audit Project (MINAP), 2003-2013. We investigated the association between comorbidities and receipt of optimal care for AMI (receipt of all eligible guideline-indicated treatments), and the effect of receipt of optimal care for comorbid AMI patients on long-term survival using flexible parametric survival models. RESULTS: A total of 412,809 [59.5%] patients with AMI had at least one comorbidity, including hypertension (302,388 [48.7%]), diabetes (122,228 [19.4%]), chronic obstructive pulmonary disease (COPD, 89,221 [14.9%]), cerebrovascular disease (51,883 [8.6%]), chronic heart failure (33,813 [5.6%]), chronic renal failure (31,029 [5.0%]) and peripheral vascular disease (27,627 [4.6%]). Receipt of optimal care was associated with greatest survival benefit for patients without comorbidities (HR 0.53, 95% CI 0.51-0.56) followed by patients with hypertension (HR 0.60, 95% CI 0.58-0.62), diabetes (HR 0.83, 95% CI 0.80-0.87), peripheral vascular disease (HR 0.85, 95% CI 0.79-0.91), renal failure (HR 0.89, 95% CI 0.84-0.94) and COPD (HR 0.90, 95% CI 0.87-0.94). For patients with heart failure and cerebrovascular disease, optimal care for AMI was not associated with improved survival. CONCLUSIONS: Overall, guideline-indicated care was associated with improved long-term survival. However, this was not the case in AMI patients with concomitant heart failure or cerebrovascular disease. There is therefore a need for novel treatments to improve outcomes for AMI patients with pre-existing heart failure or cerebrovascular disease

‘You can’t start a car when there’s no petrol left’: a qualitative study of patient, family and clinician perspectives on implantable cardioverter defibrillator deactivation

Objective: To explore the attitudes towards implantable cardioverter defibrillator (ICD) deactivation and initiation of deactivation discussions among patients, relatives and clinicians. Design: A multiphase qualitative study consisting of in situ hospital ICD clinic observations, and semistructured interviews of clinicians, patients and relatives. Data were analysed using a constant comparative approach. Setting: One tertiary and two district general hospitals in England. Participants: We completed 38 observations of hospital consultations prior to ICD implantation, and 80 interviews with patients, family members and clinicians between 2013 and 2015. Patients were recruited from preimplantation to postdeactivation. Clinicians included cardiologists, cardiac physiologists, heart failure nurses and palliative care professionals. Results: Four key themes were identified from the data: the current status of deactivation discussions; patients’ perceptions of deactivation; who should take responsibility for deactivation discussions and decisions; and timing of deactivation discussions. We found that although patients and doctors recognised the importance of advance care planning, including ICD deactivation at an early stage in the patient journey, this was often not reflected in practice. The most appropriate clinician to take the lead was thought to be dependent on the context, but could include any appropriately trained member of the healthcare team. It was suggested that deactivation should be raised preimplantation and regularly reviewed. Identification of trigger points postimplantation for deactivation discussions may help ensure that these are timely and inappropriate shocks are avoided. Conclusions: There is a need for early, ongoing and evolving discussion between ICD recipients and clinicians regarding the eventual need for ICD deactivation. The most appropriate clinician to instigate deactivation discussions is likely to vary between patients and models of care. Reminders at key trigger points, and routine discussion of deactivation at implantation and during advance care planning could prevent distressing experiences for both the patient and their family at the end of life

Validation of a priori CME arrival predictions made using real-time heliospheric imager observations

Between December 2010 and March 2013, volunteers for the Solar Stormwatch (SSW) Citizen Science project have identified and analyzed coronal mass ejections (CMEs) in the near real-time Solar Terrestrial Relations Observatory Heliospheric Imager observations, in order to make “Fearless Forecasts” of CME arrival times and speeds at Earth. Of the 60 predictions of Earth-directed CMEs, 20 resulted in an identifiable Interplanetary CME (ICME) at Earth within 1.5–6 days, with an average error in predicted transit time of 22 h, and average transit time of 82.3 h. The average error in predicting arrival speed is 151 km s−1, with an average arrival speed of 425km s−1. In the same time period, there were 44 CMEs for which there are no corresponding SSW predictions, and there were 600 days on which there was neither a CME predicted nor observed. A number of metrics show that the SSW predictions do have useful forecast skill; however, there is still much room for improvement. We investigate potential improvements by using SSW inputs in three models of ICME propagation: two of constant acceleration and one of aerodynamic drag. We find that taking account of interplanetary acceleration can improve the average errors of transit time to 19 h and arrival speed to 77 km s−1

DNA barcoding the native flowering plants and conifers of Wales

We present the first national DNA barcode resource that covers the native flowering plants and conifers for the nation of Wales (1143 species). Using the plant DNA barcode markers rbcL and matK, we have assembled 97.7% coverage for rbcL, 90.2% for matK, and a dual-locus barcode for 89.7% of the native Welsh flora. We have sampled multiple individuals for each species, resulting in 3304 rbcL and 2419 matK sequences. The majority of our samples (85%) are from DNA extracted from herbarium specimens. Recoverability of DNA barcodes is lower using herbarium specimens, compared to freshly collected material, mostly due to lower amplification success, but this is balanced by the increased efficiency of sampling species that have already been collected, identified, and verified by taxonomic experts. The effectiveness of the DNA barcodes for identification (level of discrimination) is assessed using four approaches: the presence of a barcode gap (using pairwise and multiple alignments), formation of monophyletic groups using Neighbour-Joining trees, and sequence similarity in BLASTn searches. These approaches yield similar results, providing relative discrimination levels of 69.4 to 74.9% of all species and 98.6 to 99.8% of genera using both markers. Species discrimination can be further improved using spatially explicit sampling. Mean species discrimination using barcode gap analysis (with a multiple alignment) is 81.6% within 10×10 km squares and 93.3% for 2×2 km squares. Our database of DNA barcodes for Welsh native flowering plants and conifers represents the most complete coverage of any national flora, and offers a valuable platform for a wide range of applications that require accurate species identification

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM). METHODS: RNA-sequencing was performed on CD4+, CD8+, CD14+ and CD19+ cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by 13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35. RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC. CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases

Innovative organotypic in vitro models for safety assessment: aligning with regulatory requirements and understanding models of the heart, skin, and liver as paradigms

The development of improved, innovative models for the detection of toxicity of drugs, chemicals, or chemicals in cosmetics is crucial to efficiently bring new products safely to market in a cost-effective and timely manner. In addition, improvement in models to detect toxicity may reduce the incidence of unexpected post-marketing toxicity and reduce or eliminate the need for animal testing. The safety of novel products of the pharmaceutical, chemical, or cosmetics industry must be assured; therefore, toxicological properties need to be assessed. Accepted methods for gathering the information required by law for approval of substances are often animal methods. To reduce, refine, and replace animal testing, innovative organotypic in vitro models have emerged. Such models appear at different levels of complexity ranging from simpler, self-organized three-dimensional (3D) cell cultures up to more advanced scaffold-based co-cultures consisting of multiple cell types. This review provides an overview of recent developments in the field of toxicity testing with in vitro models for three major organ types: heart, skin, and liver. This review also examines regulatory aspects of such models in Europe and the UK, and summarizes best practices to facilitate the acceptance and appropriate use of advanced in vitro models