4 research outputs found
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Secretion of IL-1ß from monocytes in gout is redox independent
The proinflammatory cytokine interleukin-1ß (IL-1ß) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1ß secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1ß secretion. Gout is a disease driven solely by IL-1ß secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1ß secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation
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OP0194 Inflammation-induced pain and fatigue in fibromyalgia and me/cfs and role of variant connective tissue
Background Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathophysiological mechanisms are under debate. It remains unclear whether dysregulated inflammation, induced either by an exogenous stimulus (eg a virus or other stressor), or autoimmunity, is of prime importance [2].Objectives 1. To determine in a novel human model the effects of an in vivo inflammatory challenge in the induction of pain and fatigue in fibromyalgia and ME/CFS compared to controls.2. Explore potential mediators and moderators involved.Methods Data were available for 48 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 22 matched controls, who had undergone a placebo controlled inflammatory challenge (typhoid vaccination) as part of ISRCTN78820481. Participants underwent full research diagnostic evaluation including a hypermobility assessment. Subjective pain and fatigue were assessed after saline injection and typhoid vaccination (VAS). Linear regression models were used to explore predictors, with adjustment for potential confounders (age/gender) and baseline levels as appropriate. Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1) pain and 2) fatigue induced by challenge and mediators/moderators included change in IL-6 induced by inflammatory challenge and hypermobility features.Results Being a patient rather than control significantly predicted inflammation-induced fatigue (B=14.89 (95%CI 3.29-26.50), t=2.56, p=0.013) and pain (B=12.88 (95%CI 0.65-25.10), t=2.11, p=0.039) after adjusting for levels induced by placebo. Induced pain was independently predicted by level of IL-6 induced by inflammatory challenge (B=23.44 (95%CI 5.15-41.72),t=2.57, p=0.013) as was induced fatigue (B=10.63 (95%CI 2.84-18.41), t=2.73, p=0.008) Mediated moderation analyses suggested the link to induced pain and fatigue through induced inflammation was associated with hypermobility features (Index of mediated moderation 11.02 (95%CI 1.45-22.73) and 6.20 (95%CI 0.07-13.64) respectively))Conclusion To our knowledge this is the first human study to evaluate directly the effect of an exogenous inflammatory challenge (typhoid vaccination) in a combined group of Fibromyalgia and ME/CFS patients. Il-6 was shown to be a critical mediator. This work strongly supports the hypothesis that inflammation is key to the pathophysiology of ME/CFS. We are evaluating associated CNS inflammation in the model, as well as other associations, such as autonomic dysfunction and hypermobility. Further understanding the mediators involved in the condition should in future open the way to testing targeted anti-inflammatory therapy.References [1]Eccles JA, Thompson B, Themelis K, Amato ML, Stocks R, Pound A, et al. Beyond bones: The relevance of variants of connective tissue (hypermobility) to fibromyalgia, ME/CFS and controversies surrounding diagnostic classification: an observational study. Clin Med (Lond). 2021;21(1):53-8.[2]Eccles JA, Davies KA. The challenges of chronic pain and fatigue. Clin Med (Lond). 2021;21(1):19-27.[3]Hayes AF. Partial, conditional, and moderated moderated mediation: Quantification, inference, and interpretation. Commun Monogr. 2018;85(1):4-40.</p
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Factors associated with HIV testing in people aged ⩾50 years: an integrated qualitative analysis of patients and healthcare providers
Background: Older people continue to be disproportionately affected by late HIV diagnosis, which results in increased morbidity and mortality. Despite high acceptance of HIV testing generally, older people are less likely to undergo testing than younger people. Two previous studies have been conducted, one focussing on patient-related and one focussing on clinician-related factors associated with HIV testing in older age (≥50 years) Objective: This study is an integrated analysis from two linked studies - one focused on patients, and one focussed on clinicians - to understand overlap in views and experiences of HIV testing in older age, to outline the clinical implications of the findings, and to highlight potential interventions to improve testing in this group. Methods: This qualitative study utilised semi-structured interviews conducted with 20 clinicians who were not HIV care specialists, but who had recently seen an older person prior to their HIV diagnosis, and 20 people who had been diagnosed late with HIV aged 50+. Interviews were audio recorded, transcribed verbatim and thematically analysed. The combined synthesis reported here was planned a priori as part of a sequential design. Results: Seven clinician and seven patient related themes were associated with undergoing HIV testing in older age. This paper discusses the four themes that were common to both groups: poor knowledge, incorrect symptom attribution, inaccurate perception of risk, and stigma. Conclusion: Both clinician and patient factors associated with testing will have to be addressed in order to increase HIV testing in older people and reduce the likelihood of late diagnosis . Findings from overlapping themes suggest several areas for intervention: (1) Routine screening as part of existing clinical contacts aimed at older people to eliminate the need to attribute symptoms to HIV or assess risk; (2) Specific and tailored education materials for clinicians and older people which utilise appropriate modalities; (3) Tailored HIV testing services: either specific clinics for older people at existing sexual health services, or dedicated services in primary care</p
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Is joint hypermobility linked to self-reported non-recovery from COVID-19? Case–control evidence from the British COVID Symptom Study Biobank
What is the clinical problem?The COVID-19 pandemic and the burden of subsequent limited recovery from COVID-191 present some of the greatest clinical challenges of a generation. Such individuals not fully recovered from COVID-19 may self-identify under the collective patient-advocated term ‘long COVID’ and/or meet one of the various clinical definitions created to describe persistent symptoms. National data from March 2023 indicate that around 3% of the UK population had not recovered fully from COVID-19 infection. The most common associated symptoms are fatigue (72%), difficulty concentrating (51%), muscle aches/pain (49%) and shortness of breath (48%). However, more than 200 symptoms, expressed across multiple organ systems, are associated with delayed recovery following acute COVID-19 infection. A history of infection with COVID-19 is now commonplace, so a precise and mechanistic understanding of factors that predispose to enduring symptoms and limit recovery will help design and deliver effective healthcare to improve the quality of life of millions of affected individuals worldwide. Evidently, the presentation of long COVID is heterogeneous. These distinct profiles need further characterisation in order to design personalised care and to target effective treatment across populations and age groups.What do we know about long COVID at this point?In addition to demographic factors, notably female sex, the likelihood of developing long COVID appears to be increased by the presence of pre-existing activity-limiting health conditions or disabilities. Fibromyalgia, irritable bowel syndrome, migraine, anxiety, depression and back pain are among a number of conditions identified as raising the risk of long COVID. However, other studies on long COVID have failed to find specific associations, particularly in relation to pre-existing affective disorders. There is growing awareness of the symptomatic overlap with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), in which viral infection is often implicated as a trigger. Indeed, such research may help elucidate the aetiology of long COVID. Moreover, cardiovascular autonomic dysfunction, particularly postural orthostatic tachycardia syndrome (POTS), may be precipitated by COVID-19 and expressed in long COVID. POTS is a chronic and often disabling disorder characterised by orthostatic intolerance with an excessive increase in heart rate without hypotension during upright posture. Patients often experience a constellation of other typical symptoms overlapping with long COVID including fatigue and exercise intolerance, and it is established that the onset of POTS may be precipitated by immunological stressors. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the precise aetiology of the syndrome is incompletely understood and is undoubtedly multifaceted. Indeed, the presence of POTS is considered to be a major sub-phenotype of long COVID, with an estimated prevalence of 30–75% in symptomatic patients, depending on methodology. These conditions (POTS, ME/CFS) are archetypes of seemingly complex poorly-understood multisystem illnesses, alongside hypermobility spectrum disorder (HSD) and Ehlers–Danlos syndrome, which we discuss further below. The mechanisms and pathobiology behind the association of long COVID with these multiple co-occurring conditions are currently poorly understood. However, convergent biological mechanisms, including dysregulated autonomic, inflammatory and metabolic processes, are increasingly implicated in the expression and maintenance of long COVID. Understanding and managing such complexity can be challenging to clinicians who may resort to heuristic classifications such as ‘functional’ disorder. As a consequence, many patients report stigmatisation and can wait years for a diagnosis to access appropriately targeted and potentially effective treatment. Similar perceptions appear to be emerging in relation to long COVID. This may compromise the planning and delivery of cost-effective and timely therapy, both at the level of the individual patients and the level of healthcare service provision.There is growing interest in how variant connective tissue (often recognised by the presence of generalised joint hypermobility (GJH)) may represent a common constitutional factor predisposing to such complex multisystem conditions and disorders. GJH is a characteristic marker of hereditary disorders of connective tissue, which ultimately compromises a matrix of proteins that includes collagens, elastins, fibrillins and tenascins. Joint hypermobility is typically more common in females and declines with age. GJH itself is not necessarily a medical problem, but certain clinical phenotypes, notably hypermobile Ehlers–Danlos syndrome (hEDS; previously known as EDS hypermobility type/EDS type-III) and hypermobility spectrum disorder (HSD) are associated with clinically significant issues, including chronic disabling fatigue and dysautonomia. Around 20% of the UK population fulfil the criteria for GJH as an indicator of variant connective tissue structure. However, less clear is whether individuals with GJH are predisposed to COVID-19 infection and impaired recovery.</p