Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Aims: Transient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis. Methods and results: TRPM7-deficient mice with deletion of the kinase domain (TRPM7+/Δkinase) were studied and molecular mechanisms investigated in TRPM7+/Δkinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGFβ) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-α] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/Δkinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/Δkinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/Δkinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/Δkinase mice. TRPM7+/Δkinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/Δkinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGFβ in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment. Conclusions: We identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes

Models of care for eating disorders : findings from a rapid review

Background: Delayed diagnosis, gaps in services and subsequent delays in specialist care and treatment lead to poorer health outcomes for individuals with eating disorders (EDs) and drive significant government healthcare expenditure. Given the significant disease burden associated with EDs, it is imperative that current implementation research is summarised to identify gaps in care and enable refinement for optimal patient outcomes. This review aimed to provide an updated synthesis on models of care for EDs in developed healthcare systems. Methods: This paper was conducted as part of a series of Rapid Reviews (RRs) to be published in a special series in the Journal of Eating Disorders. To provide a current and rigorous review, peer-reviewed articles published in the English language between 2009 and 2021 across three databases (ScienceDirect, PubMed and Ovid/Medline) were searched, with priority given to higher level evidence (e.g., meta-analyses, large population studies, Randomised Control Trials (RCTs)). The current review synthesises data from included studies investigating models of care for people with EDs. Results: Sixty-three studies (4.5% of the original RR) were identified, which included several diagnostic populations, the most common being Anorexia Nervosa (AN) (30.51%). Across EDs, specialist care was found to improve patient outcomes, with many patients effectively being treated in outpatient or day programs with multi-disciplinary teams, without the need for lengthy inpatient hospitalisation. Few studies investigated the interaction of different ED services (e.g., inpatient, community services, primary care), however stepped care models emerged as a promising approach to integrate ED services in a targeted and cost-effective way. Issues surrounding low treatment uptake, underdiagnosis, long waiting lists and limited hospital beds were also evident across services. Conclusion: Findings suggested further research into alternatives to traditional inpatient care is needed, with partial and shorter ‘hospitalisations’ emerging as promising avenues. Additionally, to tackle ongoing resource issues and ensure timely detection and treatment of EDs, further research into novel alternatives, such as active waiting lists or a greater role for primary care clinicians is needed. Plain English summary: This paper is part of a larger Rapid Review series carried out to guide Australia’s National Eating Disorders Research and Translation Strategy 2021–2031. Rapid reviews aim to thoroughly summarise an area of research over a short time period, typically to help with policymaking in this area. This Rapid Review summarises the evidence relating to how we care for people with eating disorders in Western healthcare systems. Topics covered include inpatient/hospital care, residential care, day programs, outpatient/community care, and referral pathways. Findings suggested specialist eating disorder services may enhance detection, referral, and patient care. Stepped care models presented as a cost-effective approach which may help with linkage between different eating disorder services. There was a trend towards shorter hospital stays and approaches which allow for greater connection with the community, such as day programs. Evidence was also found of treatment delays, due to system issues (long waiting lists, lack of accurate assessment and diagnosis) and patient-related barriers (stigma, recognition). Upskilling and involving primary care clinicians in diagnosis and referral as part of a stepped care model may help to address some of these concerns. Further efforts to improve mental health literacy and de-stigmatise help-seeking for eating disorders are needed

Prevention and early intervention in eating disorders : findings from a rapid review

Background Eating disorders (EDs) are complex psychological disorders, with low rates of detection and early intervention. They can lead to significant mental and physical health complications, especially if intervention is delayed. Given high rates of morbidity and mortality, low treatment uptake, and significant rates of relapse, it is important to examine prevention, early intervention, and early recognition initiatives. The aim of this review is to identify and evaluate literature on preventative and early intervention programs in EDs. Methods This paper is one of a series of Rapid Reviews, designed to inform the Australian National Eating Disorders Research and Translation Strategy 2021–2031, funded, and released by the Australian Government. To provide a current and rigorous review, peer-reviewed articles between 2009 and 2021 published in English were searched across three databases: ScienceDirect, PubMed and Ovid/Medline. Priority was given to high-level evidence including meta-analyses, systematic reviews, Randomised Control Trials, and large population studies. Findings from selected studies pertaining to prevention and early intervention in EDs were evaluated and are presented in this review. Results In total, 130 studies were identified in the current review, 72% relating to prevention and 28% to early intervention. Most programs were theory-driven and targeted one or more ED risk factors such as thin-ideal internalisation and/or body dissatisfaction. There is reasonable evidence to support prevention programs reducing risk factors, particularly as part of school or university-based programs, with established feasibility and relatively high acceptance among students. There is increasing evidence around the use of technology (to increase dissemination potential) and for use of mindfulness approaches (targeting emotional resilience). Few longitudinal studies assessing incident cases following participation in a prevention program exist. Conclusions Although several prevention and early intervention programs have been shown to significantly reduce risk factors, promote symptom recognition, and encourage help-seeking behaviour, most of these studies have been conducted in older adolescent and university aged students, past the age of peak ED onset. One of the most targeted risk factors, body dissatisfaction, is found in girls as young as 6 years old, indicating a need for further research implementing prevention initiatives at younger ages. Follow-up research is limited; thus, the long-term efficacy and effectiveness of studied programs is unknown. Greater attention should be paid to the implementation of prevention and early intervention programs in identified high-risk cohorts or diverse groups, where a more targeted approach may be necessary

TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt

Hyperaldosteronism causes cardiovascular disease as well as hypomagnesemia. Mechanisms are ill-defined but dysregulation of TRPM7, a Mg2+-permeable channel/α-kinase, may be important. We examined the role of TRPM7 in aldosterone-dependent cardiovascular and renal injury by studying aldosterone-salt treated TRPM7-deficient (TRPM7+/Δkinase) mice. Plasma/tissue [Mg2+] and TRPM7 phosphorylation were reduced in vehicle-treated TRPM7+/Δkinase mice, effects recapitulated in aldosterone-salt-treated wild-type mice. Aldosterone-salt treatment exaggerated vascular dysfunction and amplified cardiovascular and renal fibrosis, with associated increased blood pressure in TRPM7+/Δkinase mice. Tissue expression of Mg2+-regulated phosphatases (PPM1A, PTEN) was downregulated and phosphorylation of Smad3, ERK1/2, and Stat1 was upregulated in aldosterone-salt TRPM7-deficient mice. Aldosterone-induced phosphorylation of pro-fibrotic signaling was increased in TRPM7+/Δkinase fibroblasts, effects ameliorated by Mg2+ supplementation. TRPM7 deficiency amplifies aldosterone-salt-induced cardiovascular remodeling and damage. We identify TRPM7 downregulation and associated hypomagnesemia as putative molecular mechanisms underlying deleterious cardiovascular and renal effects of hyperaldosteronism

Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

yesInflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1−/− mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.British Heart Foundatio

Informing the development of Australia's national eating disorders research and translation strategy : a rapid review methodology

Background Eating disorders (EDs) are highly complex mental illnesses associated with significant medical complications. There are currently knowledge gaps in research relating to the epidemiology, aetiology, treatment, burden, and outcomes of eating disorders. To clearly identify and begin addressing the major deficits in the scientific, medical, and clinical understanding of these mental illnesses, the Australian Government Department of Health in 2019 funded the InsideOut Institute (IOI) to develop the Australian Eating Disorder Research and Translation Strategy, the primary aim of which was to identify priorities and targets for building research capacity and outputs. A series of rapid reviews (RR) were conducted to map the current state of knowledge, identify evidence gaps, and inform development of the national research strategy. Published peer-reviewed literature on DSM-5 listed EDs, across eight knowledge domains was reviewed: (1) population, prevalence, disease burden, Quality of Life in Western developed countries; (2) risk factors; (3) co-occurring conditions and medical complications; (4) screening and diagnosis; (5) prevention and early intervention; (6) psychotherapies and relapse prevention; (7) models of care; (8) pharmacotherapies, alternative and adjunctive therapies; and (9) outcomes (including mortality). While RRs are systematic in nature, they are distinct from systematic reviews in their aim to gather evidence in a timely manner to support decision-making on urgent or high-priority health concerns at the national level. Results Three medical science databases were searched as the primary source of literature for the RRs: Science Direct, PubMed and OVID (Medline). The search was completed on 31st May 2021 (spanning January 2009-May 2021). At writing, a total of 1,320 articles met eligibility criteria and were included in the final review. Conclusions For each RR, the evidence has been organised to review the knowledge area and identify gaps for further research and investment. The series of RRs (published separately within the current series) are designed to support the development of research and translation practice in the field of EDs. They highlight areas for investment and investigation, and provide researchers, service planners and providers, and research funders rapid access to quality current evidence, which has been synthesised and organised to assist decision-making

Socioeconomic deprivation and illness trajectory in the Scottish population after COVID-19 hospitalization

Background The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain. Methods A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28–60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status. Results Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation. Conclusions In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19

Modulation of vascular reactivity by perivascular adipose tissue (PVAT)

Purpose of Review: In this review we discuss the role of perivascular adipose tissue (PVAT) in the modulation of vascular contractility and arterial pressure, focusing on the role of the renin-angiotensin-aldosterone system and oxidative stress/inflammation. Recent Findings: PVAT possesses an relevant endocrine-paracrine activity, which may be altered in several pathophysiological and clinical conditions. During the last two decades it has been shown PVAT may modulate vascular reactivity. It has also been previously demonstrated that inflammation in adipose tissue may be implicated in vascular dysfunction. In particular, adipocytes secrete a number of adipokines with various functions, as well as several vasoactive factors, together with components of the renin-angiotensin system which may act at local or at systemic level. It has been shown that the anticontractile effect of PVAT is lost in obesity, probably as a consequence of the development of adipocyte hypertrophy, inflammation, and oxidative stress. Summary: Adipose tissue dysfunction is interrelated with inflammation and oxidative stress, thus contributing to endothelial dysfunction observed in several pathological and clinical conditions such as obesity and hypertension. Decreased local adiponectin level, macrophage recruitment and infiltration, and activation of renin-angiotensin-aldosterone system could play an important role in this regards