The Role of Cathepsin D in the Pathophysiology of Heart Failure and its Potentially Beneficial Properties:a translational approach

Aims: Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF. Methods and results: Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT-CHF index study. Results were validated in 1700 HF patients from the BIOSTAT-CHF validation cohort. The primary combined outcome was all-cause mortality and/or HF hospitalizations. Human pluripotent stem cell-derived cardiomyocytes were subjected to hypoxic, pro-inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin-6 and N-terminal pro-B-type natriuretic peptide (P < 0.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02–1.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09–1.40). In vitro experiments demonstrated that human stem cell-derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA-mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress-induced metabolism, and increased release of troponin T from human stem cell-derived cardiomyocytes under stress. Conclusions: Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF

Attribution of neuropsychiatric symptoms and prioritisation of evidence in the diagnosis of neuropsychiatric lupus:a mixed method study

OBJECTIVE: Neuropsychiatric lupus (NPSLE) is challenging to diagnose. Many neuropsychiatric symptoms, such as headache and hallucinations, cannot be verified by tests or clinician assessment. We investigated prioritisations of methods for diagnosing NPSLE and attributional views.METHODS: Thematic and comparative analyses were used to investigate how clinicians prioritise sources of evidence from a 13-item list, and explore discordances in clinician and patient perspectives on attribution.RESULTS: We identified high levels of variability and uncertainty in clinicians' assessments of neuropsychiatric symptoms in SLE patients. In attributional decisions, clinicians (surveys n = 400, interviews n = 50) ranked clinicians' assessments above diagnostic tests (many of which they reported were often unenlightening in NPSLE). Clinicians ranked patient opinion of disease activity last, and 46% of patients reported never/rarely having been asked if their SLE was flaring, despite experienced patients often having "attributional insight". SLE Patients (surveys n = 676, interviews n = 27) estimated higher attributability of neuropsychiatric symptoms to the direct effects of SLE on the nervous system than clinicians (p &lt; 0.001 for all symptoms excluding mania), and 24% reported that their self-assessment of disease activity was never/rarely concordant with their clinicians. Reports of misattributions were common, particularly of non-verifiable diffuse symptoms. Terminology differed between clinicians and influenced attribution estimates.CONCLUSION: NPSLE diagnostic tests and clinician assessments have numerous limitations, particularly in detecting diffuse neuropsychiatric symptoms that can be directly attributable and benefit from immunosuppression. Our findings suggest that incorporating patient attributional insights-although also subject to limitations-may improve attribution decision-making. Consensus regarding terminology and interpretations of "direct attributability" is required.</p

Technology for monitoring everyday prosthesis use : a systematic review

Abstract: Background: Understanding how prostheses are used in everyday life is central to the design, provision and evaluation of prosthetic devices and associated services. This paper reviews the scientific literature on methodologies and technologies that have been used to assess the daily use of both upper- and lower-limb prostheses. It discusses the types of studies that have been undertaken, the technologies used to monitor physical activity, the benefits of monitoring daily living and the barriers to long-term monitoring, with particular focus on low-resource settings. Methods: A systematic literature search was conducted in PubMed, Web of Science, Scopus, CINAHL and EMBASE of studies that monitored the activity of prosthesis users during daily-living. Results: Sixty lower-limb studies and 9 upper-limb studies were identified for inclusion in the review. The first studies in the lower-limb field date from the 1990s and the number has increased steadily since the early 2000s. In contrast, the studies in the upper-limb field have only begun to emerge over the past few years. The early lower-limb studies focused on the development or validation of actimeters, algorithms and/or scores for activity classification. However, most of the recent lower-limb studies used activity monitoring to compare prosthetic components. The lower-limb studies mainly used step-counts as their only measure of activity, focusing on the amount of activity, not the type and quality of movements. In comparison, the small number of upper-limb studies were fairly evenly spread between development of algorithms, comparison of everyday activity to clinical scores, and comparison of different prosthesis user populations. Most upper-limb papers reported the degree of symmetry in activity levels between the arm with the prosthesis and the intact arm. Conclusions: Activity monitoring technology used in conjunction with clinical scores and user feedback, offers significant insights into how prostheses are used and whether they meet the user’s requirements. However, the cost, limited battery-life and lack of availability in many countries mean that using sensors to understand the daily use of prostheses and the types of activity being performed has not yet become a feasible standard clinical practice. This review provides recommendations for the research and clinical communities to advance this area for the benefit of prosthesis users

Men, Mental Health and Elite Sport: a Narrative Review

Mental health in elite sport is receiving more publicity due to an increase in male athletes sharing their personal experiences. Sports injury is recognised as the major risk factor for psychological distress amongst male athletes, although anecdotally this may be that athletes are more likely to discuss their emotional wellbeing when related to the injury they are experiencing. Stress can be amplified within elite sport and the pressure they experience in relation to competition and performance can be exacerbated by adverse life events. This ongoing stress does not end when their sporting career does, it can follow them into retirement. The physical and psychological demands placed upon them by the sporting environment may predispose athletes to developing depression. As an athlete's symptoms of mental illness intensify, their performance can be negatively affected leaving them vulnerable and exposed to further symptoms of common mental disorders. The pressure of performance can also expose male athletes to overtraining syndrome which can be difficult to distinguish from depression. Male athletes are more vulnerable to eating disorders compared with males in the general population and they do have anxieties, particularly around their bodies, but find it difficult to disclose their concerns. In addition to this, male athletes are more likely to use substances, including opioids to improve both sport and non-sport performance.Despite the prevalence of common mental disorders in male athletes, stigma still exists, and although some athletes discuss their issues publicly after their career has ended, the majority of athletes prefer to remain silent. There remains a view that athletes who seek help for psychological problems may be seen as weak. Although there is an improvement in help-seeking attitudes within elite sport, further research and education is needed to encourage men to talk about their mental health, share their experiences and to enjoy a greater sense of emotional wellbeing

Neuropsychiatric symptoms in Systemic Lupus Erythematosus: mixed methods analysis of patient-derived attributional evidence in the international INSPIRE project

Objective: Attribution of neuropsychiatric symptoms in systemic lupus erythematosus (SLE) relies heavily on clinician assessment. Limited clinic time, variable knowledge, and symptom under-reporting contributes to discordance between clinician assessments and patient symptoms. We obtained attributional data directly from patients and clinicians in order to estimate and compare potential levels of direct attribution to SLE of multiple neuropsychiatric symptoms using different patient-derived measures. Methods: Quantitative and qualitative data analysed included: prevalence and frequency of neuropsychiatric symptoms, response to corticosteroids, and concurrence of neuropsychiatric symptoms with non-neuropsychiatric SLE disease activity. SLE patients were also compared with controls and inflammatory arthritis (IA) patients to explore attributability of neuropsychiatric symptoms to the direct disease effects on the brain/nervous system. Results: We recruited 2,817 participants, including 400 clinicians. SLE patients (n = 609) reported significantly higher prevalences of neuropsychiatric symptoms than controls (n = 463) and IA patients (n = 489). SLE and IA patients' quantitative data demonstrated multiple neuropsychiatric symptoms relapsing/remitting with other disease symptoms such as joint pain. Over 45% of SLE patients reported resolution/improvement of fatigue, positive sensory symptoms, severe headache, and cognitive dysfunction with corticosteroids. Evidence of direct attributability in SLE was highest for hallucinations and severe headache. SLE patients had greater reported improvement from corticosteroids (p= 0.008), and greater relapsing-remitting with disease activity (p< 0.001) in the comparisons with IA patients for severe headache. Clinician and patients reported insufficient time to discuss patient-reported attributional evidence. Symptoms viewed as indirectly related/non-attributable were often less prioritised for discussion and treatment. Conclusion: We found evidence indicating varying levels of direct attributability of both common and previously unexplored neuropsychiatric symptoms in SLE patients, with hallucinations and severe headache assessed as the most directly attributable. There may also be-currently under-estimated-direct effects on the nervous system in IA and other systemic rheumatological diseases

The main actors involved in parasitization of Heliothis virescens larva

At the moment of parasitization by another insect, the host Heliothis larva is able to defend itself by the activation of humoral and cellular defenses characterized by unusual reactions of hemocytes in response to external stimuli. Here, we have combined light and electron microscopy, staining reactions, and immunocytochemical characterization to analyze the activation and deactivation of one of the most important immune responses involved in invertebrates defense, i.e., melanin production and deposition. The insect host/parasitoid system is a good model to study these events. The activated granulocytes of the host insect are a major repository of amyloid fibrils forming a lattice in the cell. Subsequently, the exocytosed amyloid lattice constitutes the template for melanin deposition in the hemocel. Furthermore, cross-talk between immune and neuroendocrine systems mediated by hormones, cytokines, and neuromodulators with the activation of stress-sensoring circuits to produce and release molecules such as adrenocorticotropin hormone, alpha melanocyte-stimulating hormone, and neutral endopeptidase occurs. Thus, parasitization promotes massive morphological and physiological modifications in the host insect hemocytes and mimics general stress conditions in which phenomena such as amyloid fibril formation, melanin polymerization, pro-inflammatory cytokine production, and activation of the adrenocorticotropin hormone system occur. These events observed in invertebrates are also reported in the literature for vertebrates, suggesting that this network of mechanisms and responses is maintained throughout evolution

Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages

notes: PMCID: PMC4006850types: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov'tCandida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non-matured phagosomes is likely not triggered by initial recognition events via MAPK or NFκB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata.Deutsche ForschungsgemeinschaftNational Institutes for HealthWellcome TrustBBSR