Non-coding RNAs versus protein biomarkers to diagnose and differentiate acute stroke:Systematic review and meta-analysis

BACKGROUND: Stroke diagnosis is dependent on lengthy clinical and neuroimaging assessments, while rapid treatment initiation improves clinical outcome. Currently, more sensitive biomarker assays of both non-coding RNA- and protein biomarkers have improved their detectability, which could accelerate stroke diagnosis. This systematic review and meta-analysis compares non-coding RNA- with protein biomarkers for their potential to diagnose and differentiate acute stroke (subtypes) in (pre-)hospital settings.METHODS: We performed a systematic review and meta-analysis of studies evaluating diagnostic performance of non-coding RNA- and protein biomarkers to differentiate acute ischemic and hemorrhagic stroke, stroke mimics, and (healthy) controls. Quality appraisal of individual studies was assessed using the QUADAS-2 tool while the meta-analysis was performed with the sROC approach and by assessing pooled sensitivity and specificity, diagnostic odds ratios, positive- and negative likelihood ratios, and the Youden Index.SUMMARY OF REVIEW: 112 studies were included in the systematic review and 42 studies in the meta-analysis containing 11627 patients with ischemic strokes, 2110 patients with hemorrhagic strokes, 1393 patients with a stroke mimic, and 5548 healthy controls. Proteins (IL-6 and S100 calcium-binding protein B (S100B)) and microRNAs (miR-30a) have similar performance in ischemic stroke diagnosis. To differentiate between ischemic- or hemorrhagic strokes, glial fibrillary acidic protein (GFAP) levels and autoantibodies to the NR2 peptide (NR2aAb, a cleavage product of NMDA neuroreceptors) were best performing whereas no investigated protein or non-coding RNA biomarkers differentiated stroke from stroke mimics with high diagnostic potential.CONCLUSIONS: Despite sampling time differences, circulating microRNAs (&lt; 24 h) and proteins (&lt; 4,5 h) perform equally well in ischemic stroke diagnosis. GFAP differentiates stroke subtypes, while a biomarker panel of GFAP and UCH-L1 improved the sensitivity and specificity of UCH-L1 alone to differentiate stroke.</p

Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R2 0.04, R = 0.21, p = 0.001, 95% CI 0.103–0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF

Narrative medicine pinpoints loss of autonomy and stigma in Parkinson’s disease

Abstract Parkinson’s disease characteristics can create a self-perceived sense of stigmatization and disapproval by others, thereby affecting self-perceived autonomy. This study investigated the metaphors related to the loss of autonomy and stigma in stories and drawings of Parkinson’s disease. We compare a contemporary first-person illness narrative and -drawing from a person with Parkinson’s disease, with two novels (Jonathan Franzen’s The Corrections and Claudia Piñeiro’s Elena Knows), a graphic novel (Peter Dunlap-Shohl’s My Degeneration: A Journey Through Parkinson’s), a non-fiction book (Oliver Sacks’ Awakenings) and a first-person illness narrative (John Palfreman’s The Bright Side of Parkinson’s). Metaphors in the patient narrative, novels, and non-fiction work were reviewed and a list of themes or categorizations common to 2 of the metaphors was generated. Parkinson’s disease metaphors indicate a ‘Parkinson’s prism’ thereby depicting extreme experiences (24.4%) like a ‘fall by mischance’, a ‘tantrum of selfish misery’ or a ‘bottomless darkness and unreality’ (Table 1). Both novels signify a sense of ‘betrayal and disconnection’ in the Parkinson’s disease experience while non-fiction of Parkinsonism depicts a space in which one feels ‘caged and deprived’. This makes the Parkinson’s disease narrative a chaos story that could influence the decision to initiate treatment and treatment adherence. We conclude that narrative medicine can help to focus the medical consultations with affected individuals on issues that matter most to them, thereby improving self-perceived autonomy and stigma. As such, it is a critical component of the much-needed move towards personalized medicine in Parkinson’s disease, achieved through the reciprocity of thinking with stories

Diabetic Nephropathy Alters the Distribution of Circulating Angiogenic MicroRNAs Among Extracellular Vesicles, HDL, and Ago-2

Previously, we identified plasma microRNA (miR) profiles that associate with markers of microvascular injury in patients with diabetic nephropathy (DN). However, miRs circulate in extracellular vesicles (EVs) or in association with HDL or the RNA-binding protein argonaute-2 (Ago-2). Given that the EV- and HDL-mediated miR transfer toward endothelial cells (ECs) regulates cellular quiescence and inflammation, we hypothesized that the distribution of miRs among carriers affects microvascular homeostasis in DN. Therefore, we determined the miR expression in EV, HDL, and Ago-2 fractions isolated from EDTA plasma of healthy control subjects, patients with diabetes mellitus (DM) with or without early DN (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2), and patients with DN (eGFR <30 mL/min/1.73 m2). Consistent with our hypothesis, we observed alterations in miR carrier distribution in plasma of patients with DM and DN compared with healthy control subjects. Both miR-21 and miR-126 increased in EVs of patients with DN, whereas miR-660 increased in the Ago-2 fraction and miR-132 decreased in the HDL fraction. Moreover, in vitro, differentially expressed miRs improved EC barrier formation (EV-miR-21) and rescued the angiogenic potential (HDL-miR-132) of ECs cultured in serum from patients with DM and DN. In conclusion, miR measurement in EVs, HDL, and Ago-2 may improve the biomarker sensitivity of these miRs for microvascular injury in DN, while carrier-specific miRs can improve endothelial barrier formation (EV-miR-21/126) or exert a proangiogenic response (HDL-miR-132)

Erratum to: Diabetic nephropathy alters the distribution of circulating angiogenic micrornas among extracellular vesicles, hdl, and ago-2, (Diabetes 2019, 68, 2287-2300)

In the article cited above, “Amsterdam University Medical Center, Amsterdam” was mistakenly displayed for affiliations 1 and 2. The institution and city for both should have read “Leiden University Medical Center, Leiden.” The editors apologize for the errors. The online version of the article (https://doi.org/10.2337/db18-1360) has been updated to correct this

Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452

Objective: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the under lying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. Methods: Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. Results: Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and bro wn adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). Conclusion: This study identified an estradiol-drive post-transcriptional n etwork that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy. </p