Circulating exosomal microRNA expression patterns distinguish cardiac sarcoidosis from myocardial ischemia.

OBJECTIVE: Cardiac sarcoidosis is difficult to diagnose, often requiring expensive and inconvenient advanced imaging techniques. Circulating exosomes contain genetic material, such as microRNA (miRNA), that are derived from diseased tissues and may serve as potential disease-specific biomarkers. We thus sought to determine whether circulating exosome-derived miRNA expression patterns would distinguish cardiac sarcoidosis (CS) from acute myocardial infarction (AMI). METHODS: Plasma and serum samples conforming to CS, AMI or disease-free controls were procured from the Biologic Specimen and Data Repository Information Coordinating Center repository and National Jewish Health. Next generation sequencing (NGS) was performed on exosome-derived total RNA (n = 10 for each group), and miRNA expression levels were compared after normalization using housekeeping miRNA. Quality assurance measures excluded poor quality RNA samples. Differentially expressed (DE) miRNA patterns, based upon \u3e2-fold change (p \u3c 0.01), were established in CS compared to controls, and in CS compared to AMI. Relative expression of several DE-miRNA were validated by qRT-PCR. RESULTS: Despite the advanced age of the stored samples (~5-30 years), the quality of the exosome-derived miRNA was intact in ~88% of samples. Comparing plasma exosomal miRNA in CS versus controls, NGS yielded 18 DE transcripts (12 up-regulated, 6 down-regulated), including miRNA previously implicated in mechanisms of myocardial injury (miR-92, miR-21) and immune responses (miR-618, miR-27a). NGS further yielded 52 DE miRNA in serum exosomes from CS versus AMI: 5 up-regulated in CS; 47 up-regulated in AMI, including transcripts previously detected in AMI patients (miR-1-1, miR-133a, miR-208b, miR-423, miR-499). Five miRNAs with increased DE in CS included two isoforms of miR-624 and miR-144, previously reported as markers of cardiomyopathy. CONCLUSIONS: MiRNA patterns of exosomes derived from CS and AMI patients are distinct, suggesting that circulating exosomal miRNA patterns could serve as disease biomarkers. Further studies are required to establish their specificity relative to other cardiac disorders

Beryllium increases the CD14^dimCD16+ subset in the lung of chronic beryllium disease

CD14dimCD16+ and CD14brightCD16+ cells, which compose a minor population of monocytes in human peripheral blood mononuclear cells (PBMC), have been implicated in several inflammatory diseases. The aim of this study was to investigate whether this phenotype was present as a subset of lung infiltrative alveolar macrophages (AMs) in the granulomatous lung disease, chronic beryllium disease (CBD). The monocytes subsets was determined from PBMC cells and bronchoalveolar lavage (BAL) cells from CBD, beryllium sensitized Non-smoker (BeS-NS) and healthy subjects (HS) using flow cytometry. The impact of smoking on the AMs cell phenotype was determined by using BAL cells from BeS smokers (BeS-S). In comparison with the other monocyte subpopulations, CD14dimCD16+ cells were at decreased frequency in PBMCs of both BeS-NS and CBD and showed higher HLA-DR expression, compared to HS. The AMs from CBD and BeS-NS demonstrated a CD14dimCD16+phenotype, while CD14brightCD16+ cells were found at increased frequency in AMs of BeS, compared to HS. Fresh AMs from BeS-NS and CBD demonstrated significantly greater CD16, CD40, CD86 and HLA-DR than HS and BeS-S. The expression of CD16 on AMs from both CBD and BeS-NS was downregulated significantly after 10μM BeSO4 stimulation. The phagocytic activity of AMs decreased after 10μM BeSO4 treatment in both BeS-NS and CBD, although was altered or reduced in HS and BeS-S. These results suggest that Be increases the CD14dimCD16+ subsets in the lung of CBD subjects. We speculate that Be-stimulates the compartmentalization of a more mature CD16+ macrophage phenotype and that in turn these macrophages are a source of Th1 cytokines and chemokines that perpetuate the Be immune response in CBD. The protective effect of cigarette smoking in BeS-S may be due to the low expression of co-stimulatory markers on AMs from smokers as well as the decreased phagocytic function

High-resolution CT phenotypes in pulmonary sarcoidosis: a multinational Delphi consensus study

One view of sarcoidosis is that the term covers many different diseases. However, no classification framework exists for the future exploration of pathogenetic pathways, genetic or trigger predilections, patterns of lung function impairment, or treatment separations, or for the development of diagnostic algorithms or relevant outcome measures. We aimed to establish agreement on high-resolution CT (HRCT) phenotypic separations in sarcoidosis to anchor future CT research through a multinational two-round Delphi consensus process. Delphi participants included members of the Fleischner Society and the World Association of Sarcoidosis and other Granulomatous Disorders, as well as members' nominees. 146 individuals (98 chest physicians, 48 thoracic radiologists) from 28 countries took part, 144 of whom completed both Delphi rounds. After rating of 35 Delphi statements on a five-point Likert scale, consensus was achieved for 22 (63%) statements. There was 97% agreement on the existence of distinct HRCT phenotypes, with seven HRCT phenotypes that were categorised by participants as non-fibrotic or likely to be fibrotic. The international consensus reached in this Delphi exercise justifies the formulation of a CT classification as a basis for the possible definition of separate diseases. Further refinement of phenotypes with rapidly achievable CT studies is now needed to underpin the development of a formal classification of sarcoidosis

Is it time to scrap Scadding and adopt computed tomography for initial evaluation of sarcoidosis? [version 1; referees: 2 approved]

In this review, we argue for the use of high-resolution computed tomography (HRCT) over chest X-ray in the initial evaluation of patients with sarcoidosis. Chest X-ray, which has long been used to classify disease severity and offer prognostication in sarcoidosis, has clear limitations compared with HRCT, including wider interobserver variability, a looser association with lung function, and poorer sensitivity to detect important lung manifestations of sarcoidosis. In addition, HRCT offers a diagnostic advantage, as it better depicts targets for biopsy, such as mediastinal/hilar lymphadenopathy and focal parenchymal disease. Newer data suggest that specific HRCT findings may be associated with important prognostic outcomes, such as increased mortality. As we elaborate in this update, we strongly recommend the use of HRCT in the initial evaluation of the patient with sarcoidosis

Cognitive Difficulties and Health-Related Quality of Life in Sarcoidosis: An Analysis of the GRADS Cohort

Rationale: Subjective cognitive difficulties are common among sarcoidosis patients; however, previous studies have not modeled the link between cognitive difficulties and health-related quality of life (HRQOL). Objectives: To determine whether cognitive difficulties are associated with HRQOL in sarcoidosis patients after adjusting for demographics, fatigue, and physical disease severity measures. Methods: We performed a secondary analysis of the Genomic Research in Alpha-1 antitrypsin Deficiency and Sarcoidosis (GRADS) study data. We examined the association between self-reported cognitive difficulties (Cognitive Failures Questionnaire (CFQ)) and HRQOL (SF12v2 mental and physical component scores) while adjusting for the demographics, fatigue, and physical disease severity measures (i.e., organ involvement, forced vital capacity). Results: Approximately one-fourth of the patients with sarcoidosis endorsed cognitive difficulties. More frequent cognitive difficulties and more severe fatigue were significantly associated with worse mental HRQOL in the fully adjusted model, while older age was associated with better mental HRQOL. The association between cognitive difficulties and physical HRQOL was not significant in the final model. More severe fatigue, joint involvement, and reduced forced vital capacity (FVC) were associated with worse physical HRQOL, while higher income and higher education were associated with better physical HRQOL. Conclusions: Perceived cognitive difficulties are associated with diminished HRQOL after adjusting for demographics, organ involvement, pulmonary function, and fatigue. The association between cognitive difficulties and reduced HRQOL primarily occurs through the impact on mental components of HRQOL