Double-Stranded RNA Attenuates the Barrier Function of Human Pulmonary Artery Endothelial Cells

Circulating RNA may result from excessive cell damage or acute viral infection and can interact with vascular endothelial cells. Despite the obvious clinical implications associated with the presence of circulating RNA, its pathological effects on endothelial cells and the governing molecular mechanisms are still not fully elucidated. We analyzed the effects of double stranded RNA on primary human pulmonary artery endothelial cells (hPAECs). The effect of natural and synthetic double-stranded RNA (dsRNA) on hPAECs was investigated using trans-endothelial electric resistance, molecule trafficking, calcium (Ca2+) homeostasis, gene expression and proliferation studies. Furthermore, the morphology and mechanical changes of the cells caused by synthetic dsRNA was followed by in-situ atomic force microscopy, by vascular-endothelial cadherin and F-actin staining. Our results indicated that exposure of hPAECs to synthetic dsRNA led to functional deficits. This was reflected by morphological and mechanical changes and an increase in the permeability of the endothelial monolayer. hPAECs treated with synthetic dsRNA accumulated in the G1 phase of the cell cycle. Additionally, the proliferation rate of the cells in the presence of synthetic dsRNA was significantly decreased. Furthermore, we found that natural and synthetic dsRNA modulated Ca2+ signaling in hPAECs by inhibiting the sarco-endoplasmic Ca2+-ATPase (SERCA) which is involved in the regulation of the intracellular Ca2+ homeostasis and thus cell growth. Even upon synthetic dsRNA stimulation silencing of SERCA3 preserved the endothelial monolayer integrity. Our data identify novel mechanisms by which dsRNA can disrupt endothelial barrier function and these may be relevant in inflammatory processes

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Long-term effectiveness and safety of a nutraceutical based approach to reduce cholesterolemia in statin intolerant subjects with and without metabolic syndrome.

The aim of our study was to test the long-term effectiveness and tolerability of a nutraceutical based approach in reducing cholesterolemia in statin intolerant subjects with and without metabolic syndrome in primary prevention for cardiovascular disease. We carried out a prospective, clinical trial enrolling 48 subjects intolerant to more than one statin. Patients assumed one yogurt added with 2 g phytostanols each morning (Pro-Activ (R), Unilever Italy, Milan, Italy) and one pills of a registered combined nutraceutical (Armolipid Plus (R), Rottapharm-Madaus Srl, Monza, Italy) containing Berberine 500 mg and Monacoline 3 mg. Four patients dropped out from the study because of side effects (2 asymptomatic increase in CPK>5 ULN, 1 myalgia, 1 dyspepsia). After 3 months, total cholesterol decreased by 22.3 +/- 5.8%, LDL-C by 31.3 +/- 8.3%, TG by 16.11 +/- 10.7% (all, p<0.01): these reduction were confirmed each 3 month until 1-year. Fasting glycaemia decreased from the baseline only after 1-year of treatment by a 10.6 +/- 4.6% (p<0.05). Patient affected (N. 27) by metabolic syndrome also experienced a significant increase in HDL-C plasma level (p<0.01). In conclusion, a nutraceutical based approach could help the most part patients intolerant to more than one statin to achieve a moderate improvement of their dyslipidemia for at least one year