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Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). Conclusions COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020

BACKGROUND:Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation. METHODS:We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time–location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short-term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D-dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1. RESULTS:After controlling for confounders, 5 µg/m increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E-selectin. There were no other positive associations between blood markers and short- or long-term air pollution. CONCLUSIONS:These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Background & objectives Sickle cell disease (SCD) is a monogenic disorder characterised by aberrant haemoglobin production, leading to haemolytic anaemia and vaso-occlusive crises. Genetic variations and altered expression of cell adhesion molecules (CAMs) are implicated in disease pathogenesis. This cross-sectional study investigated the association between single nucleotide polymorphisms (SNPs) in the SELP, SELE, ICAM-1, and VCAM-1 genes and their protein levels in individuals with SCD. Methods A total of 140 individuals with SCD were recruited. Plasma levels of P-selectin, E-selectin, ICAM-1 and VCAM-1 were measured by ELISA method alongside a control group (n=10). The selected SNPs of SELP, SELE, ICAM-1, and VCAM-1 genes were identified through Sanger sequencing method. Results The expression of adhesion molecules were found to be significantly higher in SCD group as compared to control. Furthermore, the results showed significant associations between SNPs, SELE: c.109+138A>C (P<0.0001), SELE: c.422-25T>C (P<0.0001), and SELE: c.529+15T>C (P=<0.0001) with vaso-occlusive crises even after Bonferroni correction (corrected P=0.0025). Interpretation & conclusions Significant correlation observed between SELP, SELE, and VCAM-1 levels suggests complex interactions of these markers that may influence disease progression and identify potential therapeutic targets for managing SCD complications. Further studies are warranted to validate these findings in larger cohorts and explore the functional implications of the observed genetic and molecular associations in SCD.

Obesity is a risk factor for numerous complications, including atherosclerosis, the pathogenesis of which is complex. The aim of our study is to evaluate serum levels of E-selectin and hs-CRP and pulse wave velocity (PWV) as atherosclerosis risk factors and to explore their relationship with advanced glycation end products (AGEs), methylgioxal (MG) and skin autofluorescence (sAF). We evaluated 125 children aged 8–18 years with simple obesity, stratified into two subgroups based on SDS BMI (Group I: 2–4; Group II: >4), and compared them with 33 age-matched peers of normal weight. Children with obesity exhibited significantly elevated serum concentrations of AGEs, MG, E-selectin, and hs-CRP relative to the control group. Additionally, both height-normalized pulse wave velocity (SDS PWV) and sAF values were significantly higher in the children with obesity compared to their normal-weight counterparts. Except for sAF, which was elevated in children with obesity with a higher SDS BMI, no significant differences were observed among the subgroups of children. Positive correlations were observed between E-selectin and AGEs, MG and SDS PWV, as well as sAF and SDS BMI. Our findings indicate that children with obesity exhibit early signs of atherosclerotic changes, regardless of the degree of obesity. Moreover, circulating AGEs may represent a more reliable biomarker of atherosclerosis risk than sAF, as suggested by the strong positive correlation between AGEs and E-selectin. Further studies are warranted to validate these findings.

INTRODUCTION This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline. METHODS Data from 9414 individuals from eight Dutch cohorts were included (Ø  age‐range: 57–93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random‐effects meta‐analyses. RESULTS A higher endothelial dysfunction composite score was cross‐sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled β‐range: −0.04, −0.02). We found no association with change in cognition over time. DISCUSSION This comprehensive two‐step, individual participant data (IPD) meta‐analysis showed a small, consistent cross‐sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association. Highlights Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two‐step, individual participant data (IPD) meta‐analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic.

Studies investigating the relation between circulating vascular biomarkers reflecting endothelial dysfunction and physiological methods to evaluate vascular function remain limited. We simultaneously evaluated the relation between circulating endothelial biomarkers with physiological non-invasive vascular methods in 107 hypertensive patients with a wide range of mean estimated glomerular filtration rate (eGFR). Endothelial glycocalyx hyaluronan (HA) and syndecan-1 (SDC-1), and cellular adhesion molecules (ICAM-1, VCAM-1, and E-selectin) were measured by enzyme-linked immunosorbent assays. Aortic stiffness (cfPWV) was assessed by pulse wave analysis. Endothelial function in different vascular beds was evaluated physiological by methods: flow mediated vasodilation (large arteries), pulse wave analysis and the reflection index change, using beta 2-adrenoceptor agonist stimulation (smaller resistance arteries), and laser Doppler fluxmetry and iontophoresis (skin microvascular function). Diastolic function and left atrial size were assessed by echocardiography. Mean blood pressure (BP) was 149 ± 17/87 ± 10 mm Hg, mean eGFR 74 (21–130) ml/min x 1.73 m 2 . HA was independently related to cfPWV (β = 0.23, P  = 0.02), whereas SDC-1 was independently inversely related to skin microvascular function, (β= − 0.27, P  = 0.042) and was independently related to resistance artery endothelial function (β = 0.29, P  = 0.026). All circulating biomarkers were unrelated to physiologically measured large artery endothelial function, and with echocardiographic parameters. The glycocalyx markers were associated with physiological vascular measures independent of eGFR but should not be considered as a proxy for these measures, due to the weak relations. However, combining circulating markers with physiological measures might give additional information about vascular function.

The aim of this study was to determine plasma levels of three adhesion molecules that may contribute to the development of diabetic retinopathy; soluble endothelial selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1), in young adults, aged 15–34 years at diagnosis of diabetes, to find potential predictors for development of retinopathy, and to evaluate their relation to diabetes associated autoantibodies. Participants with type 1 (n = 169) and type 2 diabetes (n = 83) were selected from the complications trial of the Diabetes Incidence Study in Sweden and classified in two subgroups according to presence (n = 80) or absence (n = 172) of retinopathy as determined by retinal photography at follow-up 8–10 years after diagnosis of diabetes. Blood samples were collected at diagnosis in 1987–88. The levels of sE-selectin, sICAM-1, and sVCAM-1 were analysed by enzyme-linked immunosorbent assay and islet cell antibodies by a prolonged two-colour immunofluorescent assay. Mean HbA1c (p<0.001) and clinical characteristics: mean body mass index (p = 0.019), systolic blood pressure (p = 0.002), diastolic blood pressure (p = 0.003), male gender (p = 0.026), and young age at diagnosis of diabetes (p = 0.015) remained associated with development of retinopathy in type 1 diabetes. However, in a multivariate analysis only HbA1c remained as a risk factor. sE-selectin was significantly higher in the group with type 2 diabetes and retinopathy, compared to the group with type 2 diabetes without retinopathy (p = 0.04). Regarding sE-selectin, sICAM-1, and sVCAM-1 in participants with type 1 diabetes, no differences were observed between the groups with or without retinopathy. This trial confirmed the role of HbA1c and clinical characteristics as predictors for development of retinopathy in type 1 diabetes. sE-selectin stands out as a potential predictor for development of retinopathy in type 2 diabetes, whereas a predictive role for sICAM-1 and sVCAM-1 could not be identified neither for type 1 nor type 2 diabetes.

Rationale The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. Objective To compare EMP numbers in stable COPD patients with those during and after exacerbation. Methods We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41− MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. Results VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p<0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. Conclusions Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation.

Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference. Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients. Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02). Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.