Vascular Adhesion Molecule-1 Levels Research Articles

LncRNA PSMB8-AS1 Instigates Vascular Inflammation to Aggravate Atherosclerosis.

Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, PSMB8-AS1, has been implicated in the development of tumors. Nevertheless, the precise role of PSMB8-AS1 in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated. Thus, the primary aim of this investigation is to assess the influence of PSMB8-AS1 on vascular inflammation and the initiation of atherosclerosis. We generated PSMB8-AS1 knockin and Apoe (Apolipoprotein E) knockout mice (Apoe-/-PSMB8-AS1KI) and global Apoe and proteasome subunit-β type-9 (Psmb9) double knockout mice (Apoe-/-Psmb9-/-). To explore the roles of PSMB8-AS1 and Psmb9 in atherosclerosis, we fed the mice with a Western diet for 12 weeks. Long noncoding RNA PSMB8-AS1 is significantly elevated in human atherosclerotic plaques. Strikingly, Apoe-/-PSMB8-AS1KI mice exhibited increased atherosclerosis development, plaque vulnerability, and vascular inflammation compared with Apoe-/- mice. Moreover, the levels of VCAM1 (vascular adhesion molecule 1) and ICAM1 (intracellular adhesion molecule 1) were significantly upregulated in atherosclerotic lesions and serum of Apoe-/-PSMB8-AS1KI mice. Consistently, in vitro gain- and loss-of-function studies demonstrated that PSMB8-AS1 induced monocyte/macrophage adhesion to endothelial cells and increased VCAM1 and ICAM1 levels in a PSMB9-dependent manner. Mechanistic studies revealed that PSMB8-AS1 induced PSMB9 transcription by recruiting the transcription factor NONO (non-POU domain-containing octamer-binding protein) and binding to the PSMB9 promoter. PSMB9 (proteasome subunit-β type-9) elevated VCAM1 and ICAM1 expression via the upregulation of ZEB1 (zinc finger E-box-binding homeobox 1). Psmb9 deficiency decreased atherosclerotic lesion size, plaque vulnerability, and vascular inflammation in Apoe-/- mice in vivo. Importantly, endothelial overexpression of PSMB8-AS1-increased atherosclerosis and vascular inflammation were attenuated by Psmb9 knockout. PSMB8-AS1 promotes vascular inflammation and atherosclerosis via the NONO/PSMB9/ZEB1 axis. Our findings support the development of new long noncoding RNA-based strategies to counteract atherosclerotic cardiovascular disease.

Cardiovascular risk and systemic inflammation in male professional rugby: a cross-sectional study

ObjectiveTo investigate cardiovascular risk factors’ prevalence and association with systemic inflammation in professional male rugby players (RP).MethodsA cross-sectional investigation of 46 professional male RP (26.1±4.1 years) cardiovascular risk factors were...

Efficacy of montelukast as an adjuvant therapy in rheumatoid arthritis patients: A randomized controlled study

ObjectiveThis study aimed to evaluate the efficacy of montelukast in conjunction with non-biologic disease modifying anti-rheumatic drugs (nDMARDs) in rheumatoid arthritis (RA) patients. MethodsThis study was a single-center randomized double-blinded placebo-controlled study. Adult RA patients were included if they had moderate to severe disease activity and were receiving monotherapy or combination of nDMARDs. Eligible patients were randomized, in 1:1 ratio, to receive either 10 mg montelukast or placebo, once daily for 16 weeks. The primary endpoint was the change in the 28-joints disease activity score (DAS28) 16 weeks after treatment. The patients’ quality of life (QoL) was assessed by the Arabic version of the Health Assessment Questionnaire-Disability Index. Moreover, serum levels of vascular adhesion molecule-1 (VCAM-1) were measured. ResultsA total of 87 patients completed the study; 44 in the montelukast arm and 43 in the control arm. After 16 weeks of treatment, disease activity decreased significantly in the montelukast arm with mean change in DAS28 (95% CIs) of −1.5 (−1.7, −1.2) while the control arm showed no improvement (0.2 (0.0, 0.4), p < 0.01). The QoL of the patients improved significantly from baseline in the montelukast arm (p < 0.01) but not in the control arm (p = 0.08). The median (IQR) serum levels of VCAM-1 were significantly lower in the montelukast arm (22.8 (15.0–32.7)) than in the control arm (28.9 (15.4–42.8), p = 0.004). ConclusionThe co-administration of montelukast with nDMARDs in RA patients enhanced the anti-rheumatic effect which was reflected clinically by decreased disease activity.

Low Plasma Levels of Hyaluronic Acid Might Rule Out Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation.

Sinusoidal obstructive syndrome (SOS) is a potentially fatal complication secondary to hematopoietic stem cell transplant (HSCT) conditioning. Endothelial damage plasma biomarkers such as plasminogen activator inhibitor-1 (PAI-1), hyaluronic acid (HA), and vascular adhesion molecule-1 (VCAM1) represent potential diagnostic tools for SOS. We prospectively collected serial citrated blood samples (baseline, day 0, day 7, and day 14) in all adult patients undergoing HSCT at La Paz Hospital, Madrid. Samples were later analyzed by ELISA (enzyme-linked immunosorbent assay) for HA, VCAM1, and PAI-1 concentrations. During sixteen months, we prospectively recruited 47 patients. Seven patients (14%) were diagnosed with SOS according to the EBMT criteria for SOS/VOD diagnosis and received treatment with defibrotide. Our study showed a statistically significant elevation of HA on day 7 in SOS patients, preceding clinical SOS diagnosis, with a sensitivity of 100%. Furthermore, we observed a significant increase of HA and VCAM1 levels on day 14. Regarding risk factors, we observed a statistically significant association between SOS diagnosis and the fact that patients received 3 or more previous lines of treatment before HSCT. The early significant increase in HA levels observed opens the door to a noninvasive peripheral blood test which could have the potential to improve diagnosis and facilitate prophylactic and therapeutic management of SOS before clinical/histological damage is established.

The Relationship of Carotid Intima-Media Thickness with Cell Adhesion Molecules and Pentraxin-3 in Patients with Psoriatic Arthritis

Abstract Aim Cardiovascular morbidity is increased in patients with psoriatic arthritis (PsA) compared to the general population. Several recent studies have indicated that pentraxin 3 (PTX-3) and cell adhesion molecules (CAMs) might be independent biomarkers of subclinical atherosclerosis. In this study, we aimed to determine the relationship of CAMs and PTX-3 with carotid intima media thickness (CIMT) in patients with PsA and to compare CIMT and serum levels of these biomarkers in patients with healthy controls (HCs). Method PsA patients fulfilling the CASPAR (Classification criteria for Psoriatic Arthritis) criteria without traditional cardiovascular (CV) comorbidity and HCs without autoimmune and/or CV disease were included in this cross-sectional study. Carotid artery Doppler ultrasound examinations were conducted by a single radiologist blinded to the participants’ clinical characteristics. Serum vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, and PTX-3 concentrations were analized. Results 43 PsA patients (27 females, mean age 42.49±11.70 years, and a mean disease duration of 9.37±7.96 years) and 37 HCs (28 females, mean age 42.16±11.38 years) were included. In regression analyses, age and PTX-3 were found to be the best predictors of CIMT in patients with PsA. CIMT was significantly higher in PsA patients compared with HCs (0.63±0.18 vs. 0.49±0.10 mm, p&lt;0.01). In te PsA group, serum levels of PTX-3, ICAM-1, and VCAM-1 were also significantly higher than HCs. CIMT correlated positively with age, disease duration, PTX-3, ICAM-1, and VCAM-1 (p&lt;0.05). Conclusion In our study, age and serum level of PTX-3 were found to be the predictors of CIMT in patients with PsA without CV comorbidity. This outcome highlights the importance of monitoring CIMT and serum level of PTX-3 as CV risk factors in PsA patients.

Are Markers of Allergic Inflammation in Grass Pollen Allergy Influenced by H1 Antihistamines?

Soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular adhesion molecule-1 (VCAM-1) play important roles in allergic rhinitis (AR). Treatment with H1 antihistamines improves AR symptoms and in vitro reduces the levels of adhesion molecules. The aim of the study was to evaluate serum levels of ICAM-1 and VCAM-1 in patients with AR to grass pollen and their response to different H1 antihistamines. Material and methods: A total of 50 patients with grass pollen AR were clinically and biologically evaluated. ICAM-1 and VCAM-1 serum levels were evaluated during pollen season before and after treatment with levocetirizine and desloratadine through the ELISA method. Results: ICAM-1, VCAM-1, eosinophils, and total IgE were elevated in patients with AR, compared with healthy subjects. Both antihistamines improved specific symptoms of AR and increased patients’ quality of life during pollen season after one month of treatment. H1 antihistamines reduced VCAM-1, ICAM-1, and total IgE after one-month treatment but not significantly. Patients with increased baseline values tend to remain with increased values after one-month AH1 treatment. Conclusions: ICAM-1 and sVCAM-1 levels are higher in patients with grass pollen-induced AR than healthy controls during pollen exposure. Their serum levels tend to remain at high values during pollen season despite antihistaminic therapy.

The impact of OSA and CPAP treatment on cell adhesion molecules' night-morning variation.

Obstructive sleep apnea (OSA) has been related to vascular inflammation and production of endothelial cell adhesion molecules (CAMs). We aimed to determine night-morning variation of CAMs in patients with OSA compared to controls and the effect of one-night continuous positive airway pressure (CPAP) treatment on them. Nonsmoking men went through a full-attended polysomnography (PSG) study. Participants with moderate to severe OSA went through another PSG study while being treated with CPAP. Participants who did not have OSA composed the control group. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin were measured before and after sleep on both nights. Of 30 men, 20 had moderate to severe OSA while 10did not.Night and morning ICAM-1 levels of patients with OSA were significantly higher than controls (p = 0.002 and p < 0.0001 respectively), while both night and morning VCAM-1 and E-selectin levels were not. Morning ICAM-1 levels of controls were significantly lower than night levels (p = 0.031), while morning ICAM-1, VCAM-1, and E-selectin levels of patients with OSA and morning VCAM-1 and E-selectin levels of controls were not. After CPAP treatment, the morning ICAM-1 levels, but not VCAM-1 levels, of patients with OSA were significantly lower than night levels (p = 0.006) and E-selectin levels showed a tendency for reduction (p = 0.06). OSA is associated with elevated night and morning ICAM-1 levels in adult men with OSA. Even one night of CPAP treatment restores the normal night-morning variation of ICAM-1 levels and may have an effect on E-selectin levels, as well.

25‑OH‑PPD inhibits hypertrophy on diabetic cardiomyopathy via the PI3k/Akt/GSK‑3β signaling pathway

The present study investigated the inhibitory effects and the associated mechanism of the compound 25-OH-PPD (PPD) on cardiac hypertrophy, fibrosis and inflammation. The signaling pathways associated with diabetic mellitus cardiomyopathy (DMCM) were investigated using a rat model. DMCM Sprague-Dawley rats were induced by injection of streptozotocin. The animals were divided into 5 groups as follows: Normal group (NG group), diabetic group, PPD treatment group, PPD/LY294002 group (inhibitor of PI3K/Akt) and PPD/LiCl group [inhibitor of glycogen synthase kinase (GSK) 3β]. The studies were carried out during the 12 weeks following induction of diabetes and the levels of plasma brain natriuretic peptide (BNP), creatine phosphokinase isoenzyme (CK-MB) were measured. In addition, the volume of myocardial collagen fraction (CVF) was tested. The expression levels of the inflammatory cytokines, including transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), cell adhesion molecules α-smooth muscle actin (α-SMA) and vascular adhesion molecule 1 (VCAM-1) and associated signaling proteins (Akt, GSK-3β) were measured by biochemical analyses. The levels of BNP and CK-MB, the volume of CVF, the expression levels of TGF-β1, CTGF, α-SMA and VCAM-1 in the diabetic group were higher compared with those of the normal control group (P<0.05). Conversely, the levels of these molecules were significantly decreased in the PPD treatment groups (P<0.05). The aforementioned effects were partially eliminated in the PPD/LY294002 and PPD/LiCl groups. In addition, PPD treatment significantly increased the expression levels of p-Akt and decreased the levels of phosphorylated GSK-3β compared with those of the DMCM group (P<0.05). The data demonstrated that the protective effects of 25-OH-PPD against DMCM may be attributed to the PI3k/Akt/GSK-3β signaling pathway, via the suppression of the α-SMA/VCAM axis and the downregulation of TGF-β1 and CTGF expression.

Relationship Between Aqueous Humor Levels of Cytokines and Axial Length in Patients With Diabetic Retinopathy.

A negative relationship between intraocular vascular endothelial growth factor-A (VEGFA) and axial length was found, which may help explain why myopia with long axial length was a protective factor for development of diabetic retinopathy (DR). The aim of this study is to further assess the relationship between the aqueous humor levels of interlukin (IL)-8, IL-10, VEGFA, vascular adhesion molecule-1 (VCAM-1), basic fibroblast growth factor, VEGFB, and placental growth factor (PLGF) and axial length in eyes with DR. Retrospective, single-center, unmasked study. Patients with age-related cataract and with/without DR who visited the Department of Ophthalmology at the Affiliated Hospital of Inner Mongolia Medical University were enrolled. The level of IL-8, IL-10, VEGFA, VCAM-1, and basic fibroblast growth factor were measured by cytometric bead array, and VEGFB and PLGF were measured by enzyme-linked immunosorbent assay. Axial length was measured by biometry. Totally 65 eyes of 65 patients were enrolled, including 14 patients with nonproliferative diabetic retinopathy, 16 patients with proliferative diabetic retinopathy (PDR), and 35 patients with age-related cataract as control. In the nonproliferative diabetic retinopathy group, the aqueous level of PLGF was negatively correlated with axial length (r = -0.576, P = 0.031), whereas the aqueous levels of IL-10 (r = 0.533, P = 0.049) and VCAM-1 (r = 0.566, P = 0.035) were positively correlated with axial length. In the proliferative diabetic retinopathy group, all cytokines did not significantly correlate with axial length. Among patients with diabetic retinopathy, we further found that aqueous levels of PLGF were negatively correlated with axial length, whereas VCAM-1 and IL-10 were positively correlated with axial length. These findings may suggest that these cytokines play a role in the development of DR, and further explain the relationship between the axial length and DR.

Cancer-associated fibroblasts-derived VCAM1 induced by H. pylori infection facilitates tumor invasion in gastric cancer.

Cancer-associated fibroblasts (CAFs) play a major role in the progression of stomach cancer, but the related mechanisms are not fully understood. H. pylori infection is recognized as one of the strongest risk factors for gastric carcinoma, but its effects on CAFs remain unknown. We aimed to determine the causative relationship between H. pylori infection in fibroblasts and the promoted cancer pathogenesis and progression in gastric cancer. Primary CAFs and normal activated fibroblasts (NAFs) were generated from gastric cancer patients. Gene signature of H. pylori-infected human stomach fibroblasts was performed using the RNA-seq analysis. Spheroid cell invasion assay and zebrafish cell line-derived xenograft (zCDX) model were introduced to evaluate tumor invasion induced by CAFs. The molecule interactions were determined using the kinetic binding analysis with the Biolayer Interferometry (BLI). Clinical significance and relevance were also assessed using the database analyses. H. pylori infection activated stomach fibroblasts and caused multiple gene alterations, including vascular adhesion molecule 1 (VCAM1). H. pylori infection increased VCAM1 expression in CAFs in gastric carcinoma via activation of JAK/STAT1 signaling pathway, and VCAM1 levels were positively associated with tumor progression and dismal prognosis in stomach cancer patients. Furthermore, CAFs-derived VCAM1 molecularly interacted with integrin αvβ1/5 in gastric cancer cells facilitated tumor invasion in vitro and in vivo. Our results identify a novel mechanism underlying CAFs to promote tumor invasion during H. pylori infection. These studies facilitate us for a better understanding of the molecular process of gastric carcinoma progression, and provide the potential strategies for gastric cancer therapy.

Pro-inflammatory cytokine and vascular adhesion molecule levels in manganese and lead-exposed workers

Objectives: This study aimed to develop a model of the relationship between inflammatory cytokine and/or vascular adhesion molecule levels and clinical symptoms in individuals exposed to lead (Pb), manganese (Mn) or both (Pb+Mn).

504-P: TGF-ß1 and VCAM-1 as Early Diagnostic Biomarkers of Diabetic Kidney Disease Progression

Aim: To evaluate the significance of using transforming growth factor beta 1 (TGF-β1) and vascular adhesion molecule -1 (VCAM-1) as early prognostic markers of diabetic kidney disease (DKD) progression in patients with DM type 1 and 2. Materials and Methods: The study included 66 patients with T1DM, 58 with T2DM and 20 healthy volunteers. Diabetic patients were divided into three groups depending on the estimated glomerular filtration rate. All patients were equal for age and sex. The endothelial function was determined by TGF-β1 and VCAM-1 levels. Recognitive Operating Characteristic - was used to assess the discrimination ability (diagnostic test value) to be a predictor of DKD progression. Results: Patients of all study groups had significantly higher (p˂0,05) levels of TGF-b1 and VCAM-1 versus control group. That’s present endothelial dysfunction in DM patients. The diagnostic value of TGF-b1 and VCAM-1 was compared with diagnostic value of AU. The highest test’s sensitivity and specificity has TGF-b1, its predictive ability concerning DKD progression can be assessed as “excellent” for both types of DM (Se = 100.0; Sr = 100.0; AUC = 1.000; p &amp;lt; 0.001). VCAM-1 has “excellent” operating characteristics for predicting DKD progression in T2DM (Se = 100,0; SP = 88,89; AUC = 0,923; p &amp;lt;0.001) and “very good” in T1DM (Se = 86,36; Sp = 90.48; AUC = 0.866; p &amp;lt;0.001). AU has “good” operating characteristics concerning DKD progression: Se = 57,50; Sd = 97.44; AUC = 0.785; p &amp;lt;0,001 for type1 and 2 DM. That’s shows us evaluation of AU in DM has a high specificity, but low sensitivity of the prognosis DKD progression for both types of DM. Conclusion: We provide evidences that TGF-β1 and VCAM-1 can be used for prediction of DKD progression in patients with type 1 and type 2 DM. Diagnostic capabilities of VCAM-1 and TGF-β1 significantly exceed the diagnostic capabilities of AU, which determines them as early markers. Disclosure C. Daria: None. N. Pertseva: None.

Elevated Expression of Vascular Adhesion Molecule-1, Plasminogen Activator Inhibitor-1, Cyclooxygenase-2, and Thrombomodulin in Human Umbilical Vein Endothelial Cells from Hospitalized Gestational Diabetes Mellitus Patients.

Protein expression in human umbilical vein endothelial cells (HUVECs) is a useful indicator of maternal condition and the intrauterine environment during pregnancy. Therefore, we investigated protein expression in HUVECs obtained from patients with gestational diabetes mellitus (GDM). HUVECs were prepared from the umbilical cords of GDM patients and controls who underwent planned cesarean section between 2013 and 2014 at Teikyo University Hospital (Tokyo, Japan). There were no differences in blood glucose levels between the GDM patients and controls at admission. However, pre-pregnancy body mass index (BMI) was higher in GDM patients, although the changes in gestational BMI were smaller during hospitalization. To evaluate the state of the endothelium, we examined the protein expression levels of vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, thrombomodulin (TM), endothelial nitric oxide synthase, plasminogen activator inhibitor-1 (PAI-1), cyclooxygenase-2 (COX-2), and VE-cadherin, which are altered by various factors in endothelial tissue. VCAM-1, PAI-1, and COX-2 expression was higher in HUVECs from patients with GDM than the controls. Because the pre-pregnancy BMI was higher in GDM patients, we examined the relationship between BMI and protein expression. However, the expression levels of these proteins were not correlated with pre-pregnancy BMI and were higher in HUVECs from BMI-matched GDM patients than from BMI-matched controls. Intriguingly, TM expression was also higher in HUVECs from BMI-matched GDM patients. Thus, expression of VCAM-1, PAI-1, COX-2, and TM may reflect certain factors in the intrauterine environment that are altered in hospitalized GDM patients with controlled body weight.

CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease.

ObjectiveTo measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time.MethodsThe study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)–6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1–6 years).ResultsCSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia.ConclusionsNeuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.

HIV disease is associated with increased biomarkers of endothelial dysfunction despite viral suppression on long-term antiretroviral therapy in Botswana.

SummaryBackgroundUntreated HIV infection is associated with increased biomarkers of endothelial dysfunction. However, the predictors and degree of endothelial dysfunction among virally suppressed HIV–infected adults on long–term antiretroviral therapy (ART) have not been well studied in sub– Saharan Africa (SSA). MethodsWe enrolled 112 HIV–infected adults with virological suppression on long–term ART and 84 HIV–uninfected controls in Botswana. We measured plasma levels of markers of endothelial injury [soluble vascular adhesion molecule 1 (VCAM–1), intercellular adhesion molecule 1 (ICAM–1) and E–selectin] and plasma levels of biomarkers of inflammation [interleukin 6 (IL–6)] and monocyte activation (sCD163). Baseline traditional cardiovascular disease (CVD) risk factors and bilateral common carotid intima–media thickness (cIMT) were also available for all participants. We assessed whether HIV status (despite virological suppression on ART) was associated with biomarkers of endothelial dysfunction after controlling for traditional CVD risk factors in linear regression models. We additionally assessed the association between IL–6, sCD163 and cIMT with endothelial dysfunction in separate multivariate linear regression models, controlling for cIMT, among virally suppressed HIV–infected participants only.ResultsIn multivariate analysis, HIV infection was significantly associated with increased VCAM–1 (p < 0.01) and ICAM–1 (p = 0.03) but not E–selectin (p = 0.74) levels. Within the HIV–positive group, higher sCD163 levels were associated with decreased ICAM–1 and E–selectin (p < 0.01 and p = 0.01, respectively) but not VCAM–1 (p = 0.13) levels. IL–6 was not associated with any of the biomarkers of endothelial dysfunction.ConclusionHIV disease was associated with biomarkers of endothelial dysfunction among virally suppressed adults in Botswana on long–term ART after controlling for traditional CVD risk factors. Future work should explore the clinical impact of persistent endothelial dysfunction following longterm HIV viral suppression on the risk of CVD clinical endpoints among HIV–infected patients in this setting.

Evaluation of Endothelial Damage in Sinusoidal Obstructive Syndrome

Introduction: Sinusoidal Obstructive Syndrome (SOS) is a complication derived from the endothelial damage associated to hematopoietic stem-cell transplant (HSCT) conditioning. Although its appearance is highly dependent on patient risk factors, it has an estimated prevalence of 14% and is associated with a high morbidity and with mortality rates than can ascend to 90% at day +100 of transplant in severe cases. New methods to early diagnose SOS are needed in order to minimize the incidence and severity of SOS.Here we present preliminary results of our single center prospective study that aims to measure and validate a panel of biomarkers in plasma [L-Ficolin, hyaluronic acid (HA), vascular adhesion molecule-1 (VCAM1) and plasminogen activator inhibitor-1 (PAI-1)] which have been recently described to be prognostic of the development of SOS (Akil et al, Biol. Blood Marrow Transplant. 21, 1739-1745, 2015).Methods: Twenty-one adult patients undergoing HSCT were recruited (median age 43.5 years old, 20-68), 15 men and 6 women. Three patients (14%) were diagnosed of SOS and received defibrotide (Gentium/Jazz Pharmaceutical) treatment. Diagnosis of SOS was performed based on the Seattle and Baltimore modified Criteria.Citrated blood samples from all patients were obtained before starting conditioning regimen (V0), and at infusion day (V1), 7 (V2) and 14 (V3) after infusion. Three additional samples (V4, V5 and V6) were drawn from those patients with SOS (just before defibrotide and 7 and 14 days after treatment with defibrotide). Samples were centrifuged twice at 23°C (15 min at 1,500 g, and 2 min at 13,000 g) and aliquots were stored at -80ºC until analysis.Phosphatidylserine-MP (Ph-MP) and tissue factor-MP (TF-MP) dependent procoagulant activities were determined with the ZYMUPHEN kits. VCAM1, PAI-1, L-Ficolin and HA concentrations were measured by ELISA.Data from the routine laboratory analysis were also registered.Statistical analyses was performed with SPSS software. Values of p≤0.05 were considered statistically significant.Results : Considering transplant type, 9 were autologous and 9 allogenic in controls, and 3 allogenic in SOS; donor type were 3 unrelated, 6 related and 3 haploidentical in controls, and 3 related and 2 haploidentical in SOS. Conditioning regimen intensity was 7 full, 2 reduced, 8 with busulfan and 1 with total body irradiation in controls and 3 reduced and 2 with busulfan in SOS group. Controls received 2(1-4) previous chemotherapy lines whereas SOS group received 3(2-9).Regarding diseases, 4 presented acute myeloblastic leukemia, 2 acute lymphoblastic leukemia, 3 multiple myeloma, 3 non-Hodgkin's lymphoma and 6 Hodgkin's disease in control group whereas in SOS group 1 had acute myeloblastic leukemia, 1 myelodysplastic syndrome and 1 non-Hodgkin's lymphoma.As observed, occurrence of SOS did not seem to be related to either the malignant disease or number of chemotherapy drugs employed for its treatment or donor type and conditioning regimen.L-Ficolin, a complement activator involved in homeostatic clearance of mitochondria in the liver, seemed to diminished in the SOS group at V3 (wo SOS : 1025±923 ng/mL ; SOS : 680±817 ng/mL). Nevertheless, this diminution was not significant probably due to the few patients with SOS.No differences were observed between patients without and with SOS in plasma levels of markers of endothelial damage VCAM1, PAI-1 and HA, this last a direct indicator of hepatic sinusoidal endothelial cell function.Procoagulant activity associated to Ph-MP was lower in patients with SOS (p=0.023) whereas that associated to TF-MP was unaffected.Plasma levels of VCAM1 and HA increased along time in both groups. After treatment with defibrotide these values achieved steady levels in SOS patients (V4 and V5). On the other hand, PAI-1 did not change over time.SOS patients presented at V3 higher total bilirrubin (wo SOS: 0.86±0.53 mg/dL; SOS: 2.31±0.18 mg/dL, p=0.008) and lower albumin levels (wo SOS: 3.5±0.3 g/dL; SOS: 2.7±0.1 g/dL)Conclusions: Our results indicate that endothelial damage is present in all patients undergoing HSCT and that treatment of SOS patients with defibrotide might restrain this injury. Due to the low number of patients included so far, we cannot conclude anything about the value of biomarkers proposed to serve as predictors of SOS onset. Our study is still open and recruiting patients.This work was supported by Jazz Pharmaceutical DisclosuresNo relevant conflicts of interest to declare.

Correlation of Homocysteine with Cerebral Hemodynamic Abnormality, Endothelial Dysfunction Markers, and Cognition Impairment in Patients with Traumatic Brain Injury

This study aimed to assess any correlation between serum levels of homocysteine (Hcy) and markers of cerebral hemodynamics, endothelial dysfunction, and cognition impairment in patients with traumatic brain injury (TBI). By a cross-sectional study, all clinical data and serum levels of homocysteine of 85 TBI patients were collected. The pulsatility indices (PIs) of the middle cerebral artery were recorded by transcranial color-coded Doppler ultrasonography and cerebrovascular reactivity was measured by the increase in middle cerebral artery flow velocity in response to 5% inhaled CO2. Serum levels of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), cognition status by Montreal Cognitive Assessment, and Mini-Mental State Examination were measured in all participants. Totally, 85 patients including 51.76% male and the mean age of 54.48 years were studied. The level of Hcy in patients who died in the hospital or during 6 months after TBI was significantly higher than in survivors (P=0.045, P= 0.020, respectively). Also, the levels of ICAM-1, VCAM-1, and PI in deceased patients were higher than their figures in survivors in both hospital and 6-month follow-ups (P= 0.450, P= 0.000; P= 0.072, P= 0.000, P= 0.090, and P= 0.000, respectively). Cerebrovascular reactivity in deceased patients was significantly lower than that in alive individuals (P= 0.008 and P= 0.000, respectively). A significant correlation was found between Hcy with cognition impairment according to Montreal Cognitive Assessment, Mini-Mental State Examination, and cerebral hemodynamic status according to PI (P= 0.000 for all). Also, this correlation was shown between Hcy with ICAM-1 and VCAM-1 in hospital and 6-month follow-ups (P= 0.000 for both). Hcy has a significant correlation with markers of cerebrovascular, endothelial, and cognition abnormality in TBI patients.

Effects of endurance and high intensity training on ICAM-1 and VCAM-1 levels and arterial pressure in obese and normal weight adolescents

ABSTRACTObjectives: Obesity prevalence has increased in Iranian adolescents in recent years. However, few studies have examined the impact of intervention programs on this health issue. The main objective of this study was to evaluate the effects of 8-week endurance training (ET) and high intensity interval training (HIIT) on intercellular adhesion molecule-1(ICAM-1) and vascular adhesion molecule-1(VCAM-1) levels among obese and normal-weight male adolescents.Methods: Thirty obese and 30 normal-weight subjects were assigned to the ET, HIIT, or control group for eight weeks. Before and after the intervention, ICAM-1, VCAM-1, body weight, BMI, VO2max, and blood pressures were measured. SPSS (Version 21) was used for data analysis, and the significance level was set at p < 0.05.Results: Mixed design ANOVAs indicated that the obese participants had significantly (p < 0.05) lower ICAM-1 levels in the ET (from 509 ± 61 ng/ml to 387 ± 43 ng/ml) and HIIT (from 517 ± 72 ng/ml to 374 ± 50 ng/ml), but their VCAM-1 level was significantly (p < 0.05) reduced only after the HIIT (from 1689 ± 119 ng/ml to 1282 ± 63 ng/ml). Similarly, normal weight participants significantly (p < 0.05) lowered their ICAM-1 levels in the ET (from 296 ± 18 ng/ml to 216 ± 14 ng/ml) and HIIT (from 289 ± 22 ng/ml to 202 ± 12 ng/ml), but their VCAM-1 level was significantly (p < 0.05) reduced only after the HIIT (from 895 ± 50 ng/ml to 673 ± 142 ng/ml). Systolic blood pressure and diastolic blood pressures of all the participants were significantly (p < 0.01) decreased at the conclusion of the ET and HIIT.Conclusion: While both the ET and HIIT were useful in lowering the SBP and DBP of the participants, HIIT was more effective than ET in reducing ICAM-1 and VCAM-1 content in normal and obese adolescents.

Micro–RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor

Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)-driven TF expression and thrombogenicity in diabetes mellitus. Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3'-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus.

Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 μg) and folic acid (400 μg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514.