Soluble E-selectin Levels Research Articles

Association Between Soluble Cell Adhesion Molecules (sP-Selectin, sE-Selectin, and sICAM-1) and Antibodies Against the Antigens of Proteus mirabilis in Rheumatoid Arthritis Patients.

Objective The purpose of this study was to examine the association between the serum concentration of soluble cell adhesion molecules (CAMs) and antibodies against antigens of Proteus mirabilis (P. mirabilis) in rheumatoid arthritis (RA) patients, taking into consideration the implication of P. mirabilis in the etiopathogenesis of RA. Methods The serum levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by sandwich enzyme-linked immunosorbent assay (ELISA) in 59 RA patients and 36 healthy controls. Using the same ELISA method, the serum levels of class-specific antibodies against hemolysin (HpmB), urease C (UreC), and urease F (UreF) enzymes of P. mirabilis were also measured. Results In this study, increased levels of sP-selectin and sICAM-1 were observed in RA patients, while the levels of sE-selectin were increased in comparison with healthy controls but did not present a statistically significant difference. Moreover, increased levels of antibodies against HpmB, UreC, and UreF of P. mirabilis were found. Additionally, it was observed that the sE-selectin levels presented a significant correlation with IgG antibodies against the UreF antigen (there is no corresponding antigen in human tissue) in all the RA patients. A statistically significant correlation was observed between levels of soluble CAMs and antibodies against P. mirabilis in the different subgroups. Conclusion The observed correlation between soluble CAMs and antibodies against antigens of P. mirabilis, specifically in the subgroup of biologic therapy, indicates that P. mirabilis exists and provokes refractory in the treatment of RA.

247-OR: Positive Effects of Bariatric Surgery Are Associated with Attenuation of Cellular Senescence

Bariatric surgery represents the most efficient approach to treatment of obesity; however, the detailed mechanism of its positive metabolic effect is still not fully understood. Cellular senescence arrests the cell cycle in damaged cells thus preventing further spreading of the damage. Persistence of senescent cells especially in adipose tissue can, however, contribute to the development of a number of chronic diseases including obesity and its complications. Reduction of adipose tissue after bariatric surgery can therefore reduce the number of senescent cells and their negative effects on organism. 17 patients with obesity (2nd grade and higher) scheduled for bariatric surgery (sleeve gastrectomy) were included into the study. Subcutaneous (SAT) adipose tissue and plasma were collected during and 6 months after surgery. The analysis of samples included RT-qPCR (mRNA transcription in SAT) and ELISA or Luminex for detection of hormones and proteins from plasma. Our results show that bariatric surgery reduces the amount of senescent cells in adipose tissue, which results in the decrease of oxidative stress and inflammation, partially also by reduced recruitment of pro-inflammatory macrophages. In addition, we detected lower plasma levels of soluble E-selectin and ICAM-1, molecules enhancing cardiovascular damage known to be produced by senescent cells, as well as decreased expression of ACE2, whose increased expression was detected in senescent cells. Importantly, we also observed decreased expression of ADAM17 responsible for producing a soluble form of ACE2, a newly identified predictor of cardiovascular damage. In conclusion, reduction of senescent cells in adipose tissue after bariatric surgery contributes to improvement of inflammation and metabolic parameters in patients with obesity and decreases the risk of cardiovascular complications. Disclosure S.Stemberkova hubackova: None. T.Havrlantova: None. I.Simonik: None. M.Mraz: None. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. Funding Czech Health Science Foundation (NU22-01-00096); Programme EXCELES (LX22NPO5104); Czech Ministry of Health (IKEM, IN00023001)

Genetically determined deficiency of ANGPTL3 does not alter HDL ability to preserve endothelial homeostasis

Individuals with loss-of-function mutations in the ANGPTL3 gene express a rare lipid phenotype called Familial Combined Hypolipidemia (FHBL2). FHBL2 individuals show reduced plasma concentrations of total cholesterol and triglycerides as well as of lipoprotein particles, including HDL. This feature is particularly remarkable in homozygotes in whom ANGPTL3 in blood is completely absent. ANGPTL3 acts as a circulating inhibitor of LPL and EL and it is thought that EL hyperactivity is the cause of plasma HDL reduction in FHBL2. Nevertheless, the consequences of ANGTPL3 deficiency on HDL functionality have been poorly explored. In this report, HDL isolated from homozygous and heterozygous FHBL2 individuals were evaluated for their ability to preserve endothelial homeostasis as compared to control HDL. It was found that only the complete absence of ANGPTL3 alters HDL subclass distribution, as homozygous, but not heterozygous, carriers have reduced content of large and increased content of small HDL with no alterations in HDL2 and HDL3 size. The plasma content of preβ-HDL was reduced in carriers and showed a positive correlation with plasma ANGPTL3 levels. Changes in composition did not however alter the functionality of FHBL2 HDL, as particles isolated from carriers retained their capacity to promote NO production and to inhibit VCAM-1 expression in endothelial cells. Furthermore, no significant changes in circulating levels of soluble ICAM-1 and E-selectin were detected in carriers. These results indicate that changes in HDL composition associated with the partial or complete absence of ANGPTL3 did not alter some of the potentially anti-atherogenic functions of these lipoproteins.

Association of soluble E-selectin and morning blood pressure surge in patients with essential hypertension

Background: Elevated soluble E-selectin which reflects a state of endothelial activation with subsequent vasoconstriction may elevate morning blood pressure (BP) surge. This study aimed to analyze soluble E-selectin serum concentrations in patients with essential hypertension against normotensive healthy individuals and to find a role of such molecule in the phenomenon of morning BP surge. Material and methods: In this case-control study, a 24-hour ambulatory blood pressure monitoring with recording of morning BP surge and serum soluble E-selectin levels were measured for a total of 90 patients (60 patients with essential hypertension and 30 normotensive subjects as a control). Results: Hypertensive patients had higher body mass index in comparison to control subjects (30.7 ± 2.3 kg/m 2 vs. 27 ± 3.2 kg/m 2 , p < 0.001). Serum uric acid levels were higher in hypertensive patients than control subjects (7.26 ± 2.60 mg/dL vs. 5.92 ± 1.15 mg/dL, p = 0.028). Hypertensive patients had higher left ventricular mass index (LVMI) (110.5 ± 19.2 g/m2 vs. 99.8 ± 9.5 g/m 2 , p = 0.001). Patients with essential hypertension have higher level of soluble E-selectin than normotensive participants (180.6 ± 96.1 vs . 75.9 ± 31.5 ng/mL, p < 0.001). Soluble E-selectin was positively correlated with morning BP surge (r = 0.696, p ≤ 0.001). Conclusion: Patients with essential hypertension have higher level of soluble E-selectin than normotensive. Soluble E-selectin was positively correlated with morning BP surge.

Intrahepatic lipid content is independently associated with soluble E-selectin levels: The Maastricht study.

Evidence is accumulating that liver sinusoidal endothelial cells are involved in the pathogenesis of non-alcoholic fatty liver disease. Previous studies have suggested that the endothelial biomarker soluble E-selectin (sE-selectin) is to an important extent liver-derived. To study the relationship of intrahepatic lipid (IHL) content with sE-selectin at the population level. This study was conducted in participants of The Maastricht Study (n=1,634), a population-based cohort study enriched with patients with type 2 diabetes. We assessed the cross-sectional association between IHL content, quantified by MRI, and sE-selectin via multivariable regression with adjustment for age, sex, type 2 diabetes, educational level, BMI, Dutch Healthy Diet index, physical activity, and the Matsuda index. Standardized IHL content was associated with (log) sE-selectin (age-, sex- and type 2 diabetes-adjusted regression coefficient [B]: 0.048 [95%CI:0.038;0.058], p<0.001), even after full adjustment (B: 0.030 [0.019;0.042], p<0.001). Such an association was not observed for soluble vascular cell adhesion molecule 1 (sVCAM-1) levels. IHL content is an independent determinant of sE-selectin at the population level. These findings support further studies to unravel the involvement of liver sinusoidal endothelial cells in the different stages of non-alcoholic fatty liver disease and the specific role of E-selectin herein.

Association of E-Selectin Gene +A561C Polymorphism with Type 2 Diabetes in Chinese Population.

Diabetes is associated with endothelial cell dysfunction. E-selectin is an endothelial cell adhesion molecule, which is bound for endothelial cell activation. E-selectin gene+A561C polymorphism is associated with many different disorders: essential hypertension, stroke, angina pectoris, coronary heart disease, etc. But the association with type 2 diabetes remains unclear. Therefore, we aimed to investigate the role of E-selectin gene+A561C polymorphism and soluble E-selectin in type 2 diabetes in a Chinese population. This study involved 317 patients with type 2 diabetes and 285 normal healthy controls. Genotyping of E-selectin gene+A561C polymorphism was examined by polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP). Soluble E-selectin was examined by enzyme linked immunosorbent assay (ELISA). Biochemical markers were measured by Roche 7600 Automated Biochemical Analyzer. We found that C allele frequency in E-selectin A561 C polymorphism of Chinese T2DM group was higher than control group. The level of soluble E-selectin in T2DM group was higher than control group. TC, TG, LDL-C, ApoB, and sE-selectin (soluble E-selectin) in AC and CC genotypes were higher than AA genotype. Our findings showed that E-selectin +A561C polymorphism was correlated in the Chinese population with type 2 diabetes. C allele and soluble E-selectin may be predisposing factors of Chinese population with type 2 diabetes.

Genome-wide association study revealed novel candidate gene loci associated with soluble E-selectin levels in a Taiwanese population

Background and aimsIncrease soluble E-selectin (sE-selectin) levels are associated with various inflammation and cardiometabolic disorders. MethodsThis study aimed to investigate the genetic determinants of circulating sE-selectin levels by genome-wide association study (GWAS) in 4,525 Taiwan Biobank (TWB) participants and genotype-phenotype association analysis for sE-selectin level-determining alleles in over 80,000 TWB participants. ResultsBy GWAS, ABO, SELE, and FUT6 gene variants were identified as the determinants of sE-selectin levels, which reach genome-wide significance (maximum p = 3.25 × 10−271, 4.81 × 10−14, and 9.64 × 10−12, respectively). After further adjustment for the lead ABO rs2519093 genotypes, three novel gene loci, EVI5, FER and DMAC1, were associated with sE-selectin levels at p < 5 × 10−7. Three other previously reported gene loci, CELSR2, ST3GAL6-AS1, and HNF1A-AS1, also showed supportive evidence for the association with sE-selectin levels (maximum p < 0.0073). A multivariate analysis revealed age, body mass index, current smoking, hemoglobin A1C, hematocrit, leukocyte and platelet counts, serum alanine aminotransferase, triglycerides, and uric acid levels were independently associated with sE-selectin levels, in which the above ten gene loci contribute to 27.68% of the variance. For genotype-phenotype association analysis, a pleiotropic effect was demonstrated with genome-wide significant association between ABO gene variants and total and low-density-lipoprotein cholesterol levels, leukocyte counts and hematocrit. ConclusionsOur data provide novel insight into the regulation of sE-selectin levels. These results may open new avenues in understanding the critical role of E-selectin on the pathogenesis of inflammatory and cardiometabolic disorders.

Assessing bleeding risk in 18 children with Osteogenesis imperfecta

Assessing bleeding risk in 18 children with <i>Osteogenesis imperfecta</i>

Association between serum immunoglobulin E and soluble E-selectin, and atopic dermatitis

ObjectiveTo study and evaluate the role of both serum immunoglobulin E (IgE) and soluble E-selectin in patients with atopic dermatitis (AD).BackgroundAD is a chronic inflammatory skin disease that is characterized by intense itching and recurrent eczematous lesions. Although it most often starts in infancy. It is also highly prevalent in adults. Assessment of maintenance of AD could be related to serum IgE and soluble E-selectin. Treatment of AD remains a challenge.Patients and methodsThis case–control study was performed for 40 patients who were age-matched and sex-matched with 20 healthy control cases. The patient group was subdivided into two groups according to their severity. The sample comprised 28 men and 32 women. Their ages ranged between 3 and 28 years.ResultsThere was significant statistical differences between the two studied patient groups and the control group regarding total IgE and E-selectin serum levels that were higher in the patient group than the control one. There was also significant statistical increase in the level of serum IgE and soluble E-selectin in severe AD patients compared with mild cases.ConclusionThere was a positive association between serum IgE, soluble E-selectin, and AD in general and also with severity. So it may be used as a marker for AD.

Effect of a Recombinant Dimeric Tumor Necrosis Factor Receptor on Inflammatory Responses to Intravenous Endotoxin in Normal Humans

AbstractTo determine the role of tumor necrosis factor (TNF ) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from −30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 ± 42 pg/mL; P < .05). Infusion of TNFR:Fc completely neutralized endogenous TNF activity. LPS administration was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-α2 -antiplasmin complexes), followed by inhibition (plasma plasminogen activator inhibitor type I), changes that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc did not influence LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited endothelial cell activation (plasma levels of soluble E-selectin), modestly reduced neutrophil responses (neutrophilia and plasma concentrations of elastase-α1 -antitrypsin complexes and lactoferrin), but did not affect the release of secretory phospholipase A2 or lipopolysaccharide-binding protein (P < .05). Infusion of TNFR:Fc only (without LPS) in another 6 normal subjects did not induce any inflammatory response. These data indicate that TNF is involved in only some inflammatory responses to intravenous LPS in humans.

Early Initiation of Treatment with Rivipansel for Acute Vaso-Occlusive Crisis in Sickle Cell Disease (SCD) Achieves Earlier Discontinuation of IV Opioids and Shorter Hospital Stay: Reset Clinical Trial Analysis

Early Initiation of Treatment with Rivipansel for Acute Vaso-Occlusive Crisis in Sickle Cell Disease (SCD) Achieves Earlier Discontinuation of IV Opioids and Shorter Hospital Stay: Reset Clinical Trial Analysis

Association of E-Selectin gene polymorphisms and serum E-Selectin level with risk of coronary artery disease in lur population of Iran

Background Adhesion molecules like E-selectin have important role in pathogenesis of atherosclerosis. C1901T and G98T polymorphisms of E-selectin gene and E-selectin serum level may affect the risk of coronary artery disease (CAD). Methods A total of 145 normal individuals and 154 patients diagnosed with CAD from the Lur population of Iran undergoing coronary angiography were enrolled. Genetic polymorphisms of E-selectin were determined using PCR-RFLP. Serum level of soluble E-selectin was measured using Elisa. Results T allele in C1901T polymorphism was significantly associated with an increased risk of atherosclerosis (P = 0.018). No significant association was observed for G98T polymorphism. The mean serum level of soluble E-selectin in the patient group was significantly higher than the control group (P < 0.001). Conclusions Allele type in C1901T polymorphism plays a role in increasing the risk of developing CAD. Furthermore, since serum E-selectin level is associated with systemic inflammation, it contributes to the increased risk of the disease.

Interleukin-1 receptor inhibition reduces stroke size in a murine model of sickle cell disease.

Sickle cell disease (SCD) is associated with chronic hemolytic anemia and a heightened inflammatory state. The causal role of inflammatory pathways in stroke associated with SCD is unclear. Therefore, the hypothesis that deletion of the non-hematopoietic interleukin-1 receptor (IL-1R) pool may be beneficial in SCD was pursued. Since potential deleterious effects of IL-1R signaling in SCD could be mediated via downstream production of interleukin-6 (IL-6), the role of the nonhematopoietic IL-6 pool was also addressed. Bone marrow transplantation (BMT) from SCD to wild-type (WT) recipient mice was used to generate SCD mice (Wt,SCDbmt). In order to generate mice with nonhematopoietic deficiency of IL-1R or IL-6, SCD marrow was transplanted into IL-1R deficient (IL1R-/-,SCDbmt) or IL-6 deficient recipients (IL6-/-, SCDbmt). Blood counts, reticulocytes, soluble E-selectin (sEsel), and IL-6 levels were analyzed 14-15 weeks post-BMT. Ischemic stroke was induced by middle cerebral artery (MCA) photothrombosis at 16 weeks post-BMT. A separate group of Wt,SCDbmt mice was given the IL-1R inhibitor, anakinra, following stroke induction. Seventy-two hours after MCA occlusion, stroke volume was assessed by staining brain sections with 2,3,5-triphenyltetrazolium chloride. Formalin-fixed brain sections were also stained for macrophages with MAC3, for endothelial activation with ICAM-1, and for loss of blood brain barrier integrity with fibrin (ogen) staining. All SCD mice generated by BMT were anemic and the severity of anemia was not different between Wt,SCDbmt, IL1R-/-,SCDbmt, and IL-6-/-,SCDbmt mice. Three days following MCA occlusion, stroke volume was significantly reduced in IL1R-/-,SCDbmt mice compared to Wt,SCDbmt mice and IL6-/-,SCDbmt mice. Plasma levels of sEsel were lower in IL1R-/-,SCDbmt compared to Wt,SCDbmt and IL-6-/-,SCDbmt mice. Post-stroke treatment of Wt,SCDbmt mice with anakinra decreased stroke size, leukocyte infiltration, ICAM-1 expression, and fibrin(ogen) accumulation compared to vehicle-treated mice. Deficiency of non-hematopoietic IL-1R or treatment with an IL-1R antagonist is sufficient to confer protection against the increased stroke size associated with SCD. These effects of IL1R deficiency are associated with reduced endothelial activation, leukocyte infiltration, and blood brain barrier disruption, and are independent of non-hematopoietic IL-6 signaling.

Evaluation of metabolic, antioxidant and anti-inflammatory effects of Garcinia kola on diabetic rats.

Garcinia kola (G. kola), is a plant characterized by its hypoglycemic properties. We recently reported our findings on the extracts of G. kola, in which we found that it prevented the loss of inflammation-sensible neuronal populations in streptozotocin (STZ)-induced rat models of type 1 diabetes mellitus (T1DM).In the present study we assessed the effect of G. kola bioactive compounds extracted successively with water, hexane, methylene chloride, ethyl acetate, and butanol. through analyzing biochemical markers of oxidative stress, inflammation, and metabolic function in STZ-induced diabetic animals.Animals made diabetic by a single injection with STZ (60 mg/kg, i.p.), were treated daily with either vehicle solution, insulin, or G. kola extracts and its fractions from the first to the 6th-week post-injection. Biochemical markers; glucose, insulin, C-peptide, neuron-specific enolase (NSE), creatinine kinase, glutathione peroxidase, malondialdehyde (MDA), resistin, soluble E-selectin (SE-Selectin), and C-reactive proteins (CRP) levels in the sera were determined in the study groups. A marked increase in blood glucose (209.26% of baseline value), and a decrease in body weight (−12.37%) were observed in diabetic control animals but not in animals treated with either insulin or G. kola extracts and its fractions. The sub-fraction F5, G. kola ethyl acetate had the highest bioactive activities, with a maintenance of blood sugar, malondialdehyde, C-peptide, E-selectin, C-reactive protein (CRP) and neuron-specific enolase (NSE) to levels and responses comparable to healthy non-diabetic vehicle group and the positive control diabetic insulin-treated group.Our findings suggest that G. kola may have a strong therapeutic potential against T1DM and its microvascular complications.

Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study.

ObjectiveTo investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness.MethodsA prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection.ResultsFifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m.ConclusionReactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

Assessment of Serum Levels of E-Selectin and L-Selectin in Alopecia Areata

Background: Alopecia Areata (AA) is an immune system disease that invades anagen Hair Follicles (HFs) and shows multifactorial etiology. One of the essential histopathological features of AA is a lymphocytic intrusion that envelops HFs. Soluble forms of Endothelial (E), Lymphocytic (L), and Platelets (P)-selectins are known markers of persistent bothering. There are limited examinations for the assessment of serum levels of soluble E-selectin, L-selectin, and P-selectin in patients with AA. Objectives: We assessed serum levels of soluble E-selectin and L-selectin in patients with in association with the control group to determine their role in the pathogenesis of the disease. Methods: The study included 30 patients with AA and 10 healthy subjects who served as controls. Blood samples were taken from all patients and controls. The serum levels of soluble E-selectin and L-selectin were determined with the Enzyme-linked Immunosorbent Assay (ELISA) method. Results: Higher levels of sE-selectin and sL-selectin were found in AA patients than in controls. There was a significant relationship between the higher serum levels of sE-selectin and the increased size of lesions with time. There was a significant positive correlation between the serum levels of sE-selectin and sL-selectin and the percentage of hair loss. Conclusions: This study showed that sE-selectin and sL-selectin may play a significant role in the pathogenesis of AA and might open a way to future treatments for this disease.

Effects of Targeting the Interleukin-1 Receptor in a Murine Model of Sickle Cell Disease

Background: Sickle cell disease (SCD) is associated with chronic hemolytic anemia and a heightened inflammatory state. Multiple inflammatory pathways have been shown to be activated in SCD, however the causal role of these pathways in mediating organ damage and contributing to stroke is unclear. Methods: Bone marrow transplantation (bmt) from SCD (Townes) to wild-type (WT) recipient mice was used to generate SCD mice (WTSCD). To generate mice with non-hematopoietic deficiency of the interleukin-1 receptor (IL1R), SCD marrow was transplanted into IL1R deficient recipients (IL1R-/- SCD). Other WTSCD mice were given the IL1R inhibitor, anakinra, or PBS for 2 or 4 weeks before sacrifice. Iron and collagen staining were performed in multiple formalin-fixed tissues with Prussian blue and Masson's Trichrome, respectively. Complete blood counts and reticulocyte percentages were analyzed 15 weeks following BMT. Plasma levels of soluble E-selectin (sE-sel) and soluble P-selectin (sP-sel) were measured 14 weeks following bmt with ELISA. Ischemic stroke was induced by middle cerebral artery (MCA) photothrombosis at 16 weeks of age. WTSCD mice were given anakinra following stroke induction. Seventy-two hours after MCA occlusion, stroke volume was assessed by staining brain sections with 2, 3, 5-triphenyltetrazolium chloride. Formalin-fixed brain sections were also stained for macrophages. Results: All SCD mice were anemic and the severity of anemia was not different between WTSCD and IL1R-/- SCD mice. Increased circulating erythrocytes (9.01 ± 0.78 vs 6.77 ± 0.18 M/uL; p&lt;0.05) and decreased reticulocytes (25.31 ± 1.79 vs 32.45 ± 2.74%; p&lt;0.05) were observed in WTSCD mice treated with anakinra for 4 weeks. Two week anakinra treatment was sufficient to decrease organ iron deposition and lung collagen deposition. In vivo treatment with anakinra also decreased erythrocyte sickling in a whole blood ex vivo sickling assay (15.14 ± 0.94 vs 24.18 ± 1.95 % sickled; p&lt;0.01). Further, in vitro treatment of WTSCD whole blood with IL-1β increased sickling (26.70 ± 0.39 vs 22.34 ± 0.95; p&lt;0.05), and this was ameliorated with in vitro pretreatment with anakinra. Alterations to ex vivo sickling were not observed when conditions were repeated on erythrocytes alone. Stroke volume was significantly reduced in IL1R-/- SCD mice compared to WTSCD mice 3 days following MCA occlusion (8.08 ± 0.91 vs 11.10 ± 1.16 % hemisphere; p&lt;0.05). Post-stroke treatment of WTSCD mice with anakinra also decreased stroke size compared to vehicle-treated mice (14.45 ± 1.44 vs 9.7 ± 3.23 % hemisphere; p=0.05). Non-hematopoietic deficiency of IL1R decreased sE-sel (vs 50.10 ± 2.31 vs 32.12 ± 2.08 pg/mL; p&lt;0.05) and sP-sel (155.98 ± 24.44 vs 327.23 ± 18.31 ng/mL; p&lt;0.05) levels in post-stroke animals and decreased the number of macrophages observed in the peri-stroke area (0.26 ± 0.05 vs 0.722 ± 0.15 % hemisphere; p&lt;0.05). Conclusions: Deficiency of non-hematopoietic IL1R or treatment with an IL1R antagonist was appears beneficial towards several phenotypes in a mouse model of SCD. Given the safety of IL1R inhibitors in various patient populations, this study reveals a potential therapeutic intervention for treatment of sickle cell patients. Disclosures No relevant conflicts of interest to declare.

Comparison of effects of no-, medium-, and high dose dexamethasone in adult cardiac surgery – A post-hoc analysis of the prospective, observational inflacor trial

Introduction Since the introduction of cardiopulmonary bypass (CPB) patients suffered within the first postoperative days after cardiac surgery of systemic inflammatory response syndrome (SIRS). Patients discomfort and clinical symptoms of inflammation had been since target for prophylaxis and treatment with corticosteroids. High doses of corticosteroids to attenuate postoperative SIRS after CPB cardiac surgery are nowadays not recommended. This study compares the efficacy of low and high doses of dexamethasone. Methods Single center, prospective, observational study. Post-hoc analysis of n = 509 adult patients undergoing open heart surgery on CPB. Patients were grouped according to one dose of dexamethasone administered before CPB: I - none (n = 326), II - low dose - 0.4 mg/kg (n = 96), and III - high dose - 1.0 mg/kg (n = 87). Primary outcomes were: IL-6, ICAM1, soluble E-selectin levels three hours after operation, and CRP and WBC - 18 hours after operation. Secondary outcomes were: new-onset atrial fibrillation, myocardial infarction, delirium, sepsis, acute lung injury, acute kidney injury, length of stay in ICU and hospital, first-day drainage, and surgical reintervention. Stratified analyses were performed in CPB duration quartiles: 1: 11 – 100 Min. (n = 130), 2: 101-127 Min (n = 126), 3: 128-160 Min. (n = 126), 4: 161-476 Min. (n = 127). Results Dexamethasone ceased the trigger effect of CPB on levels of IL-6, ICAM1, sE-selectin at 3 hours after operation and CRP at 18 hours after operation. The levels of IL-6, soluble E-selectin, CRP and WBC didn't differ between groups II and III (p>0.05) and were lower than in group I (p Primary outcome variables were in close association with the secondary outcomes: IL-6 was a predictor for ICU-LOS (p = 0.049) and AKI (p = 0.0001); ICAM1 for ICU-LOS (p = 0.047), AKI (p Significant effects of dexamethasone were found only in detailed stratified analyses: in the third CPB quartile MI prevalence was higher in group II, compared with group I or III. In patients within the third CPB quartile, group II had higher risk of postoperative MI (aRR = 2.15; p = 0.03) in comparison to group I. Higher delirium prevalence in group III when compared with group II was observed in the first CPB quartile (aRR = 7.19; p = 0.035). Incidence of surgical reintervention was significantly lower in groups II and III, regardless of the dose, in the 4th CPB quartile, when compared with group I. Discussion CPB duration is a surrogate for complexity of the surgical procedure. Therefore AKI, sepsis, and postoperative bleeding remained in correlation with CPB duration. Dexamethasone in a dose of 0.4 mg/kg was as effective as 1.0 mg/kg in attenuating post-operative SIRS parameters, but had no significant effect on early postoperative morbidity.

Alteration in serum levels of ICAM-1 and P-, E- and L-selectins in seriously eye-injured long-term following sulfur-mustard exposure

IntroductionIn this study, the serum levels of soluble intercellular adhesion molecule 1 (ICAM-1), P-, E-, and L-selectins were investigated in seriously eye-injured patients exposed to sulfur mustard (SM). Material and methodsA total of 128 individuals with SM-induced serious eye injuries and 31 healthy male controls were included in this study. The serum concentration of soluble forms of adhesion molecules was measured by enzyme-linked immunosorbent assay (ELISA) method. ResultThe serum level of soluble ICAM-1 was significantly higher in the SM-exposed individuals with an abnormality in tear meniscus height, corneal verticillata, and pannus compared with SM-exposed individuals without these abnormalities. There were no significant differences in the level of all three measured selectins between the SM-exposed group and the control groups. SM-exposed individuals with corneal defect had a significantly higher level of soluble E-selectin than SM-exposed individuals without this abnormality. The serum level of soluble P-selectin in the SM-exposed group with limbal abnormality was significantly lower than that in the SM-exposed without this abnormality; also it was significantly higher in SM-exposed group with fundus abnormality compared to that in the control group or SM-exposed group without this abnormality. ConclusionThe changes in the levels of selectins and ICAM-1 in the SM-exposed group with various ocular abnormalities is a defense mechanism against the toxicity of SM. Further analysis is required to understand the molecular mechanisms of the relationship between adhesion molecules with ocular complications in SM-exposed individuals.

Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

BackgroundInflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood.ObjectiveTo assess genetic...