Serum levels of P-selectin in men with high-functioning autism

Immune dysfunction has been proposed as a mechanism for the pathophysiology of autistic-spectrum disorders. The selectin family of adhesion molecules plays a prominent role in immune/inflammatory responses. We determined the serum levels of three types of soluble-form selectin (sP, sL and sE) in 15 men with high-functioning autism and 22 age-matched healthy controls by enzyme-linked immunosorbent assay. Levels of sP-selectin and sL-selectin were significantly lower in patients than in controls. Furthermore, sP-selectin levels were negatively correlated with impaired social development during early childhood.     

Investigation of Thr715Pro P-selectin gene polymorphism and soluble P-selectin levels in type 2 diabetes mellitus

Increased levels of soluble P-selectin (sP-selectin) have been shown in a number of different disorders, e.g. diabetes mellitus (DM) and cardiovascular disease (CVD). Several studies have attempted to demonstrate the association of the most intensively examined variant of P-selectin gene polymorphism (Thr715Pro) with sP-selectin levels in healthy subjects and in CVD, but contradictory data have been reported. To clarify the effect of Pro715 allele on the sP-selectin levels in type 2 DM, we analysed this polymorphism in diabetic patients and compared these data with sP-selectin levels. Type 2 DM patients (n = 119), 48 BMImatched non diabetic individuals - consisting mostly of overweight subjects - and 57 healthy volunteers were included in the study. TheThr715Pro polymorphism was analysed by PCR-RFLP, while sP-selectin levels were measured by ELISA. Significantly elevated sP-selectin levels were found in both DM and in overweight subjects compared to healthy controls. We confirmed previous reports that in healthy Pro715 allele carriers lower sPselectin levels could be measured; however, this difference was only significant in case of lean subjects. No significant difference was detected in sP-selectin level among DM and overweight individuals according to this genotype. However, significant difference was observed in sP-selectin levels in older DM patients compared to younger ones, but these levels were not accounted for by the Thr715Pro polymorphism. We suggest that in type 2 DM individuals, the significantly elevated sP-selectin levels are not due to the Thr715Pro P-selectin gene polymorphism.     

Plasma levels of P-selectin are determined by platelet turn-over and the P-selectin Thr715Pro polymorphism

BACKGROUND: Plasma levels of soluble P-selectin (sP-selectin) are often used to demonstrate platelet activation. METHODS: We determined sP-selectin in a variety of disorders characterized by high or low platelet counts and compared their levels with those in healthy subjects. Furthermore, we determined the Thr715Pro polymorphism in all subjects. RESULTS: Total concentrations of sP-selectin were clearly associated with levels of platelet counts. Thus, calculation of sP-selectin per platelet showed that these levels in patients with thrombocytopenia due to marrow failure and in patients with increased platelet counts were similar to those in controls. Only patients with an increased platelet turn-over had elevated sP-selectin per platelet. While carriers of the Pro715 polymorphism had lower sP-selectin levels than non-carriers, this genetic disposition was over-ruled in patients with increased platelet turn-over. CONCLUSION: For the demonstration of platelet activation it is preferable to define sP-selectin based on platelet counts under the consideration of the Pro715Thr polymorphism.     

Association between the Thr715Pro P-selectin gene polymorphism and soluble P-selectin levels in a multiethnic population in South London

The aim was to investigate whether the Thr715Pro P-selectin polymorphism is associated with soluble P-selectin (sP-selectin) levels in individuals from different ethnic groups. Plasma sP-selectin and Thr715Pro (A/C) P-selectin gene polymorphism were measured in 237 white (106 females), 177 black African origin (92 females) and 201 South Asian (94 females) individuals living in England. All were free from coronary heart disease (CHD), stroke and other cardiovascular disease, diabetes, drug therapy for hypertension or high lipids, hormone replacement therapy or oral contraceptive pill. The Thr715Pro C allele was rare in blacks (0.8%) and intermediate in South Asians (3.0%) compared to whites (11.2%; p <0.001). sP-selectin levels were significantly lower in the individuals with the AC or CC compared to the AA genotype in both whites (-25% (95% C.I. -33.3 to -16.9); p <0.001) and South Asians (-25.2% (-40.5 to -6.1); p <0.012). There was insufficient power for this analysis in blacks. In conclusion, in whites and South Asians the C allele of the Thr715Pro P-selectin polymorphism is associated with lower sP-selectin levels. Lower levels of sP-selectin were not accounted for by this polymorphism in blacks, in whom the C allele was very rare.     

易卒中型肾血管性高血压大鼠血浆CAM-1和P-选择素的动态观察

目的动态观察易卒中型肾血管性高血压大鼠（RHRSP）血浆ICAM-1和P-选择素的活性改变。方法双肾双夹法制作RHRSP模型,分别于术前及术后2、4、6、8、10、12、16周取血,酶联免疫吸附测定（ELISA）法检测ICAM-1和P-选择素含量。结果4周始RHRSP血中ICAM-1和P-选择素含量逐渐增高,明显高于正常对照组,且ICAM-1和P-选择素呈正相关,ICAM-1和P-选择素均与大鼠收缩压密切相关。结论血浆中ICAM-1和P-选择素含量升高提示梗死或出血的危险性增加,可作为脑卒中的预测指标之一。     

P-选择素在基底动脉尖综合征患者血清中的表达及尤瑞克林对其影响

目的观察基底动脉尖综合征患者血清P-选择素的动态变化及尤瑞克林对P-选择素表达的影响。方法将22例急性基底动脉尖综合征(TOBS)患者随机分为尤瑞克林治疗组和常规治疗组各11例,两组均给予常规抗血小板聚集、抗自由基、活血化瘀治疗,治疗组加用尤瑞克林治疗;测定患者治疗前、治疗后7d和21d血清P-选择素水平,并测定21例正常对照者血清P-选择素水平。结果与正常对照组比较,TOBS患者治疗前血清P-选择素水平显著升高(P<0.01);与治疗前相比,常规治疗组在治疗后7d下降无统计学意义(P>0.05),治疗后21d差异具有统计学意义(P<0.05);尤瑞克林治疗组在治疗后7d P-选择素水平下降显著(P<0.05),治疗后21d下降更加明显(P<0.01)。两组之间相比,治疗前血清P-选择素水平无显著性差异,治疗后尤瑞克林治疗组下降明显,治疗后7d(P<0.05),治疗后21d(P<0.01)。血清P-选择素水平与NIHSS评分呈正相关。结论血清P-选择素在TOBS患者中发病后升高,治疗后逐渐出现下降,尤瑞克林可降低血清P-选择素水平。     

High levels of platelet-monocyte aggregates after valve replacement for aortic stenosis: relation to soluble P-selectin and P-selectin glycoprotein ligand-1 genes

Background

Calcific aortic valve stenosis is linked to atherosclerosis. The latter is associated with increased levels of platelets adhering to monocytes (PMA).

Objective

The hemodynamic impairment in symptomatic aortic valve stenosis can be abated by valve replacement. We investigated the effect of valve replacement on PMA and receptor-ligand axis P-selectin - P-selectin glycoprotein ligand-1 (PSGL-1) in severe aortic valve stenosis.

Patients and Methods

PMA, plasma P-selectin (sP-selectin) and polymorphisms within the coding region for PSGL-1 (SELPLG) were determined in 42 patients with severe aortic valve stenosis before and 4 to 8 months after valve replacement. Ten patients suffered from significant coronary artery disease and received also a coronary artery bypass graft. Thirty-four patients received a bioprosthetic valve and 8 patients who were < 65 years old received a mechanical valve.

Results

Before the intervention, PMA levels were significantly higher in patients with aortic valve stenosis than in two control cohorts, namely healthy indviduals and 88 age- and sex-matched patients with severe atherosclerosis, but without aortic valve stenosis (p < 0.001). PMA decreased after surgery, but normalized in only 3 patients, while further increases were noted in 11 patients. sP-selectin was elevated in 3 and 4 patients before and after valve replacement, respectively. sP-selectin increased significantly after surgery, but remained within the normal range. There was no correlation between changes of PMA and sP-selectin or any of the polymorphisms within SELPLG.

Conclusions

Exceedingly high PMA in aortic stenosis are independent of SELPLG polymorphisms, and largely of the hemodynamic compromise caused by the stenotic valve.     

急性脑血管病患者血清P-选择素的含量变化及其临床意义

目的探讨P-选择素(Ps)在脑梗死发生、发展中的作用。方法采用ELISA测定54例脑梗死患者、15例脑出血患者、20例正常对照血清Ps含量。结果脑梗死组发病3d内血清Ps水平明显高于脑出血组及对照组,后两组无显著差异;脑梗死组发病3d内血清Ps水平与发病后1周无显著差异,但均明显高于发病后2周,发病后2周与对照组无显著差异;脑梗死组发病3d内血清Ps水平与梗死灶体积呈正相关。结论Ps参与脑缺血再灌注损伤,可作为脑梗死早期诊断及鉴别诊断的依据,干预其产生和作用途径可改善脑梗死的预后。     

急性脑血管病患者血清P-选择素的含量变化及其临床意义

目的 探讨P-选择素（Ps）在脑梗死发生、发展中的作用.方法 采用ELISA测定54例脑梗死患者、15例脑出血患者、20例正常对照血清Ps含量.结果 脑梗死组发病3d内血清Ps水平明显高于脑出血组及对照组,后两组无显著差异;脑梗死组发病3d内血清Ps水平与发病后1周无显著差异,但均明显高于发病后2周,发病后2周与对照组无显著差异;脑梗死组发病3d内血清Ps水平与梗死灶体积呈正相关.结论 Ps参与脑缺血再灌注损伤,可作为脑梗死早期诊断及鉴别诊断的依据,干预其产生和作用途径可改善脑梗死的预后.     

Association of elevated soluble P-selectin levels with fetal loss in women with a history of venous thromboembolism

Introduction

An association between pregnancy complications such as fetal loss with inherited and acquired thrombophilic defects has frequently been reported. Recently, the cell adhesion molecule P-selectin has been identified to be a strong risk factor for venous thromboembolism (VTE).

Patients and Methods

The aim of our study was to investigate whether soluble P-selectin (sP-selectin) is also associated with fetal loss (e.g. miscarriage or stillbirth) in 304 women (median age [25th-75th percentile]: 45 [37-54] years) with a history of VTE, in whom data on pregnancy-associated complications had been evaluated. At the time of sP-selectin measurement none of the women was pregnant or had an acute VTE.

Results

The prevalence of miscarriage was 21.4% and that of stillbirth was 4.6%. The median sP-selectin level of the total study population was 38.0 [31.7-44.4] ng/mL. In subjects with elevated sP-selectin levels (defined as sP-selectin ≥ 44.4 ng/mL, representing the 75th percentile of levels in the study population) the prevalence of stillbirth was significantly higher compared to those with lower levels (10.5% vs. 2.6%, p = 0.008), whereas no statistically significant difference in the prevalence of miscarriage was observed between women with and without elevated sP-selectin (17.1% vs. 22.9%, p = 0.303). The odds ratio [95% CI] of elevated sP-selectin was 4.2 [1.5-12.7] for stillbirth and 0.7 [0.4-1.3] for miscarriage.

Conclusions

Elevated sP-selectin plasma levels were associated with a 4.2-fold risk for stillbirth in women with a history of VTE. Our data support a possible role of P-selectin in late pregnancy loss.     

Effects of toll-like receptor-4 gene polymorphisms on soluble P-selectin and von Willebrand factor levels in hypercholesterolemic patients

Toll-like receptor-4 (TLR-4) gene polymorphisms have been associated with a lower risk of atherosclerosis. High levels of soluble P-selectin (sP-selectin) and von Willebrand factor predict an increased risk for cardiovascular events and correlate to atherosclerotic risk factors. The relationship between these markers and TLR-4 gene polymorphisms was evaluated in a cohort of consecutive hypercholesterolemic outpatients. TLR-4 gene polymorphisms were detected in 48 out of 330 (14%) patients with hypercholesterolemia. Lipid and inflammatory markers, sP-selectin and von Willebrand were evaluated in carriers and in 96 (ratio 2:1 to cases) age- and sex-matched TLR-4 wild-type patients randomly selected from the same population. A cohort of normocholesterolemic outpatients (n = 262) served as the control group. sP-selectin was sensibly lower in carriers of TLR-4 variants as compared to wild-types and controls (89 ng/ml vs. 162 ng/ml and 163 ng/dl, respectively, p = 0.0001). Similarly, carriers showed lower von Willebrand factor values (683 mU/ml) than wild-types (910 mU/ml; p = 0.001). In multivariate analysis, TLR-4 gene polymorphisms were positively associated with sP-selectin, whereas the relationship with von Willebrand factor was no longer significant. HMG-CoA reductase inhibitors reduced sP-selectin and von Willebrand factor levels independently of TLR-4 gene variants. Plasma concentrations of these markers, however, remained lower in carriers of TLR-4 gene polymorphisms even after cholesterol lowering. In conclusion, carriership of Asp299 and Thr399Ile TLR-4 gene polymorphisms is associated with lower levels of sP-selectin and von Willebrand factor among hypercholesterolemic patients. While the underlying mechanisms remain to be investigated, such an association may indicate a protective effect of TLR-4 variants for atherosclerosis.     

P-选择素与缺血性脑卒中

血小板活化在缺血性脑卒中的发生、发展过程中起着重要作用,P-选择素（CD62p）的表达是血小板活化的标志。抗CD62p治疗可以减轻缺血性脑损伤症状。因此,研究CD62p在缺血性脑卒中的发生和卒中后再损伤过程中的作用,对缺血性脑卒中的防治具有重要意义。     

P-selectin gene haplotypes modulate soluble P-selectin concentrations and contribute to the risk of venous thromboembolism

The cell adhesion molecule P-selectin mediates the interaction of activated platelets or endothelial cells with leukocytes. In arterial and venous thromboembolism (VTE) increased soluble P-selectin (sP-selectin) concentrations have been found, and associations of P-selectin genotypes with thrombotic disease have been proposed. We assessed the effect of four single nucleotide polymorphisms (SNPs) [one in the promoter region (c.-2123C>G) and three (S290N, c.1087G>A; D562N, c.1902G>A; T715P, c.2363A>C) in the coding region] and the calculated haplotypes in the P-selectin gene (SELP) on sP-selectin concentrations and VTE risk. The analysis was carried out in 116 high-risk patients with a history of objectively confirmed recurrent VTE and 129 age- and sex-matched healthy individuals. Haplotypes were generated using computer-assisted haplotype reconstruction with Phase 2.1. sP-selectin (microg/l) was measured by ELISA. Frequencies of all four individual SNPs were not statistically significantly different between patients and controls. Ten haplotypes were obtained for the control population, and nine for the patient group. The most frequent haplotype among controls was CGGA (major allele at all positions) (27.8%; frequency in patients 19.0%), which was used as reference for statistical analyses. Among patients GGAA was most frequent (23.3%; frequency in controls 17.5%). Haplotypes were significantly associated with sP-selectin concentrations in patients and in controls (p<0.001 and p=0.011). Compared to CGGA some but not all haplotypes conferred an increased risk for VTE with odds ratios (ORs) between 5.4 (95% CI: 2.5-12.2) for CAGA, 3.3 (1.2-9.2) for CGAC, and 2.4 (1.3-4.7) for GGAA. All ORs remained statistically significant after adjustment for the factor V Leiden mutation, located in close proximity to SELP on chromosome 1, as well as all other established risk factors for VTE. In conclusion, SELP haplotypes modulate plasma concentrations of sP-selectin and affect the risk of recurrent VTE.     

P-selectin antagonism causes dose-dependent venous thrombosis inhibition

Inhibition of P-selectin by antibody or selectin antagonist decreases inflammation and thrombosis. This study evaluates the dose-response relationship using a selectin receptor antagonist. Eight male baboons (Papio anubis) underwent inferior vena caval thrombosis using a 6 h balloon occlusion model. Three animals received 500 microg/kg P-selectin antagonist (rPSGL-Ig) and five 1 mg/kg rPSGL-Ig with or without a non-anticoagulant dose of Dalteparin. These animals were compared to our published results in this model with 4 saline controls and 8 animals that received 4 mg/kg rPSGL-Ig. A statistically significant dose-response relationship existed between rPSGL-Ig dose and thrombosis (p < 0.01), and between rPSGL-Ig dose and spontaneous recanalization (p<0.05). Inflammatory assessment revealed decreased gadolinium enhancement in all rPSGL-Ig groups compared to previously reported control, despite no significant differences in inflammatory cell extravasation. No dose of rPSGL-Ig caused anticoagulation. Selectin antagonism results in a dose-dependent decrease in thrombosis and increase in spontaneous recanalization.     

Elevated P-selectin on platelets in depression: response to bupropion

Increased platelet activation has been suggested as a possible reason for the increased vulnerability of depressed patients to ischemic heart disease (IHD). Translocation of p-selectin, an integral -granule membrane protein, to the platelet surface is a measure of platelet activation. Herein, western blots of platelet plasma membranes containing p-selectin were quantified in patients with major depression (n=19; mean AGE=39 ± 2 years) and healthy comparison subjects (n=17; mean AGE=36 ± 2 years). None evidenced clinical signs of IHD, and only two patients had a lifestyle IHD risk factor (smoking). Blood was obtained from all 19 depressed patients before treatment, and 15 returned after 6–8 weeks of open-label bupropion treatment. Bupropion was chosen as the antidepressant because it did not elevate plasma norepinephrine or serotonin, endogenous agonists that can induce platelet degranulation. Western blotting revealed more p-selectin immunoreactivity (75 kD band) in depressed patients compared to healthy controls (P=0.003). After bupropion treatment, p-selectin remained high in depressed patients. β3-Integrin, a reference plasma membrane protein that does not translocate during activation, was of equivalent density in depressed patients and healthy control subjects, and was unchanged after treatment with bupropion. p-Selectin failed to correlate with severity of illness based on the Hamilton Depression scale, or with the post-treatment plasma concentration of bupropion. The results suggest an elevation in p-selectin on platelet plasma membranes might be a trait marker for depression.