| 1. |
- Ahmad, Abrar, et al.
(författare)
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Evaluation of Expression Level of Apolipoprotein M as a Diagnostic Marker for Primary Venous Thromboembolism
- 2018
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Ingår i: Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1938-2723 .- 1076-0296. ; 24:3, s. 416-422
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Tidskriftsartikel (refereegranskat)abstract
- Recently, decreased levels of apolipoprotein M (ApoM) were shown to be associated with higher risk of recurrent venous thromboembolism (VTE) in male patients. However, the role of ApoM in primary VTE is unknown. We aimed in our study to analyze the plasma levels of ApoM in patients with VTE in order to evaluate the diagnostic importance of ApoM in primary VTE. A total of 357 patients with suspected first episode of VTE were recruited prospectively in the SCORE study. Plasma samples from 307 patients were available for quantifying the plasma levels of ApoM in patients with VTE using sandwich enzyme-linked immunosorbent assay method. Among the whole population, plasma levels (mean [standard deviation]) of ApoM were not significantly different between patients with VTE (0.72 [0.20]) and non-VTE patients (0.72 [0.16]), P = .99. Similarly, in regression analyses, no significant association of ApoM plasma levels with the risk of VTE was found on univariate (odds ratio [OR] =1.0, 95% confidence interval [CI] 0.21-4.84, P = .99) and multivariate analysis (OR = 1.25, 95% CI = 0.19-8.34, P = .819) after adjusting for age, body mass index, and smoking. Moreover, results did not differ significantly after stratification of data according to sex ( P > .05). In this study, our results do not suggest a diagnostic role for ApoM plasma levels in patients with primary VTE. Moreover, the current study suggests that role of ApoM as a risk factor may differ for primary VTE and recurrent VTE in male patients.
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| 2. |
- Ahmad, Abrar, et al.
(författare)
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Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism
- 2016
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 116:3, s. 41-432
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein M (ApoM) plasma levels have been reported to be associated with risk of venous thromboembolism (VTE) recurrence. However, the role of genetic alterations in the ApoM gene in VTE recurrence remains unknown. The aim of this study was to identify genetic aberrations in ApoM gene in VTE recurrence and their role in prediction of VTE recurrence in a prospective follow-up study of 1465 VTE patients. During follow-up, 156 (10.6 %) patients had VTE recurrence. First screening of whole ApoM gene was performed by Sanger's sequencing in selected age and sex matched non-recurrent and recurrent patients (n=95). In total six polymorphisms were identified and two polymorphisms (rs805297 and rs9404941) with minor allele frequency (MAF) ≥5 % were further genotyped in the whole cohort by Taqman PCR. ApoM rs805297 polymorphism was significantly associated with higher risk of VTE recurrence in males but not in females on both univariate (p= 0.038, hazard ratio = 1.72, confidence interval = 1.03-2.88) and on multivariate analysis adjusted with mild and severe thrombophilia, family history, location and acquired risk factors for VTE. However, ApoM rs9404941 polymorphism showed no significant association with risk of VTE recurrence in all patients as well as in different gender groups. Moreover, ApoM rs805297 and rs9404941 polymorphisms were not associated with the ApoM plasma levels. In conclusion, for the first time we have sequenced whole ApoM gene in VTE and identified six polymorphisms. ApoM rs805297 was significantly associated with higher risk of VTE recurrence in male but not in female patients.
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| 3. |
- Berggren, Peter, 1971-
(författare)
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Assessing Shared Strategic Understanding
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the development of an instrument for assessing shared understanding in teams. The purpose was to develop an instrument that would be usable, understandable, objective, flexible and self-explanatory. Teams working in naturalistic settings are expected to have a shared understanding concerning common goals and how to achieve these. The problem investigated in this thesis is that current techniques and instruments for assessing shared understanding in teams generally suffer from one or more of the following drawbacks, namely that they are expensive, difficult to use, time-consuming, requiring expertise, and are often based on subjective perceptions. Departing from existing theory in team cognition techniques and theories, the research questions posed in this thesis are: 1) How can shared understanding be measured without the disadvantages of existing methods? 2) How can shared understanding be assessed without the bias of self-ratings and/or assessments by experts/observers? 3) Can team performance be better understood by the outcomes of an instrument that measures shared understanding?These research questions are answered through six studies that are presented in this thesis. Over the six studies an instrument was iterated and subsequently developed, called the “shared priorities instrument”. When using this instrument, team members are instructed to generate items and rank these in order of importance. By comparing these rank orders from different participants, a team measure of shared understanding can be calculated. The advantages of this instrument compared to earlier measures are that it is less expensive, easier to use, less time-consuming, does not require subject matter expertise, and that the instrument is distanced from subjective perceptions. Furthermore, the final study provides results where outcomes from the shared priorities instrument correlate with performance, supporting earlier research connecting shared understanding in teams with team performance. A structural equation model, a result of the final study, shows that the instrument is both valid and reliable.
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| 4. |
- Bosteen, Markus Hoeybye, et al.
(författare)
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Protein Unfolding allow use of Commercial Antibodies in an Apolipoprotein M sandwich ELISA.
- 2015
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Ingår i: Journal of Lipid Research. - 1539-7262. ; 56:3, s. 754-759
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein M (apoM) is a member of the lipocalin super family and circulates in plasma attached to high density lipoprotein particles. ApoM plays a role in cholesterol metabolism and has recently been identified as transporter for the signaling lipid Sphingosine-1-Phosphate (S1P) in plasma. S1P is implicated in several inflammatory diseases such as Multiple Sclerosis and Rheumatoid Arthritis. The ability to accurately measure apoM is crucial for investigating its biological functions and possible clinical implications. However, reliable commercial methods have been lacking so far. Therefore we have developed an assay that specifically recognizes human apoM in plasma using commercially available reagents. Commercial apoM antibodies were screened for compatibility in a sandwich ELISA-based assay. One optimal pair of antibodies was chosen and sample preparation, buffers and incubation times were optimized to generate a simple and easily reproducible method. Validation and comparison to a previously described ELISA for apoM confirmed that the assay displays a high degree of sensitivity, specificity and precision. Our results show that commercially available antibodies can be used to accurately measure human plasma apoM. This method can be implemented in every laboratory and will help promote high quality research.
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| 5. |
- Brinck, Jonas W., et al.
(författare)
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High-density lipoprotein from end-stage renal disease patients exhibits superior cardioprotection and increase in sphingosine-1-phosphate
- 2018
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 48:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic kidney disease (CKD) exacerbates the risk of death due to cardiovascular disease (CVD). Modifications to blood lipid metabolism which manifest as increases in circulating triglycerides and reductions in high-density lipoprotein (HDL) cholesterol are thought to contribute to increased risk. In CKD patients, higher HDL cholesterol levels were not associated with reduced mortality risk. Recent research has revealed numerous mechanisms by which HDL could favourably influence CVD risk. In this study, we compared plasma levels of sphingosine-1-phosphate (S1P), HDL-associated S1P (HDL-S1P) and HDL-mediated protection against oxidative stress between CKD and control patients. Methods: High-density lipoprotein was individually isolated from 20 CKD patients and 20 controls. Plasma S1P, apolipoprotein M (apoM) concentrations, HDL-S1P content and the capacity of HDL to protect cardiomyocytes against doxorubicin-induced oxidative stress in vitro were measured. Results: Chronic kidney disease patients showed a typical profile with significant reductions in plasma HDL cholesterol and albumin and an increase in triglycerides and pro-inflammatory cytokines (TNF-alpha and IL-6). Unexpectedly, HDL-S1P content (P = .001) and HDL cardioprotective capacity (P = .034) were increased significantly in CKD patients. Linear regression analysis of which factors could influence HDL-S1P content showed an independent, negative and positive association with plasma albumin and apoM levels, respectively. Discussion: The novel and unexpected observation in this study is that uremic HDL is more effective than control HDL for protecting cardiomyocytes against oxidative stress. It is explained by its higher S1P content which we previously demonstrated to be the determinant of HDL-mediated cardioprotective capacity. Interestingly, lower concentrations of albumin in CKD are associated with higher HDL-S1P.
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| 6. |
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| 7. |
- Dahlbäck, Björn
(författare)
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Lean ApoM−/− Mice with Hyperactive Brown Adipose Tissue
- 2018
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Ingår i: Trends in Endocrinology and Metabolism. - : Elsevier BV. - 1043-2760. ; 29:5, s. 283-284
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Tidskriftsartikel (refereegranskat)abstract
- In Cell Reports, Christoffersen et al. [1] demonstrate that sphingosine 1-phosphate (S1P) bound to apolipoprotein M (apoM) regulates the activity and mass of brown adipose tissue (BAT). They found mice lacking apoM to have hyperactive BAT with high triglyceride (TG) utilization, resulting in low white adipose tissue (WAT) mass and low body weight.
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| 8. |
- Dahlbäck, Björn, et al.
(författare)
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New functional test for the TFPIα cofactor activity of Protein S working in synergy with FV-Short
- 2019
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 17:4, s. 585-595
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Tidskriftsartikel (refereegranskat)abstract
- Essentials Protein S and FV-Short are synergistic cofactors to Tissue Factor Pathway Inhibitor α (TFPIα). An assay for the TFPIα synergistic cofactor activity of protein S with FV-Short was developed. The assay was specific for the synergistic TFPIα-cofactor activity of free protein S. Protein S deficient individuals with known mutations were correctly distinguished from controls. Summary: Background Protein S is an anticoagulant cofactor to both activated protein C and tissue factor pathway inhibitor (TFPIα). The TFPIα-cofactor activity of protein S is stimulated by a short isoform of factor V (FV-Short), the two proteins functioning in synergy. Objective Using the synergistic TFPIα-cofactor activity between protein S and FV-Short to develop a functional test for plasma protein S. Patients/Methods TFPIα-mediated inhibition of FXa in the presence of FV-Short, protein S and negatively charged phospholipid vesicles was monitored in time by synthetic substrate S2765. TFPIα, FXa and FV-Short were purified proteins, whereas diluted plasma from protein S deficient patients or controls were used as source for protein S. Results The assay was specific for free protein S demonstrating good correlation to free protein S plasma levels (r = 0.92) with a Y-axis intercept of −5%. Correlation to concentrations of total protein S (free and C4BPβ+-bound) was lower (r = 0.88) and the Y-axis intercept was +46%, which is consistent with the specificity for free protein S. The test distinguished protein S-deficient individuals from 6 families with known ProS1 mutations from family members having no mutation. Protein S levels of warfarin-treated protein S deficient cases were lower than protein S in cases treated with warfarin for other causes. Conclusions We describe a new assay measuring the TFPIα-cofactor activity of plasma protein S. The test identifies type I/III protein S deficiencies and will be a useful tool to detect type II protein S deficiency having defective TFPIα-cofactor activity.
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| 9. |
- Dahlbäck, Björn
(författare)
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Pro- and anticoagulant properties of factor V in pathogenesis of thrombosis and bleeding disorders
- 2016
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Ingår i: International Journal of Laboratory Hematology. - : Wiley. - 1751-5521. ; 38, s. 4-11
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Tidskriftsartikel (refereegranskat)abstract
- Factor V (FV) serves an important role in the regulation of blood coagulation, having both pro- and anticoagulant properties. The circulating high molecular weight single-chain FV molecule undergoes a series of proteolytic cleavages during both activation of coagulation and during anticoagulant regulation of coagulation by activated protein C (APC). It is noteworthy that mutations in the factor V gene (F5) either cause thrombosis or bleeding. New insights into the importance and complexity of FV functions have been generated from elucidation of the pathogenic mechanisms of two familial mutations in the F5 gene. The first mutation was identified as a result of the discovery of APC resistance as the most common risk factor for venous thrombosis. The mutation (FV Leiden) predicts the Arg506Gln replacement, which impairs the normal regulation of FVa by APC, as the Arg506 site is an important APC cleavage site. In addition, elucidation of APC resistance resulted in the discovery of the anticoagulant APC cofactor activity of FV. The second FV mutation (FVA2440G), identified in a family with an autosomal dominant bleeding disorder, has led to the discovery of an alternative splicing generating a previously unidentified FV isoform (FV-Short), which inhibits coagulation via an unexpected and intriguing mechanism involving the coagulation inhibitor TFPI-α. These are naturally occurring mutations in the F5 gene that have generated new knowledge on the role of FV in regulation of coagulation and the importance of genetic risk factors for thrombosis and bleeding.
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| 10. |
- Dahlbäck, Björn
(författare)
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Treating hemophilia by targeting protein S?
- 2018
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 131:12, s. 1271-1272
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Tidskriftsartikel (refereegranskat)abstract
- In this issue of Blood, Prince et al report that by targeting anticoagulant protein S (PS), they could achieve hemostasis and prevent hemarthrosis in murine models of hemophilia.1
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