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- Bruzelius, M., et al.
(författare)
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Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors
- 2015
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 13:2, s. 219-227
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFamily history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing. ObjectivesWe investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE. Patients/MethodA total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC). ResultsSeven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included. ConclusionPrediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.
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- Bergendal, Erik, et al.
(författare)
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Tuneable interfacial surfactant aggregates mimic lyotropic phases and facilitate large scale nanopatterning
- 2021
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Ingår i: Nanoscale. - : Royal Society of Chemistry. - 2040-3364 .- 2040-3372. ; 13:1, s. 371-379
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Tidskriftsartikel (refereegranskat)abstract
- It is shown that the air-liquid interface can be made to display the same rich curvature phenomena as common lyotropic liquid crystal systems. Through mixing an insoluble, naturally occurring, branched fatty acid, with an unbranched fatty acid of the same length, systematic variation in the packing constraints at the air-water interface could be obtained. The combination of atomic force microscopy and neutron reflectometry is used to demonstrate that the water surface exhibits significant tuneable topography. By systematic variation of the two fatty acid proportions, ordered arrays of monodisperse spherical caps, cylindrical sections, and a mesh phase are all observed, as well as the expected lamellar structure. The tuneable deformability of the air-water interface permits this hitherto unexplored topological diversity, which is analogous to the phase elaboration displayed by amphiphiles in solution. It offers a wealth of novel possibilities for the tailoring of nanostructure
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- Bergendal, A, et al.
(författare)
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Extent of salmeterol-mediated reassertion of relaxation in guinea-pig trachea pretreated with aliphatic side chain structural analogues
- 1996
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Ingår i: British Journal of Pharmacology. - 1476-5381. ; 117:6, s. 1009-1015
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Tidskriftsartikel (refereegranskat)abstract
- 1. Salmeterol is a potent, selective and long acting beta 2-adrenoceptor agonist. In vitro, salmeterol exerts 'reassertion' relaxation of airways smooth muscle. Reassertion relaxation refers to the capacity of salmeterol to cause repeated functional antagonism of induced contraction when airway smooth muscle is intermittently exposed to, then washed free from, beta-adrenoceptor antagonists such as sotalol. The mechanism(s) underlying reassertion relaxation are unknown but may relate to high affinity binding of the long aliphatic side chain of salmeterol to an accessory site, distinct from the agonist recognition site, in or near the beta 2-adrenoceptor (exosite binding hypothesis). 2. In order to test the exosite hypothesis, three pure analogues of salmeterol, each exactly preserving the molecular structure of the aliphatic side chain but with zero or low efficacy at the beta 2-adrenoceptor were synthesized. The effect of pre-incubating guinea-pig tracheal smooth muscle with these analogues on salmeterol-induced reassertion relaxation was determined. 3. Computer Assisted Molecular Modelling of these molecules revealed that each of them exactly preserved the low energy linear conformation of the aliphatic side chain of salmeterol. Measurement of lipophilicity (octanol:water partition coefficient; log P) and direct partition into synthetic membranes (membrane partition coefficient; Kpmem) showed that all compounds had high affinity for lipids and membranes. In particular the biophysical properties of CGP 59162 (log P 1.89, Kpmem 16500) were very similar to salmeterol (log P 1.73, Kpmem 16800). 4. Two of the analogues, CGP 54103 and D 2543 (1 microM), which are structural mimics of the side chain of salmeterol, differing slightly in their length, did not prevent either the initial relaxation induced by salmeterol (0.1 microM) or the reassertion relaxation; however, it was not possible to determine whether either of these molecules occupied the beta 2-adrenoceptor. 5. The third analogue, CGP 59162, which has the substituents on the active saligenin head group of salmeterol in transposed positions, itself exerted a weak beta 2-adrenoceptor-mediated relaxation antagonized by ICI 118551 (beta 2-selective antagonist) but not CGP 20712 (beta 1-selective antagonist) and, at higher concentrations CGP 59162 caused reassertion relaxation suggesting that it may occupy and activate the beta 2-adrenoceptor in a manner analogous to salmeterol. 6. CGP 59162, at concentrations up to ten fold molar excess, did not prevent or reduce salmeterol-induced reassertion relaxation. 7. In conclusion these data are not consistent with the existence of a distinct 'exosite' recognising the aliphatic side chain of salmeterol mediating reassertion.
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