| 1. |
- Knevel, R., et al.
(författare)
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A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis
- 2013
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 65:3, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.
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| 2. |
- Vlemmings, W. H. T., et al.
(författare)
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ALMA observations of the variable (CO)-C-12/(CO)-C-13 ratio around the asymptotic giant branch star R Sculptoris
- 2013
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 556, s. L1-
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Tidskriftsartikel (refereegranskat)abstract
- The (CO)-C-12/(CO)-C-13 ratio is often used as a measure of the C-12/C-13 ratio in the circumstellar environment, carrying important information about the stellar nucleosynthesis. External processes can change the (CO)-C-12 and (CO)-C-13 abundances, and spatially resolved studies of the (CO)-C-12/(CO)-C-13 ratio are needed to quantify the effect of these processes on the globally determined values. Additionally, such studies provide important information on the conditions in the circumstellar environment. The detached-shell source R Scl, displaying CO emission from recent mass loss, in a binary-induced spiral structure as well as in a clumpy shell produced during a thermal pulse, provides a unique laboratory for studying the differences in CO isotope abundances throughout its recent evolution. We observed both the (CO)-C-12(J = 3 -> 2) and the (CO)-C-13(J = 3 -> 2) line using ALMA. We find significant variations in the (CO)-C-12/(CO)-C-13 intensity ratios and consequently in the abundance ratios. The average CO isotope abundance ratio is at least a factor three lower in the shell (similar to 19) than that in the present-day (less than or similar to 300 years) mass loss (>60). Additionally, variations in the ratio of more than an order of magnitude are found in the shell itself. We attribute these variations to the competition between selective dissociation and isotope fractionation in the shell, of which large parts cannot be warmer than similar to 35 K. However, we also find that the (CO)-C-12/(CO)-C-13 ratio in the present-day mass loss is significantly higher than the C-12/C-13 ratio determined in the stellar photosphere from molecular tracers (similar to 19). The origin of this discrepancy is still unclear, but we speculate that it is due to an embedded source of UV-radiation that is primarily photo-dissociating (CO)-C-13. This radiation source could be the hitherto hidden companion. Alternatively, the UV-radiation could originate from an active chromosphere of R Scl itself. Our results indicate that caution should be taken when directly relating the (CO)-C-12/(CO)-C-13 intensity and C-12/C-13 abundance ratios for specific asymptotic giant branch stars, in particular binaries or stars that display signs of chromospheric stellar activity.
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| 3. |
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| 4. |
- de Rooy, D. P. C., et al.
(författare)
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Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts
- 2014
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 73:7, s. 1384-1387
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Tidskriftsartikel (refereegranskat)abstract
- Background Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since deleterious, protective and neutral observations have been made. Objective To determine the effect of smoking on joint damage progression. Methods Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis. Results When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29). Conclusions This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.
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| 5. |
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| 6. |
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| 7. |
- Knevel, Rachel, et al.
(författare)
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A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis
- 2014
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA. Methods: 1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied. Results: We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10(-4)). This variant was also significant after Bonferroni correction. Conclusions: These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.
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| 8. |
- Knevel, R., et al.
(författare)
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Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 71:10, s. 1651-1657
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Tidskriftsartikel (refereegranskat)abstract
- Background Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA. Method 1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. Results Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09- fold rate of joint destruction compared to other patients (p = 4.0x10(-6), p = 3.8x10(-4), p = 5.0x10(-3), p = 5.0x10(-3) and p = 9.4x10(-3)). Discussion Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p < 0.001; rs7665842, p < 0.001; rs4371699, p = 0.01; rs6821171, p = 0.01). These SNPs were also significant after correction for multiple testing. Conclusion Genetic variants in IL-15 are associated with progression of joint destruction in RA.
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| 9. |
- Lindqvist, Daniel, et al.
(författare)
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Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress.
- 2014
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 42:Jun 12, s. 81-88
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammation may be involved in combat-related post-traumatic stress disorder (PTSD) and may help explain comorbid physical diseases. However, the extent to which combat exposure per se, depression, or early life trauma, all of which are associated with combat PTSD, may confound the relationship between PTSD and inflammation is unclear.
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| 10. |
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| 11. |
- Maercker, Matthias, 1979, et al.
(författare)
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Unexpectedly large mass loss during the thermal pulse cycle of the red giant star R Sculptoris
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 232-234
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Tidskriftsartikel (refereegranskat)abstract
- The asymptotic giant branch star R Sculptoris is surrounded by a detached shell of dust and gas. The shell originates from a thermal pulse during which the star undergoes a brief period of increased mass loss. It has hitherto been impossible to constrain observationally the timescales and mass-loss properties during and after a thermal pulse - parameters that determine the lifetime on the asymptotic giant branch and the amount of elements returned by the star. Here we report observations of CO emission from the circumstellar envelope and shell around R Sculptoris with an angular resolution of 1.3 arcsec. What was hitherto thought to be only a thin, spherical shell with a clumpy structure, is revealed to contain a spiral structure. Spiral structures associated with circumstellar envelopes have been seen previously, from which it was concluded that the systems must be binaries. Using the data, combined with hydrodynamic simulations, we conclude that R Sculptoris is a binary system that underwent a thermal pulse approximately 1800 years ago, lasting approximately 200 years. About 0.003 Msun of mass was ejected at a velocity of 14.3 km s-1 and at a rate approximately 30 times higher than the prepulse mass-loss rate. This shows that approximately 3 times more mass is returned to the interstellar medium during and immediately after a pulse than previously thought.
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| 12. |
- Ramstedt, Sofia, et al.
(författare)
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The wonderful complexity of the Mira AB system
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570, s. Art. no. L14-
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Tidskriftsartikel (refereegranskat)abstract
- We have mapped the (CO)-C-12(3-2) line emission around the Mira AB system at 0 ''.5 resolution using the Atacama Large Millimeter/submillimeter Array (ALMA). The CO map shows amazing complexity. The circumstellar gas has been shaped by different dynamical actors during the evolution of the system, and several morphological components can be identified. The companion is marginally resolved in continuum emission and is currently at 0 ''.487 +/- 0 ''.006 separation. In the main line component, centered on the stellar velocity, spiral arcs around Mira A are found. The spiral appears to be relatively flat and oriented in the orbital plane. An accretion wake behind the companion is clearly visible, and the projected arc separation is about 5 ''. In the blue wing of the line emission, offset from the main line, several large (similar to 5-10 '') opposing arcs are found. We tentatively suggest that this structure is created by the wind of Mira B blowing a bubble in the expanding envelope of Mira A.
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| 13. |
- Vlemmings, Wouter, 1974, et al.
(författare)
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ALMA observations of the variable 12CO/13CO ratio around the asymptotic giant branch star R Sculptoris
- 2013
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 556, s. Art. no. L1-
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Tidskriftsartikel (refereegranskat)abstract
- The 12CO/13CO ratio is often used as a measure of the 12C/13C ratio in the circumstellar environment, carrying important information about the stellar nucleosynthesis. External processes can change the 12CO and 13CO abundances, and spatially resolved studies of the 12CO/13CO ratio are needed to quantify the effect of these processes on the globally determined values. Additionally, such studies provide important information on the conditions in the circumstellar environment. The detached-shell source R Scl, displaying CO emission from recent mass loss, in a binary-induced spiral structure as well as in a clumpy shell produced during a thermal pulse, provides a unique laboratory for studying the differences in CO isotope abundances throughout its recent evolution. We observed both the 12CO(J = 3 → 2) and the 13CO(J = 3 → 2) line using ALMA. We find significant variations in the 12CO/13CO intensity ratios and consequently in the abundance ratios. The average CO isotope abundance ratio is at least a factor three lower in the shell (~19) than that in the present-day (≤300 years) mass loss (>60). Additionally, variations in the ratio of more than an order of magnitude are found in the shell itself. We attribute these variations to the competition between selective dissociation and isotope fractionation in the shell, of which large parts cannot be warmer than ~35 K. However, we also find that the 12CO/13CO ratio in the present-day mass loss is significantly higher than the 12C/13C ratio determined in the stellar photosphere from molecular tracers (~19). The origin of this discrepancy is still unclear, but we speculate that it is due to an embedded source of UV-radiation that is primarily photo-dissociating 13CO. This radiation source could be the hitherto hidden companion. Alternatively, the UV-radiation could originate from an active chromosphere of R Scl itself. Our results indicate that caution should be taken when directly relating the 12CO/13CO intensity and 12C/13C abundance ratios for specific asymptotic giant branch stars, in particular binaries or stars that display signs of chromospheric stellar activity. © ESO, 2013.
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| 14. |
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| 15. |
- Castro-Carrizo, A., et al.
(författare)
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Mapping the 12CO J = 1-0 and J = 2-1 emission in AGB and early post-AGB circumstellar envelopes. I. The COSAS program, first sample
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 523:4, s. A59-
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Tidskriftsartikel (refereegranskat)abstract
- We present COSAS (CO Survey of late AGB Stars), a project to map and analyze the 12CO J = 1−0 and J = 2−1 line emission in a representative sample of circumstellar envelopes around AGB and post-AGB stars. The survey was undertaken with the aim of investigating small- and large-scale morphological and kinematical properties of the molecular environment surrounding stars in the late AGB and early post-AGB phases. For this, COSAS combines the high sensitivity and spatial resolving power of the IRAM Plateau de Bure interferometer with the better capability of the IRAM 30 m telescope to map extended emission. The global sample encompasses 45 stars selected to span a range in chemical type, variability type, evolutionary state, and initial mass. COSAS provides means to quantify variations in the mass-loss rates, assess morphological and kinematical features, and to investigate the appearance of fast aspherical winds in the early post-AGB phase. This paper, which is the first of a series of COSAS papers, presents the results from the analyses of a first sample of 16 selected sources. The envelopes around late AGB stars are found to be mostly spherical, often mingled with features such as concentric arcs (R Cas and TX Cam), a broken spiral density pattern (TX Cam), molecular patches testifying to aspherical mass-loss (WX Psc, IK Tau, V Cyg, and S Cep), and also with well-defined axisymmetric morphologies and kinematical patterns (X Her and RX Boo). The sources span a wide range of angular sizes, from relatively compact (CRL 2362, OH 104.9+2.4 and CRL 2477) to very large (χ Cyg and TX Cam) envelopes, sometimes partially obscured by self-absorption features, which particularly for IK Tau and χ Cyg testifies to the emergence of aspherical winds in the innermost circumstellar regions. Strong axial structures with more or less complex morphologies are detected in four early post-AGB stars (IRAS 20028+3910, IRAS 23321+6545, IRAS 19475+3119 and IRAS 21282+5050) of the sub-sample.
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| 16. |
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| 17. |
- de Rooy, Diederik P. C., et al.
(författare)
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Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis
- 2013
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 72:5, s. 769-775
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Tidskriftsartikel (refereegranskat)abstract
- Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction. Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.
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| 18. |
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| 19. |
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| 20. |
- Lindqvist Appell, Malin, et al.
(författare)
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Nomenclature for alleles of the thiopurine methyltransferase gene
- 2013
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Ingår i: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:4, s. 242-248
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Forskningsöversikt (refereegranskat)abstract
- The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (Gandgt;A) from TPMT*24 to TPMT*30 and position 611 (Tandgt;C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. Pharmacogenetics and Genomics 23: 242-248
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| 25. |
- Marti-Vidal, Ivan, 1980, et al.
(författare)
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On the calibration of full-polarization 86GHz global VLBI observations
- 2012
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 542, s. A107-
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Tidskriftsartikel (refereegranskat)abstract
- We report the development of a semi-automatic pipeline for the calibration of 86GHz full-polarization observations performed with the Global Millimeter-VLBI array (GMVA) and describe the calibration strategy followed in the data reduction. Our calibration pipeline involves non-standard procedures, since VLBI polarimetry at frequencies above 43GHz has not yet been well established. We also present, for the first time, a full-polarization global-VLBI image at 86GHz (source 3C 345), as an example of the final product of our calibration pipeline, and discuss the effect of instrumental limitations on the fidelity of the polarization images. Our calibration strategy is not exclusive to the GMVA, and could be applied to other VLBI arrays at millimeter wavelengths. The use of this pipeline will allow GMVA observers to obtain fully calibrated datasets shortly after the data correlation.
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