| 1. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 2. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 3. |
- Andaloussi, Mounir, et al.
(författare)
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Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
- 2011
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 54:14, s. 4964-4976
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Tidskriftsartikel (refereegranskat)abstract
- The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.
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| 4. |
- Palstam, Annie, 1981, et al.
(författare)
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Perceived exertion at work in women with fibromyalgia: Explanatory factors and comparison with healthy women
- 2014
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Ingår i: Journal of Rehabilitation Medicine. - : Medical Journals Sweden AB. - 1650-1977 .- 1651-2081. ; 46, s. 773-780
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate perceived exertion at work in women with fibromyalgia. Design: A controlled cross-sectional multi-centre study. Subjects and methods: Seventy-three women with fibromyalgia and 73 healthy women matched by occupation and physical workload were compared in terms of perceived exertion at work (0–14), muscle strength, 6-min walk test, symptoms rated by Fibromyalgia Impact Questionnaire (FIQ), work status (25–100%), fear avoidance work beliefs (0–42), physical activity at work (7–21) and physical workload (1–5). Spearman’s correlation coefficient and linear regression analysis were conducted. Results: Perceived exertion at work was significantly higher in the fibromyalgia group than in the reference group (p = 0.002), while physical activity at work did not differ between the groups. Physical capacity was lower and symptom severity higher in fibromyalgia compared with references (p < 0.05). In fibromyalgia, perceived exertion at work showed moderate correlation with physical activity at work, physical workload and fear avoidance work beliefs (rs = 0.53– 0.65, p < 0.001) and a fair correlation with anxiety (rs = 0.26, p = 0.027). Regression analysis indicated that the physical activity at work and fear avoidance work beliefs explained 50% of the perceived exertion at work. Conclusion: Women with fibromyalgia perceive an elevated exertion at work, which is associated with physical workrelated factors and factors related to fear and anxiety.
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| 6. |
- Gunnarsdottir, Anna, et al.
(författare)
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Transanal Endorectal vs. Duhamel Pull-Through for Hirschsprung's Disease.
- 2010
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Ingår i: European Journal of Pediatric Surgery. - : Georg Thieme Verlag KG. - 1439-359X .- 0939-7248. ; Mar 4, s. 242-246
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The aim of this study was to test the hypothesis that the early functional outcome for patients with rectosigmoid Hirschsprung's disease (HD) is comparable for the Duhamel pull-through procedure and the transanal endorectal pull-through (TERPT) procedure, with less discomfort for the patient postoperatively after the TERPT technique. MATERIAL AND METHODS: Eleven patients operated on with the TERPT technique (T Group) were prospectively registered and compared retrospectively with 18 patients operated on with the Duhamel pull-through (D Group). Data recorded included patient demographics, operative treatment, complications, hospital stay and bowel functions. The follow-up time was limited to 24 months. RESULTS: The T Group started oral feeding sooner, their bowel movements started sooner and they had less need for analgesia postoperatively and a significantly shorter hospital stay. 71% of the patients in the D Group needed re-intervention compared to only 18% of the T Group. Enterocolitis was seen in two patients in both groups. At the last clinical control ten patients had constipation (59%) and three had soiling (18%) in the D Group. Three patients in the T Group had constipation (27%) and one had soiling (9%). CONCLUSION: Our results support the use of the TERPT method rather than the Duhamel pull-through for rectosigmoid HD.
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| 9. |
- Larsson, Malin, et al.
(författare)
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On the use of electronic descriptors for QSAR modelling of PCDDs, PCDFs and dioxin-like PCBs£ :
- 2013
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Ingår i: SAR and QSAR in environmental research (Print). - : Taylor & Francis Group. - 1062-936X .- 1029-046X. ; 24:6, s. 461-479
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Tidskriftsartikel (refereegranskat)abstract
- The electronic properties of 29 polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls that have been included in the toxic equivalency factor system have been investigated and used to derive quantum mechanical (QM) chemical descriptors for QSAR modelling. Their utility in this context was investigated alongside descriptors based on ultraviolet absorption data and traditional 2D descriptors including log Kow, polarizability, molecular surface properties, van der Waals volume and selected connectivity indices. The QM descriptors were calculated using the semi-empirical AM1 method and the density functional theory method B3-LYP/6-31G(∗∗). Atom-specific and molecular quantum chemical descriptors were calculated to compare the electronic properties of dioxin-like compounds regardless of their chemical class, with particular emphasis on the lateral positions. Multivariate analysis revealed differences between the chemical classes in terms of their electronic properties and also highlighted differences between congeners. The results obtained demonstrated the importance of considering molecular orbital energies, but also indicated that the ratios of the coefficients of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) at the lateral carbons were important. In addition, the digitalized UV spectra contained chemical information that provided crucial insights into dioxin-like activity.
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