| 1. |
- Andersson, C, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Boman, Karolina, et al.
(författare)
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Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer
- 2013
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 108:11, s. 2321-2328
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Tidskriftsartikel (refereegranskat)abstract
- Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.
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| 5. |
- Lundström, Ulf, et al.
(författare)
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X-ray phase contrast for CO2 microangiography
- 2012
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Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 57:9, s. 2603-2617
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate a laboratory method for imaging small blood vessels using x-ray propagation-based phase-contrast imaging and carbon dioxide (CO2) gas as a contrast agent. The limited radiation dose in combination with CO2 being clinically acceptable makes the method promising for small-diameter vascular visualization. We investigate the possibilities and limitations of the method for small-animal angiography and compare it with conventional absorption-based x-ray angiography. Photon noise in absorption-contrast imaging prevents visualization of blood vessels narrower than 50 mu m at the highest radiation doses compatible with living animals, whereas our simulations and experiments indicate the possibility of visualizing 20 mu m vessels at radiation doses as low as 100 mGy. Experimental computed tomography of excised rat kidney shows blood vessels of diameters down to 60 mu m with improved image quality compared to absorption-based methods. With our present prototype x-ray source, the acquisition time for a tomographic dataset is approximately 1 h, which is long compared to the 1-20 min common for absorption-contrast micro-CT systems. Further development of the liquid-metal-jet microfocus x-ray sources used here and high-resolution x-ray detectors shows promise to reduce exposure times and make this high-resolution method practical for imaging of living animals.
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| 6. |
- Stranneheim, Henrik, et al.
(författare)
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Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism
- 2014
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 15, s. 1090-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine. Results: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome. Conclusions: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.
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| 7. |
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| 8. |
- Burvall, Anna, et al.
(författare)
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Phase retrieval in X-ray phase-contrast imaging suitable for tomography
- 2011
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Ingår i: Optics Express. - 1094-4087. ; 19:11, s. 10359-10376
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Tidskriftsartikel (refereegranskat)abstract
- In-line phase-contrast X-ray imaging provides images where both absorption and refraction contribute. For quantitative analysis of these images, the phase needs to be retrieved numerically. There are many phase-retrieval methods available. Those suitable for phase-contrast tomography, i.e., non-iterative phase-retrieval methods that use only one image at each projection angle, all follow the same pattern though derived in different ways. We outline this pattern and use it to compare the methods to each other, considering only phase-retrieval performance and not the additional effects of tomographic reconstruction. We also outline derivations, approximations and assumptions, and show which methods are similar or identical and how they relate to each other. A simple scheme for choosing reconstruction method is presented, and numerical phase-retrieval performed for all methods.
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| 9. |
- Burvall, Anna, et al.
(författare)
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Phase-retrieval methods with applications in composite-material tomography
- 2013
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Ingår i: 11th International Conference On X-Ray Microscopy (XRM2012). - : Institute of Physics Publishing (IOPP). ; , s. 012015-
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Konferensbidrag (refereegranskat)abstract
- In-line phase-contrast x-ray imaging is emerging as a method for observing small details when the contrast in absorption x-ray imaging is low. It gives images with strong edge enhancement, and phase retrieval is necessary to obtain quantitative thickness information. In particular for tomography, clarity can be enhanced by phase retrieval, as here demonstrated on a 3D-weave reinforced composite material. Seven suitable phase-retrieval methods are identified and integrated into a single method, where each version is marked by variations in particular steps. The general method and its variations are outlined and a comparison shows which methods are most suitable in different situations.
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| 10. |
- Dahlman-Höglund, Anna, 1964, et al.
(författare)
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Salmon allergen exposure, occupational asthma, and respiratory symptoms among salmon processing workers.
- 2012
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Ingår i: American journal of industrial medicine. - : Wiley. - 1097-0274 .- 0271-3586. ; 55:7, s. 624-30
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Tidskriftsartikel (refereegranskat)abstract
- This investigation was triggered by three cases of asthma-about 10% of the workforce-occurring in a salmon processing plant over a short period of time. The aim of the investigation was to characterize the work exposure of inhalable organic particles with personal measurements. Respiratory symptoms at work among workers were also assessed.
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