| 1. |
- Bayley, PJ, et al.
(author)
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2013 SYR Accepted Poster Abstracts
- 2013
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In: International journal of yoga therapy. - 1531-2054. ; 23:1, s. 32-53
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Journal article (peer-reviewed)
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- Woo, Daniel, et al.
(author)
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Meta-Analysis of Genome-Wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:4, s. 511-521
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Journal article (peer-reviewed)abstract
- Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
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| 12. |
- Devan, William J., et al.
(author)
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Heritability Estimates Identify a Substantial Genetic Contribution to Risk and Outcome of Intracerebral Hemorrhage
- 2013
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In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:6, s. 1578-1583
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Journal article (peer-reviewed)abstract
- Background and Purpose-Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods-We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results-ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOE loci and at 12% (SE, 4%) for APOE. Conclusions-Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.
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| 13. |
- Falcone, Guido J., et al.
(author)
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Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage
- 2012
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In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43:11, s. 2877-2883
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Journal article (peer-reviewed)abstract
- Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.)
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| 20. |
- Wegmann, F., et al.
(author)
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Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens
- 2012
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 30:9
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Journal article (peer-reviewed)abstract
- Protection against mucosally transmitted infections probably requires immunity at the site of pathogen entry(1), yet there are no mucosal adjuvant formulations licensed for human use. Polyethyleneimine (PEI) represents a family of organic polycations used as nucleic acid transfection reagents in vitro and DNA vaccine delivery vehicles in vivo(2,3). Here we show that diverse PEI forms have potent mucosal adjuvant activity for viral subunit glycoprotein antigens. A single intranasal administration of influenza hemagglutinin or herpes simplex virus type-2 (HSV-2) glycoprotein D with PEI elicited robust antibody-mediated protection from an otherwise lethal infection, and was superior to existing experimental mucosal adjuvants. PEI formed nanoscale complexes with antigen, which were taken up by antigen-presenting cells in vitro and in vivo, promoted dendritic cell trafficking to draining lymph nodes and induced non-proinflammatory cytokine responses. PEI adjuvanticity required release of host double-stranded DNA that triggered Irf3-dependent signaling. PEI therefore merits further investigation as a mucosal adjuvant for human use.
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| 21. |
- Anderson, Christopher D., et al.
(author)
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Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage
- 2013
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In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:3, s. 612-619
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Journal article (peer-reviewed)abstract
- Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.)
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| 26. |
- Chapuis, AG, et al.
(author)
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HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo
- 2011
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117:20, s. 5391-5402
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Journal article (peer-reviewed)abstract
- Most HIV+ individuals require lifelong highly active antiretroviral therapy (HAART) to suppress HIV replication, but fail to eliminate the virus in part because of residual replication in gut-associated lymphoid tissues (GALT). Naturally elicited HIV-specific CD8+ T cells generated in the acute and chronic infectious phases exhibit antiviral activity, but decrease in number after HAART. Therapeutic vaccines represent a potential strategy to expand cellular responses, although previous efforts have been largely unsuccessful, conceivably because of a lack of responding HIV-specific central-memory CD8+ T cells (Tcm). To determine whether patients receiving HAART possess CD8+ T cells with Tcm qualities that are amenable to augmentation, HIV-specific CD8+ T-cell clones were derived from HIV-reactive CD28+CD8+ T-cell lines isolated from 7 HIV+ HAART-treated patients, expanded ex vivo, and reinfused into their autologous host. Tracking of the cells in vivo revealed that clones could persist for ≥ 84 days, maintain expression and/or re-express CD28, up-regulate CD62L, secrete IL-2, proliferate on cognate Ag encounter and localize to the rectal mucosa. These results suggest some infused cells exhibited phenotypic and functional characteristics shared with Tcm in vivo, and imply that more effective therapeutic vaccination strategies targeting CD8+ Tcm in patients on HAART might provide hosts with expanded, long-lasting immune responses not only systemically but also in GALT. This study is registered at www.clinicaltrials.gov as NCT00110578.
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| 28. |
- Hart, Paul BJ, et al.
(author)
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Familiarity with a partner facilitates the movementof drift foraging juvenile grayling (Thymallus thymallus) into a new habitatarea
- 2014
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In: Environmental Biology of Fishes. - : Springer Science and Business Media LLC. - 0378-1909 .- 1573-5133. ; 97:5, s. 515-522
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Journal article (peer-reviewed)abstract
- Preferring one social partner over another can enhance fitness. This paper reports that juvenile grayling were significantly more likely to enter and forage in new, upstream habitats when paired with familiar versus unfamiliar social partners. Fish paired with unfamiliar partners or when alone were more reluctant to enter the new area. The entry times for both fish in a familiar pair were significantly correlated, but uncorrelated for unfamiliar fish. These differences between familiars and unfamiliars were consistent over a 2-week period. Fish with familiar partners spent more time within three body lengths of each other than did those with unfamiliars. The results are discussed in relation to optimality models of drift foraging, which do not included sociality. It is suggested that the social dimension creates a more dynamic foraging response to variable environmental conditions and could have consequences for growth.
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| 29. |
- Mackay, Donna S, et al.
(author)
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Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-Phenotype Correlations
- 2013
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In: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 34:11, s. 1537-1546
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Journal article (peer-reviewed)abstract
- This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
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| 31. |
- Norrgård, Johnny R, 1976-, et al.
(author)
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Multiplicative loss of landlocked Atlantic salmon Salmo salar L. smolts during downstream migration through multiple dams
- 2013
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In: Rivers Research and Applications. - : John Wiley & Sons. - 1535-1459 .- 1535-1467. ; 29:10, s. 1306-1317
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Journal article (peer-reviewed)abstract
- Relatively little is known about the downstream migration of landlocked stocks of Atlantic salmon Salmo salar L. smolts, as earlier migration studies have generally focused on upstream migration. However, in watersheds with many hydroelectric plants (HEPs), multiplicative loss of downstream-migrating salmon smolts can be high, contributing to population declines or extirpations. Here we report the results from a study of wild landlocked Atlantic salmon smolts in the River Klaralven. Salmon smolts, tagged with acoustic transmitters, were released at different locations and followed as they passed 37 receivers along a 180-km-long river segment, including eight dams as well as free-flowing control stretches. We found that 16% of the smolts successfully migrated along the entire river segment. Most losses occurred during HEP passages, with 76% of the smolts being lost during these passages, which contrasts with the 8% smolt loss along unregulated control stretches. Migration speed was 83% slower along regulated stretches than along unregulated stretches. The observed lower migration speed at regulated stretches was dependent on fish size, with large fish moving slower than small fish. Discharge affected migration speed but not losses. As previously shown for anadromous populations, our study of landlocked salmon demonstrates similar negative effects of multiple passages of HEPs by downstream-migrating smolts. On the basis of this and previous migration studies, we advocate using a holistic approach in the management and conservation of migratory fish in regulated rivers, which includes safe passage for both upstream- and downstream-migrating fish. Copyright (c) 2012 John Wiley & Sons, Ltd.
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| 32. |
- Norrgård, J R, et al.
(author)
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Multiplicative loss of landlocked salmon Salmo salar L. smolts during downstream migration through multiple dams
- 2013
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In: Rivers Research and Applications. - : Wiley. - 1535-1459 .- 1535-1467. ; 29:10, s. 1306-1317
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Journal article (peer-reviewed)abstract
- Relatively little is known about the downstream migration of landlocked stocks of Atlantic salmon Salmo salar L. smolts, as earlier migration studies have generally focused on upstream migration. However, in watersheds with many hydroelectric plants (HEPs), multiplicative loss of downstream-migrating salmon smolts can be high, contributing to population declines or extirpations. Here we report the results from a study of wild landlocked Atlantic salmon smolts in the River Klarälven. Salmon smolts, tagged with acoustic transmitters, were released at different locations and followed as they passed 37 receivers along a 180-km-long river segment, including eight dams as well as free-flowing control stretches. We found that 16% of the smolts successfully migrated along the entire river segment. Most losses occurred during HEP passages, with 76% of the smolts being lost during these passages, which contrasts with the 8% smolt loss along unregulated control stretches. Migration speed was 83% slower along regulated stretches than along unregulated stretches. The observed lower migration speed at regulated stretches was dependent on fish size, with large fish moving slower than small fish. Discharge affected migration speed but not losses. As previously shown for anadromous populations, our study of landlocked salmon demonstrates similar negative effects of multiple passages of HEPs by downstream-migrating smolts. On the basis of this and previous migration studies, we advocate using a holistic approach in the management and conservation of migratory fish in regulated rivers, which includes safe passage for both upstream- and downstream-migrating fish.
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| 36. |
- Okada, Yukinori, et al.
(author)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Journal article (peer-reviewed)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 37. |
- Piccolo, John J, 1964-, et al.
(author)
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Conservation of endemic landlocked salmonids in regulated rivers : a case-study from Lake Vänern, Sweden
- 2012
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In: Fish and Fisheries. - : Wiley. - 1467-2960 .- 1467-2979. ; 13:4, s. 418-433
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Journal article (peer-reviewed)abstract
- Conservation of migratory salmonids requires understanding their ecology at multiple scales, combined with assessing anthropogenic impacts. We present a case-study from over 100 years of data for the endemic landlocked Atlantic salmon (Salmo salar, Salmonidae) and brown trout (Salmo trutta, Salmonidae) in Lake Vänern, Sweden. We use this case-study to develop life history-based research and monitoring priorities for migratory salmonids. In Vänern, small wild populations of salmon and trout remain only in the heavily regulated Rivers Klar (Klarälven) and Gullspång (Gullspångsälven), and commercial and sport fisheries are maintained by hatchery stocking. These populations represent some of the last remaining large-bodied (up to 20 kg) landlocked salmon stocks worldwide. We found that one of four stocks of wild fish has increased since 1996; the other three remain critically low. Hatchery return rates for three of four stocks appear stable at roughly 1% and annual fisheries catch is roughly 75 metric tons, with an estimated 7.5% of hatchery smolts being recruited to the fishery; this also appears relatively stable since 1990. Our analysis reveals much uncertainty in key data requirements, including both river return and fisheries catch rates, estimates of wild smolt production and survival, and hatchery breeding and genetics protocols. These uncertainties, coupled with a lack of information on their riverine and lacustrine ecology, preclude effective management of these unique populations. We conclude with a framework for a life history-based approach to research and monitoring for Vänern salmon and trout, which should be applicable for all endemic, migratory salmonid populations.
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| 38. |
- Wardlaw, Joanna M., et al.
(author)
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Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration
- 2013
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In: Lancet Neurology. - 1474-4465. ; 12:8, s. 822-838
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Research review (peer-reviewed)abstract
- Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for Reporting Vascular changes on nEuroimaging (STRIVE).
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| 39. |
- Watz, Johan, 1977-, et al.
(author)
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Temperature-dependent prey capture efficiency and foraging modes of brown trout Salmo trutta
- 2012
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In: Journal of Fish Biology. - : Wiley. - 0022-1112 .- 1095-8649. ; 81:1, s. 345-350
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Journal article (peer-reviewed)abstract
- Prey capture success and foraging mode were studied in brown trout Salmo trutta at temperatures ranging from 5·7 to 14·0° C. At low temperatures, there was a positive correlation between prey capture success and the proportion of time that the fish spent holding feeding stations. This correlation was not found at temperatures >10° C.
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