| 1. |
- Taal, H. Rob, et al.
(författare)
-
Common variants at 12q15 and 12q24 are associated with infant head circumference
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 532-538
-
Tidskriftsartikel (refereegranskat)abstract
- To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
|
|
| 2. |
- Andresen, Astri, et al.
(författare)
-
Barnen och välfärdspolitiken : Nordiska barndomar 1900-2000
- 2011. - 1
-
Bok (övrigt vetenskapligt/konstnärligt)abstract
- Dagens diskussion om barn och barns rättigheter och villkor tar ofta sin utgångspunkt i 1989 års barnkonvention, men dessa frågor hör inte bara till vår egen tid. I Norden har barn under hela 1900-talet haft en viktig plats i det offentliga samtalet och i välfärdspolitiken, men det uppmärksammas sällan i forskningen. I den här boken beskrivs den välfärdshistoriska utvecklingen utifrån ämnet barn i ett jämförande nordiskt perspektiv. De nordiska länderna har mycket gemensamt och det har under hela 1900-talet funnits ett nära samarbete när det gäller barnpolitik och barns rättigheter.Barnen har setts, inte bara som de enskilda nationernas framtid utan som Nordens framtid.Boken diskuterar vad nordiskt samarbete inneburit för barn både i fråga om lagstiftning och barnpolitik i praktiken, och i vilken utsträckning nordisk välfärdspolitik har utvecklats som ett resultat av samarbete, tävlan och politik komparation. Vad är nordiskt, vad är nationellt och vad är internationellt i nordiska välfärdsmodeller?
|
|
| 3. |
- Berndt, Sonja I., et al.
(författare)
-
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
-
Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
|
|
| 4. |
- Craddock, Nick, et al.
(författare)
-
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
-
Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
|
|
| 5. |
- Do, Ron, et al.
(författare)
-
Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
-
Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
|
|
| 6. |
- Drong, Alexander W, et al.
(författare)
-
The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue.
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.
|
|
| 7. |
- Engdahl, Cecilia, et al.
(författare)
-
The Rift Valley Fever virus protein NSm and putative cellular protein interactions
- 2012
-
Ingår i: Virology Journal. - 1743-422X. ; 9, s. 139-
-
Tidskriftsartikel (refereegranskat)abstract
- Rift Valley Fever is an infectious viral disease and an emerging problem in many countries of Africa and on the Arabian Peninsula. The causative virus is predominantly transmitted by mosquitoes and high mortality and abortion rates characterize outbreaks in animals while symptoms ranging from mild to life-threatening encephalitis and hemorrhagic fever are noticed among infected humans. For a better prevention and treatment of the infection, an increased knowledge of the infectious process of the virus is required. The focus of this work was to identify protein-protein interactions between the non-structural protein (NSm), encoded by the M-segment of the virus, and host cell proteins. This study was initiated by screening approximately 26 million cDNA clones of a mouse embryonic cDNA library for interactions with the NSm protein using a yeast two-hybrid system. We have identified nine murine proteins that interact with NSm protein of Rift Valley Fever virus, and the putative protein-protein interactions were confirmed by growth selection procedures and beta-gal activity measurements. Our results suggest that the cleavage and polyadenylation specificity factor subunit 2 (Cpsf2), the peptidyl-prolyl cistrans isomerase (cyclophilin)-like 2 protein (Ppil2), and the synaptosome-associated protein of 25 kDa (SNAP-25) are the most promising targets for the NSm protein of the virus during an infection.
|
|
| 8. |
- Fall, Tove, et al.
(författare)
-
The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
-
Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
|
|
| 9. |
- Flannick, Jason, et al.
(författare)
-
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
-
Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
|
|
| 10. |
- Forsberg, Lars A., et al.
(författare)
-
Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:6, s. 624-628
-
Tidskriftsartikel (refereegranskat)abstract
- Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
|
|
| 11. |
- Grundberg, Elin, et al.
(författare)
-
Mapping cis- and trans-regulatory effects across multiple tissues in twins.
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
-
Tidskriftsartikel (refereegranskat)abstract
- Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
|
|
| 12. |
|
|
| 13. |
- Heid, Iris M, et al.
(författare)
-
Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
-
Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
|
|
| 14. |
- Ikram, M. Arfan, et al.
(författare)
-
Common variants at 6q22 and 17q21 are associated with intracranial volume
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 539-544
-
Tidskriftsartikel (refereegranskat)abstract
- During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
|
|
| 15. |
- Keildson, Sarah, et al.
(författare)
-
Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity.
- 2014
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:3
-
Tidskriftsartikel (refereegranskat)abstract
- Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10(-5)) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10(-4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10(-6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016-0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r(2) = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10(-3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.
|
|
| 16. |
- Lange, Leslie A, et al.
(författare)
-
Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
-
Tidskriftsartikel (refereegranskat)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
|
|
| 17. |
- Lango Allen, Hana, et al.
(författare)
-
Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
-
Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
|
|
| 18. |
- Lim, Elaine T, et al.
(författare)
-
Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.
- 2014
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10-8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10-117). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10-4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
|
|
| 19. |
- Lind, Judith, 1971-, et al.
(författare)
-
Adoptivfamiljen
- 2012. - 2
-
Ingår i: Nätverksfamiljen. - : Natur och kultur. - 9789127133044 ; , s. 239-256
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Kärnfamiljen är fortfarande den vanligaste samlevnadsformen i vårt land men samhällstrenden visar på en allt större variation i samlevnadsmönster. Familjer bryter upp och nya par flyttar samman. Med barnen som länkar bildas nätverk av relationer.Den senmoderna familjen utgör en nätverksfamilj. Med nätverket som metafor upplöses familjen som en sluten social enhet.I stället ställs relationerna och det vardagliga familjelivet i fokus. Invanda levnadsmönster, traditionella roller och könsidentiteter utmanas och ifrågasätts. Uppbrotten kan även splittra familjer mellan länder och världsdelar. Vad är en familj? Vilka familjekonstellationer är tänkbara? Hur påverkar de nya strukturerna barns och föräldrars roller?Denna bok skildrar samtidens mångfald i samlevnadsformer, t ex den traditionella kärnfamiljen, nya familjebildningar med styvföräldrar och egna samt gemensamma barn, ensam mor-familjen, heltids-eller deltidspappan, den homosexuella familjen och den inflyttade familjen från en annan kultur. I bokens andra del fördjupas resonemangen kring det nya fader- och moderskapet, fosterfamiljen, den utsatta familjen, våld i familjen och problematik kring barnlöshet. Boken vill beskriva och analysera hur män och kvinnor i nya familjemönster praktiskt utformar föräldraskap, parförhållande liksom ansvar för och omsorg om familjen. Familjen skapas genom sina vardagshandlingar.
|
|
| 20. |
- Lind, Lars, et al.
(författare)
-
Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample
- 2014
-
Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 133, s. 135-140
-
Tidskriftsartikel (refereegranskat)abstract
- Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures > 80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p < 0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.
|
|
| 21. |
- Lind, Lars, et al.
(författare)
-
Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
|
|
| 22. |
- Lindgren, Cecilia, 1958-, et al.
(författare)
-
ADMA Levels and Arginine/ADMA Ratios Reflect Severity of Disease and Extent of Inflammation After Subarachnoid Hemorrhage
- 2014
-
Ingår i: Neurocritical Care. - : Springer Science and Business Media LLC. - 1541-6933 .- 1556-0961. ; 21:1, s. 91-101
-
Tidskriftsartikel (refereegranskat)abstract
- Subarachnoid hemorrhage (SAH) is characterized by an inflammatory response that might induce endothelial dysfunction. The aim of this study was to evaluate if ADMA and arginine/ADMA ratios after SAH (indicators of endothelial dysfunction) are related to clinical parameters, inflammatory response, and outcome. Prospective observational study. ADMA, arginine, C-reactive protein (CRP), and cytokines were obtained 0-240 h (h) after SAH. Definition of severe clinical condition was Hunt&Hess (H&H) 3-5 and less severe clinical condition H&H 1-2. Impaired cerebral circulation was assessed by clinical examination, transcranial doppler, CT-scan, and angiography. Glasgow outcome scale (GOS) evaluated the outcome. Compared to admission, 0-48 h after SAH, the following was observed 49-240 h after SAH; (a) ADMA was significantly increased at 97-240 h (highest 217-240 h), (b) CRP was significantly increased at 49-240 h (highest 73-96 h), (c) interleukin-6 (IL-6) was significantly lower at 97-240 h (highest 49-96 h), p < 0.05. ADMA, CRP, and IL-6 were significantly lower and peak arginine/ADMA ratio was significantly higher in patients with H&H 1-2 compared to patients with H&H 3-5, p < 0.05. The peak ADMA or the nadir arginine/ADMA ratio did not differ significantly between patients with (55 %) or without (45 %) signs of impaired cerebral circulation. The peak ADMA or the nadir arginine/ADMA ratio did not differ significantly between patients with GOS 1-3 and patients with GOS 4-5. ADMA increased significantly after SAH, and the increase in ADMA started after the pro-inflammatory markers (CRP and IL-6) had peaked. This might indicate that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation.
|
|
| 23. |
- Lindgren, Cecilia, 1969-
(författare)
-
Adoption. Samarbete för rättslikhet
- 2011. - 1
-
Ingår i: Barnen och välfärdspolitiken. - Stockholm : Dialogos Förlag. - 9789175042343 ; , s. 216-270
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Dagens diskussion om barn och barns rättigheter och villkor tar ofta sin utgångspunkt i 1989 års barnkonvention, men dessa frågor hör inte bara till vår egen tid. I Norden har barn under hela 1900-talet haft en viktig plats i det offentliga samtalet och i välfärdspolitiken, men det uppmärksammas sällan i forskningen. I den här boken beskrivs den välfärdshistoriska utvecklingen utifrån ämnet barn i ett jämförande nordiskt perspektiv. De nordiska länderna har mycket gemensamt och det har under hela 1900-talet funnits ett nära samarbete när det gäller barnpolitik och barns rättigheter.Barnen har setts, inte bara som de enskilda nationernas framtid utan som Nordens framtid.Boken diskuterar vad nordiskt samarbete inneburit för barn både i fråga om lagstiftning och barnpolitik i praktiken, och i vilken utsträckning nordisk välfärdspolitik har utvecklats som ett resultat av samarbete, tävlan och politik komparation. Vad är nordiskt, vad är nationellt och vad är internationellt i nordiska välfärdsmodeller?
|
|
| 24. |
- Lindgren, Cecilia
(författare)
-
Barnets väl - samhällets ansvar : Utredning av blivande adoptivföräldrar 1955-2008
- 2011
-
Ingår i: Föräldraskapets politik. - Stockholm : Dialogos förlag. - 9789175042381 ; , s. 27-53
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Under de senaste hundra åren har betydelsen av goda familjeförhållanden och gott föräldraskap betonats allt mer i debatt och politik. Men vad utgör ett gott föräldraskap, och hur skapas goda mödrar och fäder? Svaret på dessa frågor förändrats under det senaste seklet.Såväl föräldraskapet självt som försöken att påverka det genomgår ständiga förändringar. Adoptionsutredningar, assisterad befruktning för lesbiska par samt föräldrars engagemang i sina barns skolgång är några av de frågor som i boken får belysa samhällsutvecklingen. Att vara förälder till ett barn kan tyckas vara en naturlig och ursprunglig relation, men påverkas i högsta grad av tid, plats och sociala villkor
|
|
| 25. |
- Lindgren, Cecilia, et al.
(författare)
-
Cortisol levels are influenced by sedation in the acute phase after subarachnoid haemorrhage
- 2013
-
Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 57:4, s. 452-460
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a life-threatening condition that may be aggravated by acute pituitary damage and cortisol insufficiency. Robust diagnostic criteria for critical illness-related corticosteroid insufficiency (CIRCI) are lacking. The aim of this study was to assess the frequency of CIRCI in the acute phase (0-240 h) after SAH and to evaluate associations between cortisol levels and clinical parameters (sedation, circulatory failure, gender, age, severity of disease, treatment). CIRCI was defined as a single morning serum cortisol (mSC) < 200 nmol/L. The lower limit for calculated free cortisol (cFC) was set at < 22 nmol/L, and for saliva cortisol at < 7.7 nmol/L.METHODS: Fifty patients were included. Serum/saliva cortisol and corticosteroid-binding globulin were obtained every second morning. A logistic regression model was used for multivariate analysis comparing cortisol levels with clinical parameters.RESULTS: Of the patients, 21/50 (42%) had an mSC < 200 nmol/L and 30/50 (60%) had a cFC < 22 nmol/L. In patients with continuous intravenous sedation, the odds ratio for a mSC to be < 200 nmol/L was 18 times higher (95% confidence interval 4.2-85.0, P < 0.001), and the odds ratio for a cFC to be < 22 nmol/L was 2.4 times higher (95% confidence interval 1.2-4.7, P < 0.05) compared with patients with no continuous intravenous sedation.CONCLUSIONS: Continuous intravenous sedation was significantly associated with cortisol values under defined limits (mSC < 200, cFC < 22 nmol/L). The possibility that sedating drugs per se may influence cortisol levels should be taken into consideration before CIRCI is diagnosed.
|
|
| 26. |
- Lindgren, Cecilia, et al.
(författare)
-
Frequency of non-convulsive Seizures and non-convulsive status Epilepticus in Subarachnoid Hemorrhage patients in need of controlled ventilation and sedation
- 2012
-
Ingår i: Neurocritical Care. - : Springer. - 1541-6933 .- 1556-0961. ; 17:3, s. 367-373
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Non-convulsive seizures (NCSZ) can be more prevalent than previously recognized among comatose neuro-intensive care patients. The aim of this study was to evaluate the frequency of NCSZ and non-convulsive status epilepticus (NCSE) in sedated and ventilated subarachnoid hemorrhage (SAH) patients.METHODS: Retrospective study at a university hospital neuro-intensive care unit, from January 2008 until June 2010. Patients were treated according to a local protocol, and were initially sedated with midazolam or propofol or combinations of these sedative agents. Thiopental was added for treatment of intracranial hypertension. No wake-up tests were performed. Using NicoletOne((R)) equipment (VIASYS Healthcare Inc., USA), continuous EEG recordings based on four electrodes and a reference electrode was inspected at full length both in a two electrode bipolar and a four-channel referential montage.RESULTS: Approximately 5,500 h of continuous EEG were registered in 28 SAH patients (33 % of the patients eligible for inclusion). The median Glasgow Coma scale was 8 (range 3-14) and the median Hunt and Hess score was 4 (range 1-4). During EEG registration, no clinical seizures were observed. In none of the patients inter ictal epileptiform activity was seen. EEG seizures were recorded only in 2/28 (7 %) patients. One of the patients experienced 4 min of an NCSZ and one had a 5 h episode of an NCSE.CONCLUSION: Continuous EEG monitoring is important in detecting NCSZ in sedated patients. Continuous sedation, without wake-up tests, was associated with a low frequency of subclinical seizures in SAH patients in need of controlled ventilation.
|
|
| 27. |
- Lindgren, Cecilia, 1969-, et al.
(författare)
-
Here and now - there and then : Narrative time and space in intercountry adoptees' stories about background, origin and roots
- 2014
-
Ingår i: Qualitative Social Work. - : Sage Publications. - 1473-3250 .- 1741-3117. ; 13:4, s. 539-554
-
Tidskriftsartikel (refereegranskat)abstract
- Intercountry adoption policy emphasizes openness in relation to adoptees’ background. However, because intercountry adoption is a complex web of relations including individuals, institutions and countries, it is impossible to foresee what background, origin and roots will mean to the adopted individual. The present article examines what meanings adoptees themselves ascribe to background, origin and roots. A total of 22 internationally adopted men and women participated in focus group conversations. The participants were invited to discuss their diverse experiences and opinions on these matters and their stories were analyzed from a narrative perspective. The analysis focuses how time and space were made significant in narratives about background, origin and roots. Two contrasting stories – the here-and-now narrative and the there-and-then narrative – are discerned, but further analysis of the narrative space and time dimensions shows a much more complex pattern beyond these extremes. Adoptee narratives characterized by an open time dimension deal with what could have happened, alternative lives, and the analysis shows how these alternative lives are storied and valued. Furthermore, when adoptees tell their stories about background and roots, ‘there’, i. e. the birth country, is ascribed different meanings. Our analysis shows that the categorization of space as wide or narrow, in the sense of collective or personal, respectively, is useful in understanding the different approaches to background and roots. Based on the present results, we suggest that social workers may wish to organize their counseling along the time and space dimensions of adoptees’ narratives.
|
|
| 28. |
- Lindgren, Cecilia, 1969-
(författare)
-
Internationell adoption i Sverige : Politik och praktik från sextiotal till nittiotal
- 2010
-
Bok (övrigt vetenskapligt/konstnärligt)abstract
- Sedan 1960-talets slut har närmare 50 000 barn kommit till Sverige genom internationell adoption. Adoption är en avgörande händelse som påverkar resten av livet för dem som berörs, och det är därför en viktig samhällsfråga. Den här boken handlar om hur internationell adoption etablerades och utvecklades i Sverige från 1960-talet till 1990-talet, om hur internationell adoption diskuterats och reglerats i politik och lagstiftning och om hur förmedlingen av adoptioner organiserats. Den handlar också om hur samarbetet mellan Sverige och de många ursprungsländerna fungerat och om hur man resonerat kring ursprungets betydelse för adopterade. Studien bygger på offentligt tryck, arkivmaterial från nämnder och myndigheter som ansvarat för internationella adoptionsfrågor samt intervjuer med personer som var aktiva inom adoptionsfältet under den aktuella perioden.
|
|
| 29. |
|
|
| 30. |
- Lindgren, Cecilia, 1958-
(författare)
-
Subarachnoid haemorrhage : clinical and epidemiological studies
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Subarachnoid haemorrhage (SAH) is a severe stroke that in 85% of all cases is caused by the rupture of a cerebral aneurysm. The median age at onset is 50-55 years and the overall mortality is approximately 45%.Sufficient cortisol levels are important for survival. After SAH hypothalamic/pituitary blood flow may be hampered this could result in inadequate secretion of cortisol. SAH is also associated with a substantial inflammatory response. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and increased ADMA levels may be involved in inflammation and endothelial dysfunction. Continuous electroencephalogram (EEG) monitoring can be used to detect non-convulsive seizures, leading to ischemic insults in sedated SAH patients. Elevated ADMA levels are risk factors for vascular diseases. Vascular disease has been linked to stress, inflammation and endothelial dysfunction. SAH possesses all those clinical features and theoretically SAH could thus induce vascular disease.Aims: 1. Assess cortisol levels after SAH, and evaluate associations between cortisol and clinical parameters. 2. Assess ADMA levels and arginine/ADMA ratios after SAH and evaluate associations between ADMA levels and arginine/ADMA ratios with severity of disease, co-morbidities, sex, age and clinical parameters. 3. Investigate occurrence of subclinical seizures in sedated SAH patients. 4. Evaluate if patients that survive a SAH ≥ one year have an increased risk of vascular causes of death compared to a normal population.Results: Continuous infusion of sedative drugs was the strongest predictor for a low (<200 nmol/L) serum cortisol. The odds ratio for a sedated patient to have a serum cortisol < 200 nmol/L was 18.0 times higher compared to an un-sedated patient (p < 0.001). Compared to admission values, 0-48 hours after SAH, CRP increased significantly already in the time-interval 49-72 hours (p<0.05), peaked in the time-interval 97-120 hours after SAH and thereafter decreased. ADMA started to increase in the time-interval 97-120 hours (p<0.05). ADMA and CRP levels were significantly higher, and arginine/ADMA ratios were significantly lower in patients with a more severe condition (p<0.05). Epileptic seizure activity, in sedated SAH patients, was recorded in 2/28 (7.1%) patients during 5/5468 (0.09%) hours of continuous EEG monitoring. Cerebrovascular disease was significantly more common as a cause of death in patients that had survived a SAH ≥ one year, compared to the population from the same area (p<0.0001).Conclusions: Continuous infusion of sedative drugs was associated with low (<200 nmol/L) cortisol levels. ADMA increased significantly after SAH, after CRP had peaked, indicating that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation. Patients with a more severe condition had significantly higher ADMA and CRP levels, and significantly lower arginine/ADMA ratio. Continuous sedation in sedated SAH patients seems to be beneficial in protecting from subclinical seizures. Cerebrovascular causes of death are more common in SAH survivors.
|
|
| 31. |
- Lindgren, Monica, 1958, et al.
(författare)
-
Musikalisk ämneskunskap i förändring - didaktiska utmaningar.
- 2014
-
Ingår i: NÄD, Nationell ämnesdidaktisk konferens, Göteborg 2014.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Den svenska lärarutbildningen har sedan mitten på 1900-talet varit föremål för omfattande reformeringar. När det gäller musiklärarutbildningen så har en rad utbildnings- och kulturpolitiska reformer legat till grund för försök att implementera nytänkande i takt med samhällets utveckling och därigenom öka förutsättningarna för en slags musikalisk medborgerlig yttrandefrihet. Där 1950-talets reformer lade vikt vid en demokratisering av bildning vad gäller musikkulturella värden, fokuserades i 1970-talets reformer en breddning av musikgenrer i syfte att utmana konstmusikens hegemoni och möta ungdomsmusiken. Tiden efter 1995 har beskrivits som tredje positionens musikpedagogik, en pedagogik som utgår från kulturella omvärderingar och mediers utbredning. Här handlar det exempelvis om digitaliseringen av musikområdet men också om en breddning av musikbegreppet som sådant. Didaktiska modeller grundade i en stark idétradition om musikens performativa sida kan ses som en av de utmaningar som dagens musiklärarutbildning har att brottas med. Idag kan vi konstatera att barn och unga lär sig kommunicera med hjälp av musik via helt andra kompetenser och på helt andra "scener" än de gängse, vilket måste ses som utmanande för dagens musiklärare. Mot bakgrund av förändrade tekniska möjligheter diskuterar nu forskare nya innebörder i begrepp som musikalisk kreativitet, musiklyssning och musikskapande. Med empiriska exempel hämtade från aktuella forskningsprojekt kring grundskolans musikundervisning kommer ett antal frågor kring dagens och morgondagens musiklärarutbildning att diskuteras. Vilka är framtidens utmaningar inom ämnesdidaktisk undervisning och forskning i musik?
|
|
| 32. |
- Lindgren, Niklas, et al.
(författare)
-
A Model of GDNF Gene Therapy in Mice with 6-Hydroxydopamine Lesions: Time Course of Neurorestorative Effects and ERK1/2 Activation
- 2012
-
Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 2:4, s. 333-348
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. Objective: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. Methods: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed immunohistochemically for tyrosine hydroxylase (TH) and markers of extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation at the same time points. Results: Lentiviral GDNF significantly inhibited both spontaneous and amphetamine-induced rotation. Compared to the control vector, lentiviral GDNF resulted in a partial protection of TH-positive cells in the substantia nigra, and in a nearly total restoration of striatal TH immunostaining by 35 weeks. A progressive sprouting of TH-positive neurites occurred in both the globus pallidus and the substantia nigra, reaching a 4-5 fold increase above controls by 35 weeks. This effect was paralleled by a long-term supranormal activation of ERK1/2 and its downstream target, phospho-Ser31 TH. Conclusions: Lentiviral GDNF delivery produced robust long-term signaling responses and neurorestoration. This experimental model of GDNF gene therapy will be particularly suitable to study the molecular mechanisms of dopaminergic fiber sprouting, a long-term response to GDNF delivery that also occurs in Parkinson's disease patients.
|
|
| 33. |
- McCue, Molly E., et al.
(författare)
-
A High Density SNP Array for the Domestic Horse and Extant Perissodactyla : Utility for Association Mapping, Genetic Diversity, and Phylogeny Studies
- 2012
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:1, s. e1002451-
-
Tidskriftsartikel (refereegranskat)abstract
- An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of similar to 43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50-100 kb and reached background levels within 1-2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of similar to 750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species.
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
- Nakeva von Mentzer, Cecilia, et al.
(författare)
-
Computer-assisted intervention for children with hearing impairment : Cognitive factors and phonological change
- 2013
-
Ingår i: CHSCOM2013. - : Linköping University Electronic Press.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Thirty-two children with hearing impairment (HI) using cochlear implants (CI) and/or hearing aids (HA), and sixteen with normal hearing (NH) participated in a computer-assisted intervention study that focused on perceiving and memorizing phonemic sounds. The first purpose was to study cognitive abilities in NH and HI children, how they related to phonological processing skills (PhPS) pre intervention and to phonological growth post intervention. The second purpose was to analyze children’s performance at different fine-grained levels of phonological processing, i.e. how they manipulated, stored and produced phonological entities of different size with or without semantic content. This was put in relation to children’s type of auditory stimulation (electrical; bilateral CI, bimodal: CI + HA and acoustical; bilateral HA). Results showed significant correlations between complex working memory and PhPS in children with HI but not in children with NH. This suggests different cognitive strategies in the children when dealing with phonological processing tasks. Poor phoneme discrimination was the strongest predictor of phonological growth in the children with HI as a function of training. Thus, the computer-assisted program was beneficial for HI children with weak initial phoneme discrimination skills. Children with CI showed reduced performance at fine-grained levels of receptive phonological processing but not on expressive phonological lexical tasks.
|
|
| 37. |
- Nakeva von Mentzer, Cecilia, et al.
(författare)
-
Computer-assisted intervention for Deaf and Hard of hearing (D/HH) children with cochlear implants or hearing aids : Cognitive factors and phonological change
- 2013
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Aim: Study cognitive abilities; specifically working memory and lexical access in NH and DHH children, and their correlations to phonological processing skills (PhPS) pre intervention. Analyze how cognitive abilities related to phonological change post intervention. Material and Method: Tasks for lexical access, complex and visual working memory and Phpr were assessed pre and post intervention.Conclusion: DHH children performed at a lower level than NH children on lexical access but equally on complex and visual working memory. Significant correlations between complex working memory and PhPS were evident in DHH children but not in NH. This suggests that DHH children recruit more cognitive resources when performing PhPr tasks. Weak initial performance on a task for phonological representations (Phrep) was the only significant predictor of phonological change in DHH children. Weak PhRep was associated with a higher age at diagnosis, higher age at implant, and shorter usage-time with CI.
|
|
| 38. |
- Nakeva von Mentzer, Cecilia, et al.
(författare)
-
Computer-assisted reading intervention with a phonics approach for children using cochlear implants or hearing aids
- 2014
-
Ingår i: Scandinavian Journal of Psychology. - : Wiley. - 0036-5564 .- 1467-9450. ; 55:5, s. 448-455
-
Tidskriftsartikel (refereegranskat)abstract
- The present study examined computer-assisted reading intervention with a phonics approach for deaf and hard of hearing (DHH) children in Sweden using cochlear implants or hearing aids, or a combination of both. The study included 48 children, 5, 6 and 7years of age. Sixteen children with normal hearing (NH) served as a reference group. The first purpose of the study was to compare NH and DHH children's reading ability at pre and post-intervention. The second purpose was to investigate effects of the intervention. Cognitive and demographic factors were analyzed in relation to reading improvement. Results showed no statistically significant difference for reading ability at the group level, although NH children showed overall higher reading scores at both test points. Age comparisons revealed a statistically significant higher reading ability in the NH 7-year-olds compared to the DHH 7-year-olds. The intervention proved successful for word decoding accuracy, passage comprehension and as a reduction of nonword decoding errors in both NH and DHH children. Reading improvement was associated with complex working memory and phonological processing skills in NH children. Correspondent associations were observed with visual working memory and letter knowledge in the DHH children. Age was the only demographic factor that was significantly correlated with reading improvement. The results suggest that DHH children's beginning reading may be influenced by visual strategies that might explain the reading delay in the older children.
|
|
| 39. |
- Nakeva von Mentzer, Cecilia, 1968-, et al.
(författare)
-
Computer-assisted training of phoneme-grapheme correspondence for children who are deaf and hard of hearing : Effects on phonological processing skills
- 2013
-
Ingår i: International Journal of Pediatric Otorhinolaryngology. - Amsterdam, Netherlands : Elsevier. - 0165-5876 .- 1872-8464. ; 77:12, s. 2049-2057
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Examine deaf and hard of hearing (DHH) children's phonological processing skills in relation to a reference group of children with normal hearing (NH) at two baselines pre intervention. Study the effects of computer-assisted phoneme-grapheme correspondence training in the children. Specifically analyze possible effects on DHH children's phonological processing skills.Methods: The study included 48 children who participated in a computer-assisted intervention study, which focuses on phoneme-grapheme correspondence. Children were 5, 6, and 7 years of age. There were 32 DHH children using cochlear implants (CI) or hearing aids (HA), or both in combination, and 16 children with NH. The study had a quasi-experimental design with three test occasions separated in time by four weeks; baseline 1 and 2 pre intervention, and 3 post intervention. Children performed tasks measuring lexical access, phonological processing, and letter knowledge. All children were asked to practice ten minutes per day at home supported by their parents.Results: NH children outperformed DHH children on the majority of tasks. All children improved their accuracy in phoneme-grapheme correspondence and output phonology as a function of the computer-assisted intervention. For the whole group of children, and specifically for children with CI, a lower initial phonological composite score was associated with a larger phonological change between baseline 2 and post intervention. Finally, 18 DHH children, whereof 11 children with CI, showed specific intervention effects on their phonological processing skills, and strong effect sizes for their improved accuracy of phoneme-grapheme correspondence.Conclusion: For some DHH children phonological processing skills are boosted relatively more by phoneme-grapheme correspondence training. This reflects the reciprocal relationship between phonological change and exposure to and manipulations of letters.
|
|
| 40. |
|
|
| 41. |
- Nakeva von Mentzer, Cecilia, et al.
(författare)
-
Coputer based phonological intervention : Effects on phonological processing
- 2012
-
Konferensbidrag (refereegranskat)abstract
- Children with mild to profound hearing impairment (HI) using cochlear implants (CI) and/or hearingaids (HA), and children with normal hearing (NH) participated in a phonological intervention study, bymeans of a computer‐based intervention program (Graphogame, Lyytinen et al., 2009). Children were 5,6 and 7 years of age. Thirty‐two of the children used CI and/or HA. 16 children with NH served as thecontrol group. The main design was a quasi‐experimental 3 x 3 design. Each test session was separatedin time with four weeks. All children were asked to practice 10 minutes per day at home supported bytheir parents, with an intervention program primarily developed to enhance phonemic differentiation.Results showed that the children with HI displayed a heterogeneous pattern of results, specifically withrespect to their performance on the phonological tasks. Approximately 20 percent performed within therange of NH children; these were all children with HA except one child with CI/HA. Children with CIdisplayed considerable difficulty with phonological working memory whereas children with HAshowed less knowledge in letter tasks. Intervention revealed positive effects on accuracy of phonemegraphemecorrespondence for all children and a significant positive change on phonological processingskills for children with weak initial phonological skills. Enhanced phoneme‐grapheme connections maybuild associations between the phonological lexicon and the sub‐lexical phonological representations,thereby improving underlying skills essential for word learning and the development of literacy. Implicationsof this are discussed within theoretical models of phonological and lexical processing (Goswami,2000; Ramus, 2001).
|
|
| 42. |
- Nakeva von Mentzer, Cecilia, 1968-, et al.
(författare)
-
Datorbaserad fonologisk intervention för barn med cochleaimplantat (CI) och/eller hörapparat (HA) : effekter på fonologiska färdigheter
- 2012
-
Ingår i: Logopednytt. - Stockholm, Sweden : Svenska Logopedförbundet (SLOF). - 1102-500X. ; :3, s. 18-23
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Children with mild to profound hearing impairment 5, 6 and 7 years of age, thirty-two using cochlear implants and/or hearing aids, and sixteen normal hearing children participated in a computer based phonological intervention study.The main design was a quasi-experimental design with three test sessions separated in time with four weeks. Each test session included tasks for phonological skills and letter knowledge. All children were asked to practice 10 minutes per day.Results showed that children with HI displayed a heterogeneous pattern of results with respect to phonological skills. Only 20 percent performed within the range of NH children; these were children with HA, except one child with CI/HA.Group comparisons at the first and last test session revealed that children with CI displayed difficulty with phonological working memory whereas children with HA showed less letter knowledge. Intervention revealed positive effects on accuracy of phoneme-grapheme correspondence for all children and a significant positive change on phonological processing skills for children with weak initial phonological skills.
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
- Nakeva von Mentzer, Cecilia, et al.
(författare)
-
Predictors of phonological change in deaf and hard of hearing children who use cochlear implants or hearing aids
- 2014
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: The purpose of the present study was to examine cognitive abilities (i.e., working memory (WM), lexical access, phonological processing skills (PhPS), and letter knowledge) in deaf and hard of hearing (D/HH) children in relation to a reference group with normal hearing (NH) children pre intervention with a computer-assisted program that focused on phonological coding. A more specific purpose was to explore how cognitive abilities were associated to PhPS pre intervention and to phonological change post intervention in D/HH children in general, and specifically in D/HH children with weak initial PhPS.Methods: Participants were thirty-two children using cochlear implants or hearing aids, or both in combination, and sixteen children with NH 5, 6 and 7 years of age. Children practiced with phonological coding 10 min per day for 4 weeks with support by their parents. Cognitive abilities were examined pre and post intervention.Results: NH and D/HH children displayed a similar performance level on the majority of cognitive tasks, but the D/HH children demonstrated weaker lexical access and PhPS. A significant correlation between complex WM and PhPS pre intervention was only observed in D/HH children. Weak initial performance on one phonological processing task capturing both lower level and higher level auditory processing was the main significant predictor of phonological change in all D/HH children. In D/HH children with weak initial PhPS letter naming was associated with phonological change.Conclusions: The associations between complex working memory and PhPS in D/HH children and the lack of such associations in children with NH may indicate that phonological processing skills require more cognitive resources in the D/HH children. Letter knowledge can act as a driving force for phonological change following intervention in D/HH children with weak PhPS.
|
|
