| 1. |
|
|
| 2. |
- Cervenka, Simon, et al.
(författare)
-
Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder
- 2012
-
Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 2
-
Tidskriftsartikel (refereegranskat)abstract
- The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (behavior). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [C-11]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (Po0.005). Using a repeated measures analysis of covariance, significant effects for time and time x LSAS(anx) change on D2-R-binding potential (BPND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BPND and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain P<0.05. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD. Translational Psychiatry (2012) 2, e120; doi:10.1038/tp.2012.40; published online 22 May 2012
|
|
| 3. |
- Cho, Yoon Shin, et al.
(författare)
-
Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:1
-
Tidskriftsartikel (refereegranskat)abstract
- We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.
|
|
| 4. |
- Hedman, E., et al.
(författare)
-
Effectiveness of Internet-based cognitive behaviour therapy for depression in routine psychiatric care
- 2014
-
Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 155:1, s. 49-58
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Efficacy of guided Internet-based cognitive behaviour therapy (ICBT) for depression has been demonstrated in several randomised controlled trials. Knowledge on the effectiveness of the treatment, i.e. how it works when delivered within routine care, is however scarce. The aim of this study was to investigate the effectiveness of ICBT for depression.Methods: We conducted a cohort study investigating all patients (N =1203) who had received guided ICBT for depression between 2007 and 2013 in a routine care setting at an outpatient psychiatric clinic providing Internet-based treatment The primary outcome measure was the Montgomery Asberg Depression Rating Scale-Self rated (MADRS-S).Results: Patients made large improvements from pre-treatment assessments to post-treatment on the primary outcome (effect size d on the MADRS-S = 1.27, 99% CI, 1.14-1.39). Participants were significantly improved in terms of suicidal ideation and sleep difficulties improvements were sustained at 6-month follow-up.Limitations: Attrition was rather large at 6-month follow-up. However, additional data was collected through telephone interviews with dropouts and advanced statistical models indicated that missing data did not bias the findings.Conclusions: ICBT for depression can be highly effective when delivered within the context of routine psychiatric care. This study suggests that the effect sizes are at least as high when the treatment is delivered in routine psychiatric care by qualified staff as when delivered in a controlled trial setting.
|
|
| 5. |
- Hedman, J., et al.
(författare)
-
Applying a customised DNA polymerase blend in forensic DNA profiling
- 2011
-
Ingår i: Book of Abstracts. ; , s. 161-
-
Konferensbidrag (refereegranskat)abstract
- Crime scene stains often contain extraneous compounds that may interfere with PCR-based DNA analysis,resulting in partial or negative/blank DNA profiles. Extensive DNA purification may remove PCR inhibitors, butinvolve a risk of DNA loss and introduction of contaminations. Customising the chemical content of the PCRreaction is a strategy that may increase PCR inhibitor tolerance without manipulating the sample. Previously wehave shown that crime scene stain analysis can be significantly improved by replacing the commonly used DNApolymerase AmpliTaq Gold with either individual alternative DNA polymerases or a blend of such enzymes [1,2].Here we present the validation of AmpFℓSTR SGM Plus with a modified PCR chemistry for routine casework,applying a 1:1 blend of the DNA polymerases ExTaq Hot Start and PicoMaxx High Fidelity. Allele callings areidentical to standard analysis, and stutters sizes and balance values are indistinguishable. The modified chemistryprovides increased resistance to PCR inhibitors, resulting in an elevated number of detected alleles for crimescene stains of both blood and secretion/saliva. Additionally, the detection limit is improved.[1] Hedman, J., Nordgaard, A., Rasmusson, B., Ansell, R. and Rådström, P. (2009) Improved forensic DNA analysis through the use of alternativeDNA polymerases and statistical modeling of DNA profiles. Biotechniques, 47, 951-958.[2] Hedman, J., Nordgaard, A., Dufva, C., Rasmusson, B., Ansell, R. and Rådström, P. (2010) Synergy between
|
|
| 6. |
- Hedman, J., et al.
(författare)
-
Applying a PCR inhibitor tolerant DNA polymerase blend in forensic DNA profiling
- 2011
-
Ingår i: Forensic Science International: Genetics, Supplement Series. - : Elsevier. - 1875-1768. ; 3:1, s. e349-e350
-
Tidskriftsartikel (refereegranskat)abstract
- Crime scene samples often contain extraneous compounds that may interfere with PCR-based DNA analysis, resulting in imbalanced, partial or blank/negative DNA profiles. Customising the chemical content of the PCR reaction is a strategy that may increase PCR inhibitor tolerance without manipulating the sample. We have validated a modified version of AmpFlSTR SGM Plus, replacing AmpliTaq Gold DNA polymerase with a customised blend of two alternative polymerases, ExTaq Hot Start and PicoMaxx High Fidelity. Allele calls are identical to standard analysis. Stutter sizes and balance values are indistinguishable. The modified chemistry provides increased resistance to PCR inhibitors, resulting in an elevated number of detected alleles for various problematic crime scene samples.
|
|
| 7. |
- Kooner, Jaspal S, et al.
(författare)
-
Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:10
-
Tidskriftsartikel (refereegranskat)abstract
- We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
|
|
| 8. |
- Mousis, O., et al.
(författare)
-
Scientific rationale for Saturn's in situ exploration
- 2014
-
Ingår i: Planetary and Space Science. - : Elsevier BV. - 0032-0633 .- 1873-5088. ; 104, s. 29-47
-
Tidskriftsartikel (refereegranskat)abstract
- Remote sensing observations meet some limitations when used to study the bulk atmospheric composition of the giant planets of our solar system. A remarkable example of the superiority of in situ probe measurements is illustrated by the exploration of Jupiter, where key measurements such as the determination of the noble gases' abundances and the precise measurement of the helium mixing ratio have only been made available through in situ measurements by the Galileo probe. This paper describes the main scientific goals to be addressed by the future in situ exploration of Saturn placing the Galileo probe exploration of Jupiter in a broader context and before the future probe exploration of the more remote ice giants. In situ exploration of Saturn's atmosphere addresses two broad themes that are discussed throughout this paper: first, the formation history of our solar system and second, the processes at play in planetary atmospheres. In this context, we detail the reasons why measurements of Saturn's bulk elemental and isotopic composition would place important constraints on the volatile reservoirs in the protosolar nebula. We also show that the in situ measurement of CO (or any other disequilibrium species that is depleted by reaction with water) in Saturn's upper troposphere may help constraining its bulk O/H ratio. We compare predictions of Jupiter and Saturn's bulk compositions from different formation scenarios, and highlight the key measurements required to distinguish competing theories to shed light on giant planet formation as a common process in planetary systems with potential applications to most extrasolar systems. In situ measurements of Saturn's stratospheric and tropospheric dynamics, chemistry and cloud-forming processes will provide access to phenomena unreachable to remote sensing studies. Different mission architectures are envisaged, which would benefit from strong international collaborations, all based on an entry probe that would descend through Saturn's stratosphere and troposphere under parachute down to a minimum of 10 bar of atmospheric pressure. We finally discuss the science payload required on a Saturn probe to match the measurement requirements.
|
|
| 9. |
- Small, K. S., et al.
(författare)
-
Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes
- 2011
-
Ingår i: Nat Genet. ; 43:6, s. 561-4
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits.
|
|
| 10. |
- Andersson, E, et al.
(författare)
-
Internet-based cognitive behaviour therapy for obsessive-compulsive disorder: a randomized controlled trial
- 2012
-
Ingår i: Psychological Medicine. - : Cambridge University Press (CUP). - 0033-2917 .- 1469-8978. ; 42:10, s. 2193-2203
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Cognitive behaviour therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD) but access to CBT is limited. Internet-based CBT (ICBT) with therapist support is potentially a more accessible treatment. There are no randomized controlled trials testing ICBT for OCD. The aim of this study was to investigate the efficacy of ICBT for OCD in a randomized controlled trial. less thanbrgreater than less thanbrgreater thanMethod. Participants (n=101) diagnosed with OCD were randomized to either 10 weeks of ICBT or to an attention control condition, consisting of online supportive therapy. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS) administered by blinded assessors. less thanbrgreater than less thanbrgreater thanResults. Both treatments lead to significant improvements in OCD symptoms, but ICBT resulted in larger improvements than the control condition on the YBOCS, with a significant between-group effect size (Cohens d) of 1.12 (95% CI 0.69-1.53) at post-treatment. The proportion of participants showing clinically significant improvement was 60% (95% CI 46-72) in the ICBT group compared to 6% (95% CI 1-17) in the control condition. The results were sustained at follow-up. less thanbrgreater than less thanbrgreater thanConclusions. ICBT is an efficacious treatment for OCD that could substantially increase access to CBT for OCD patients. Replication studies are warranted.
|
|
| 11. |
- Arridge, Christopher S., et al.
(författare)
-
Uranus Pathfinder : exploring the origins and evolution of Ice Giant planets
- 2012
-
Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 33:2-3, s. 753-791
-
Tidskriftsartikel (refereegranskat)abstract
- The "Ice Giants" Uranus and Neptune are a different class of planet compared to Jupiter and Saturn. Studying these objects is important for furthering our understanding of the formation and evolution of the planets, and unravelling the fundamental physical and chemical processes in the Solar System. The importance of filling these gaps in our knowledge of the Solar System is particularly acute when trying to apply our understanding to the numerous planetary systems that have been discovered around other stars. The Uranus Pathfinder (UP) mission thus represents the quintessential aspects of the objectives of the European planetary community as expressed in ESA's Cosmic Vision 2015-2025. UP was proposed to the European Space Agency's M3 call for medium-class missions in 2010 and proposed to be the first orbiter of an Ice Giant planet. As the most accessible Ice Giant within the M-class mission envelope Uranus was identified as the mission target. Although not selected for this call the UP mission concept provides a baseline framework for the exploration of Uranus with existing low-cost platforms and underlines the need to develop power sources suitable for the outer Solar System. The UP science case is based around exploring the origins, evolution, and processes at work in Ice Giant planetary systems. Three broad themes were identified: (1) Uranus as an Ice Giant, (2) An Ice Giant planetary system, and (3) An asymmetric magnetosphere. Due to the long interplanetary transfer from Earth to Uranus a significant cruise-phase science theme was also developed. The UP mission concept calls for the use of a Mars Express/Rosetta-type platform to launch on a Soyuz-Fregat in 2021 and entering into an eccentric polar orbit around Uranus in the 2036-2037 timeframe. The science payload has a strong heritage in Europe and beyond and requires no significant technology developments.
|
|
| 12. |
- Glass, Daniel, et al.
(författare)
-
Gene expression changes with age in skin, adipose tissue, blood and brain.
- 2013
-
Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 14:7
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.RESULTS: Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.CONCLUSIONS: Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.
|
|
| 13. |
- 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.
|
|
| 14. |
- Hedman, E., et al.
(författare)
-
Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder
- 2012
-
Ingår i: Acta Psychiatrica Scandinavica. - : John Wiley and Sons. - 0001-690X .- 1600-0447. ; 126:2, s. 126-136
-
Tidskriftsartikel (refereegranskat)abstract
- Hedman E, Andersson E, Ljotsson B, Andersson G, Andersson E, Schalling M, Lindefors N, Ruck C. Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder (SAD). Objective: No study has investigated clinical or genetic predictors and moderators of Internet-based cognitive behavior therapy (ICBT) compared with cognitive behavioral group therapy for (CBGT) for SAD. Identification of predictors and moderators is essential to the clinician in deciding which treatment to recommend for whom. We aimed to identify clinical and genetic (5-HTTLPR, COMTval158met, and BDNFval66met) predictors and moderators of ICBT and CBGT. Method: We performed three types of analyses on data from a sample comprising participants (N = 126) who had undergone ICBT or CBGT in a randomized controlled trial. Outcomes were i) end state symptom severity, ii) SAD diagnosis, and iii) clinically significant improvement. Results: The most stable predictors of better treatment response were working full time, having children, less depressive symptoms, higher expectancy of treatment effectiveness, and adhering to treatment. None of the tested gene polymorphisms were associated with treatment outcome. Comorbid general anxiety and depression were moderators meaning that lower levels were associated with a better treatment response in ICBT but not in CBGT. Conclusion: We conclude that demographic factors, symptom burden, adherence, and expectations may play an important role as predictors of treatment outcome. The investigated gene polymorphisms do not appear to make a difference.
|
|
| 15. |
- Hedman, E., et al.
(författare)
-
Cost-effectiveness and long-term effectiveness of Internet-based cognitive behaviour therapy for severe health anxiety
- 2013
-
Ingår i: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 43:2, s. 363-374
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Severe health anxiety is a common condition associated with functional disability, making it a costly disorder from a societal perspective. Internet-based cognitive behaviour therapy (ICBT) is a promising treatment but no previous study has assessed the cost-effectiveness or long-term outcome of ICBT for severe health anxiety. The aim of this study was to investigate the cost-effectiveness and 1-year treatment effects of ICBT for severe health anxiety. Method Cost-effectiveness and 1-year follow-up data were obtained from a randomized controlled trial (RCT) comparing ICBT (n = 40) to an attention control condition (CC, n = 41). The primary outcome measure was the Health Anxiety Inventory (HAI). A societal perspective was taken and incremental cost-effectiveness ratios (ICERs) were calculated using bootstrap sampling.RESULTS: The main ICER was -£1244, indicating the societal economic gain for each additional case of remission when administering ICBT. Baseline to 1-year follow-up effect sizes on the primary outcome measure were large (d = 1.71-1.95).CONCLUSIONS: ICBT is a cost-effective treatment for severe health anxiety that can produce substantial and enduring effects.
|
|
| 16. |
- Hedman, E., et al.
(författare)
-
Effectiveness of Internet-based cognitive behaviour therapy for panic disorder in routine psychiatric care
- 2013
-
Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 128:6, s. 457-467
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectiveGuided Internet-based cognitive behaviour therapy (ICBT) for panic disorder has been shown to be efficacious in several randomized controlled trials. However, the effectiveness of the treatment when delivered within routine psychiatric care has not been studied. The aim of this study was to investigate the effectiveness of ICBT for panic disorder within the context of routine psychiatric care. MethodWe conducted a cohort study investigating all patients (n=570) who had received guided ICBT for panic disorder between 2007 and 2012 in a routine care setting at an out-patient psychiatric clinic providing Internet-based treatment. The primary outcome measure was the Panic Disorder Severity Scale-Self-report (PDSS-SR). ResultsParticipants made large improvements from screening and pretreatment assessments to posttreatment (Cohen's d range on the PDSS-SR=1.07-1.55). Improvements were sustained at 6-month follow-up. ConclusionThis study suggests that ICBT for panic disorder is as effective when delivered in a routine care context as in the previously published randomized controlled trials.
|
|
| 17. |
- Hedman, E., et al.
(författare)
-
Internet administration of self-report measures commonly used in research on social anxiety disorder : a psychometric evaluation
- 2010
-
Ingår i: Computers in human behavior. - : Elsevier BV. - 0747-5632 .- 1873-7692. ; 26:4, s. 736-740
-
Tidskriftsartikel (refereegranskat)abstract
- The Internet has become increasingly popular as a way to administer self-report questionnaires, especially in the field of Internet delivered psychological treatments. Collecting questionnaire data over the Internet has advantages, such as ease of administration, and automated scoring. However, psychometric properties cannot be assumed to be identical to the paper-and-pencil versions. The aim of this study was to test the equivalence of paper-and-pencil and Internet administered versions of self-report questionnaires used in social phobia research. We analyzed data from two trials in which samples were recruited in a similar manner. One sample (N = 64) completed the paper-and-pencil version of questionnaires and the second sample (N = 57) completed the same measures online. We included the Liebowitz Social Anxiety Scale-self-assessment (LSAS-SR), the Social Interaction and Anxiety Scale (SIAS), and the Social Phobia Scale (SPS) as measures of social anxiety. Also included were the Montgomery sberg Depression Rating Scale-self-assessment (MADRS-S), the Beck Anxiety Inventory (BAI), and the Quality of Life Inventory (QOLI). Results showed equivalent psychometric properties across administration formats. Cronbach's α ranged between 0.77 and 0.94. There was an indication of a somewhat higher construct validity when participants filled out questionnaires using paper-and-pencil. We conclude that the LSAS-SR, SIAS, and SPS can be administered via the Internet with maintained psychometric properties.
|
|
| 18. |
|
|
| 19. |
- 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.
|
|
| 20. |
- Kjellin, A., et al.
(författare)
-
Hybrid simulation : bringing motivation to the art of teamwork training in the operating room
- 2014
-
Ingår i: Scandinavian Journal of Surgery. - : SAGE Publications. - 1457-4969 .- 1799-7267. ; 103:4, s. 232-236
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Crew resource management-based operating room team training will be an evident part of future surgical training. Hybrid simulation in the operating room enables the opportunity for trainees to perform higher fidelity training of technical and non-technical skills in a realistic context. We focus on situational motivation and self-efficacy, two important factors for optimal learning in light of a prototype course for teams of residents in surgery and anesthesiology and nurses. Material and Methods: Authentic operating room teams consisting of residents in anesthesia (n = 2), anesthesia nurses (n = 3), residents in surgery (n = 2), and scrub nurses (n = 6) were, during a one-day course, exposed to four different scenarios. Their situational motivation was self-assessed (ranging from 1 = does not correspond at all to 7 = corresponds exactly) immediately after training, and their self-efficacy (graded from 1 to 7) before and after training. Training was performed in a mock-up operating theater equipped with a hybrid patient simulator (SimMan 3G; Laerdal) and a laparoscopic simulator (Lap Mentor Express; Simbionix). The functionality of the systematic hybrid procedure simulation scenario was evaluated by an exit questionnaire (graded from 1 = disagree entirely to 5 = agree completely). Results and Conclusions: The trainees were mostly intrinsically motivated, engaged for their own sake, and had a rather great degree of self-determination toward the training situation. Self-efficacy among the team members improved significantly from 4 to 6 (median). Overall evaluation showed very good result with a median grading of 5. We conclude that hybrid simulation is feasible and has the possibility to train an authentic operating team in order to improve individual motivation and confidence.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- Nica, Alexandra C, et al.
(författare)
-
The architecture of gene regulatory variation across multiple human tissues : the MuTHER study.
- 2011
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:2
-
Tidskriftsartikel (refereegranskat)abstract
- While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
|
|
| 24. |
- Parts, Leopold, et al.
(författare)
-
Extent, causes, and consequences of small RNA expression variation in human adipose tissue.
- 2012
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:5
-
Tidskriftsartikel (refereegranskat)abstract
- Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
