| 891. |
- Mataix-Cols, David, et al.
(författare)
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Nordic OCD & Related Disorders Consortium : Rationale, design, and methods.
- 2020
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 183:1, s. 38-50
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Tidskriftsartikel (refereegranskat)abstract
- Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder, yet its etiology is unknown and treatment outcomes could be improved if biological targets could be identified. Unfortunately, genetic findings for OCD are lagging behind other psychiatric disorders. Thus, there is a pressing need to understand the causal mechanisms implicated in OCD in order to improve clinical outcomes and to reduce morbidity and societal costs. Specifically, there is a need for a large-scale, etiologically informative genetic study integrating genetic and environmental factors that presumably interact to cause the condition. The Nordic countries provide fertile ground for such a study, given their detailed population registers, national healthcare systems and active specialist clinics for OCD. We thus formed the Nordic OCD and Related Disorders Consortium (NORDiC, www.crowleylab.org/nordic), and with the support of NIMH and the Swedish Research Council, have begun to collect a large, richly phenotyped and genotyped sample of OCD cases. Our specific aims are geared toward answering a number of key questions regarding the biology, etiology, and treatment of OCD. This article describes and discusses the rationale, design, and methodology of NORDiC, including details on clinical measures and planned genomic analyses.
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| 892. |
- Mataix-Cols, David, et al.
(författare)
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Operational Definitions of Treatment Response and Remission in Obsessive-Compulsive Disorder Capture Meaningful Improvements in Everyday Life
- 2022
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Ingår i: Psychotherapy and Psychosomatics. - : S. Karger AG. - 0033-3190 .- 1423-0348. ; 91:6, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The operational definitions of treatment response, partial response, and remission in obsessive-compulsive disorder (OCD) are widely used in clinical trials and regular practice. However, the clinimetric sensitivity of these definitions, that is, whether they identify patients that experience meaningful changes in their everyday life, remains unexplored.Objective: The objective was to examine the clinimetric sensitivity of the operational definitions of treatment response, partial response, and remission in children and adults with OCD.Methods: Pre- and post-treatment data from five clinical trials and three cohort studies of children and adults with OCD (n = 1,528; 55.3% children, 61.1% female) were pooled. We compared (1) responders, partial responders, and non-responders and (2) remitters and non-remitters on self-reported OCD symptoms, clinician-rated general functioning, and self-reported quality of life. Remission was also evaluated against post-treatment diagnostic interviews.Results: Responders and remitters experienced large improvements across validators. Responders had greater improvements than partial responders and non-responders on self-reported OCD symptoms (Cohen’s d 0.65–1.13), clinician-rated functioning (Cohen’s d 0.53–1.03), and self-reported quality of life (Cohen’s d 0.63–0.73). Few meaningful differences emerged between partial responders and non-responders. Remitters had better outcomes across most validators than non-remitters. Remission criteria corresponded well with absence of post-treatment diagnosis (sensitivity/specificity: 93%/83%). Using both the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression Scale yielded more conservative results and more robust changes across validators, compared to only using the Y-BOCS.Conclusions: The current definitions of treatment response and remission capture meaningful improvements in the everyday life of individuals with OCD, whereas the concept of partial response has dubious clinimetric sensitivity.
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| 893. |
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| 894. |
- McKay, James D., et al.
(författare)
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Lung cancer susceptibility locus at 5p15.33
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:12, s. 1404-1406
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P - 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.
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| 895. |
- McKeown, Nicola M., et al.
(författare)
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Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway : a meta-analysis
- 2018
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:2, s. 317-330
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Methods: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. Results: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10−3) and higher fasting insulin (0.030 ± 0.005 [loge pmol/l], p = 2.0 × 10−10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 loge pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. Conclusions/interpretation: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trial registration: Trials related to this study were registered at clinicaltrials.govas NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses’ Health Study).
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| 896. |
- McManus, David D, et al.
(författare)
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Relations of circulating resistin and adiponectin and cardiac structure and function : the Framingham Offspring Study.
- 2012
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 20:9, s. 1882-1886
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is associated with pathological cardiac remodeling and risk of heart failure (HF). Adipocytokines (ADKs) may mediate the increased risk of cardiovascular disease associated with excess adiposity. Yet data relating ADKs to cardiac remodeling phenotypes are sparse. We related two circulating ADKs, resistin and adiponectin, to three important echocardiographic markers of cardiac remodeling, left ventricular mass (LVM), left atrial diameter (LAD), and LV fractional shortening (LVFS) in 2,615 participants (mean age 61 years, 55% women) in the Framingham Offspring Study. Adiponectin concentrations were inversely related to LVM in multivariable linear regression models adjusting for key clinical correlates including BMI (regression coefficient per s.d.-increment in ln-adiponectin = -3.37, P = 0.02; P for trend across quartiles = 0.02). Adiponectin was not associated with LAD or LVFS (P > 0.56). Resistin concentrations were inversely related to LVFS (regression coefficient per s.d.-increment in ln-resistin = -0.01, P = 0.03; P for trend across quartiles = 0.04). Resistin was not associated with LVM or LAD (P > 0.05). In our moderate-sized, community-based sample, higher circulating concentrations of adiponectin and resistin were associated with lower LVM and lower LVFS, respectively. In conclusion, these associations identify potential mechanisms by which excess adiposity may mediate adverse cardiac remodeling and HF risk.
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| 897. |
- McQuillan, Ruth, et al.
(författare)
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Evidence of Inbreeding Depression on Human Height
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:7, s. e1002655-
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Tidskriftsartikel (refereegranskat)abstract
- Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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| 898. |
- Miadlikowska, Jolanta, et al.
(författare)
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A multigene phylogenetic synthesis for the class Lecanoromycetes (Ascomycota): 1307 fungi representing 1139 infrageneric taxa, 317 genera and 66 families.
- 2014
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Ingår i: Molecular Phylogenetics and Evolution. - : Elsevier BV. - 1095-9513 .- 1055-7903. ; 79:Online 18 April 2014, s. 132-168
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Tidskriftsartikel (refereegranskat)abstract
- The Lecanoromycetes is the largest class of lichenized Fungi, and one of the most species-rich classes in the kingdom. Here we provide a multigene phylogenetic synthesis (using three ribosomal RNA-coding and two protein-coding genes) of the Lecanoromycetes based on 635 newly generated and 3307 publicly available sequences representing 1139 taxa, 317 genera, 66 families, 17 orders and five subclasses (four currently recognized: Acarosporomycetidae, Lecanoromycetidae, Ostropomycetidae, Umbilicariomycetidae; and one provisionarily recognized, 'Candelariomycetidae'). Maximum likelihood phylogenetic analyses on four multigene datasets assembled using a cumulative supermatrix approach with a progressively higher number of species and missing data (5-gene, 5+4-gene, 5+4+3-gene and 5+4+3+2-gene datasets) show that the current classification includes non-monophyletic taxa at various ranks, which need to be recircumscribed and require revisionary treatments based on denser taxon sampling and more loci. Two newly circumscribed orders (Arctomiales and Hymeneliales in the Ostropomycetidae) and three families (Ramboldiaceae and Psilolechiaceae in the Lecanorales, and Strangosporaceae in the Lecanoromycetes inc. sed.) are introduced. The potential resurrection of the families Eigleraceae and Lopadiaceae is considered here to alleviate phylogenetic and classification disparities. An overview of the photobionts associated with the main fungal lineages in the Lecanoromycetes based on available published records is provided. A revised schematic classification at the family level in the phylogenetic context of widely accepted and newly revealed relationships across Lecanoromycetes is included. The cumulative addition of taxa with an increasing amount of missing data (i.e., a cumulative supermatrix approach, starting with taxa for which sequences were available for all five targeted genes and ending with the addition of taxa for which only two genes have been sequenced) revealed relatively stable relationships for many families and orders. However, the increasing number of taxa without the addition of more loci also resulted in an expected substantial loss of phylogenetic resolving power and support (especially for deep phylogenetic relationships), potentially including the misplacements of several taxa. Future phylogenetic analyses should include additional single copy protein-coding markers in order to improve the tree of the Lecanoromycetes. As part of this study, a new module ("Hypha") of the freely available Mesquite software was developed to compare and display the internodal support values derived from this cumulative supermatrix approach.
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| 899. |
- Middleton, Matthew J., et al.
(författare)
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Bright radio emission from an ultraluminous stellar-mass microquasar in M 31
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 493:7431, s. 187-190
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Tidskriftsartikel (refereegranskat)abstract
- A subset of ultraluminous X-ray sources (those with luminosities of less than 10(40) erg s(-1); ref. 1) are thought to be powered by the accretion of gas onto black holes with masses of similar to 5-20M(circle dot), probably by means of an accretion disk(2,3). The X-ray and radio emission are coupled in such Galactic sources; the radio emission originates in a relativistic jet thought to be launched from the innermost regions near the black hole(4,5), with the most powerful emission occurring when the rate of infalling matter approaches a theoretical maximum (the Eddington limit). Only four such maximal sources are known in the Milky Way(6), and the absorption of soft X-rays in the interstellar medium hinders the determination of the causal sequence of events that leads to the ejection of the jet. Here we report radio and X-ray observations of a bright new X-ray source in the nearby galaxy M 31, whose peak luminosity exceeded 10(39) erg s(-1). The radio luminosity is extremely high and shows variability on a timescale of tens of minutes, arguing that the source is highly compact and powered by accretion close to the Eddington limit onto a black hole of stellar mass. Continued radio and X-ray monitoring of such sources should reveal the causal relationship between the accretion flow and the powerful jet emission.
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| 900. |
- Miron, Richard J., et al.
(författare)
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Twenty years of enamel matrix derivative : the past, the present and the future
- 2016
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Ingår i: Journal of Clinical Periodontology. - : Blackwell Munksgaard. - 0303-6979 .- 1600-051X. ; 43:8, s. 668-683
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Forskningsöversikt (refereegranskat)abstract
- Background On June 5th, 2015 at Europerio 8, a group of leading experts were gathered to discuss what has now been 20years of documented evidence supporting the clinical use of enamel matrix derivative (EMD). Original experiments led by Lars Hammarstrom demonstrated that enamel matrix proteins could serve as key regenerative proteins capable of promoting periodontal regeneration including new cementum, with functionally oriented inserting new periodontal ligament fibres, and new alveolar bone formation. This pioneering work and vision by Lars Hammarstrom has paved the way to an enormous amount of publications related to its biological basis and clinical use. Twenty years later, it is clear that all these studies have greatly contributed to our understanding of how biologics can act as mediators for periodontal regeneration and have provided additional clinical means to support tissue regeneration of the periodontium. Aims This review article aims to: (1) provide the biological background necessary to understand the rational for the use of EMD for periodontal regeneration, (2) present animal and human histological evidence of periodontal regeneration following EMD application, (3) provide clinically relevant indications for the use of EMD and (4) discuss future avenues of research including key early findings leading to the development of Osteogain, a new carrier system for EMD specifically developed with better protein adsorption to bone grafting materials
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