Showing papers by "University of Gothenburg published in 2010"
Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Cristen J. Willer3, Sonja I. Berndt +410 more•Institutions (86)
TL;DR: Genetic loci associated with body mass index map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor, which may provide new insights into human body weight regulation.
Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
2,632 citations
TL;DR: A novel and critical role for pericytes is indicated in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the blood–brain barrier.
Abstract: The blood–brain barrier is a gatekeeper between the central nervous system and the rest of the body, and is made up of vascular endothelial cells. Previous work upheld the notion that the barrier was formed postnatally as a result of signalling from non-neuronal cells called astrocytes to endothelial cells. Now, two independent studies demonstrate that the barrier is in fact formed during embryogenesis, with the critical factor being the interaction between blood-vessel-surrounding cells called pericytes and epithelial cells. A better understanding of the tight relationship between pericytes, neuroendothelial cells and astrocytes in blood–brain barrier function will contribute to our understanding of the breakdown of the barrier during central nervous system injury and disease. The blood–brain barrier (BBB) is made up of vascular endothelial cells and was thought to have formed postnatally from astrocytes. Two independent studies demonstrate that this barrier forms during embryogenesis, with pericyte/endothelial cell interactions being critical to regulate the BBB during development. A better understanding of the relationship among pericytes, neuroendothelial cells and astrocytes in BBB function will contribute to our understanding of BBB breakdown during central nervous system injury and disease. The blood–brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS)1. The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport2. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes3, but the relative contribution of these different components to the BBB remains largely unknown1,3. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.
2,182 citations
TL;DR: In this article, the effect of heart rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure was evaluated in a randomized, double-blind, placebo-controlled, parallel-group study.
2,039 citations
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
1,919 citations
University of Amsterdam1, Naturalis2, Utrecht University3, Central University of Venezuela4, Ecopetrol5, Spanish National Research Council6, Petrobras7, Smithsonian Tropical Research Institute8, Federal University of Uberlandia9, Universidade Federal do Acre10, Academy of Natural Sciences of Drexel University11, ETH Zurich12, University of Oxford13, University of Gothenburg14, University of Zurich15
TL;DR: It is shown that Andean uplift was crucial for the evolution of Amazonian landscapes and ecosystems, and that current biodiversity patterns are rooted deep in the pre-Quaternary.
Abstract: The Amazonian rainforest is arguably the most species-rich terrestrial ecosystem in the world, yet the timing of the origin and evolutionary causes of this diversity are a matter of debate. We review the geologic and phylogenetic evidence from Amazonia and compare it with uplift records from the Andes. This uplift and its effect on regional climate fundamentally changed the Amazonian landscape by reconfiguring drainage patterns and creating a vast influx of sediments into the basin. On this “Andean” substrate, a region-wide edaphic mosaic developed that became extremely rich in species, particularly in Western Amazonia. We show that Andean uplift was crucial for the evolution of Amazonian landscapes and ecosystems, and that current biodiversity patterns are rooted deep in the pre-Quaternary.
1,790 citations
TL;DR: It is shown that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, and indicates that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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.
1,768 citations
TL;DR: The rationales behind and the diagnostic performances of the core cerebrospinal fluid biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-β are presented.
Abstract: Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-beta immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-beta. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.
1,659 citations
University of Tartu1, University of Gothenburg2, American Museum of Natural History3, University of Aberdeen4, Centraalbureau voor Schimmelcultures5, Max Planck Society6, University of Oslo7, University of Copenhagen8, Finnish Forest Research Institute9, Manchester Metropolitan University10, Macaulay Institute11, University of Washington12
1,471 citations
Copenhagen University Hospital1, French Institute of Health and Medical Research2, St George's, University of London3, University of Gothenburg4, The Catholic University of America5, University of Western Australia6, Columbia University7, University of Milan8, New York University9, Forest Research Institute10, University of Amsterdam11, Hacettepe University12, University of Copenhagen13
TL;DR: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated LP(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD.
Abstract: AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.
1,446 citations
University of Oxford1, King's College London2, University of Manchester3, Radboud University Nijmegen4, Wellcome Trust Sanger Institute5, University of London6, University of Sheffield7, Trinity College, Dublin8, Wellcome Trust9, Medical University of Graz10, University of Erlangen-Nuremberg11, Queen Mary University of London12, Western Infirmary13, Karolinska Institutet14, St George's, University of London15, University of Dundee16, University of Göttingen17, University of Gothenburg18, Sapienza University of Rome19, University of Cambridge20, University of Münster21, University College London22, Moorfields Eye Hospital23, University of Bristol24
TL;DR: These findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis and report compelling evidence for an interaction between the HLA-C and ERAP1 loci.
Abstract: To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
919 citations
Iris M. Heid1, Anne U. Jackson2, Joshua C. Randall3, Tthomas W. Winkler1 +352 more•Institutions (90)
TL;DR: A meta-analysis of genome-wide association studies for WHR adjusted for body mass index provides evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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.
TL;DR: The authors' analysis confirms that high heart rate is a risk factor for cardiovascular events in heart failure and selective lowering of heart rates with ivabradine improves cardiovascular outcomes.
Goethe University Frankfurt1, GE Healthcare2, Federal Institute for Drugs and Medical Devices3, University of Rostock4, Center for Drug Evaluation and Research5, University of Manchester6, Trinity College, Dublin7, University of Bonn8, Ludwig Maximilian University of Munich9, Food and Drug Administration10, University of Gothenburg11
TL;DR: There is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates.
Abstract: Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies
TL;DR: The definition of acute symptomatic seizures for epidemiological studies is considered, and the criteria used to distinguish these seizures from unprovoked seizures for specific etiologies are refined.
Abstract: Acute symptomatic seizures must be distinguished from unprovoked seizures and separately categorized for epidemiologic purposes. These recommendations are based upon the best available data at the ...
TL;DR: It is suggested that the clinical and functional outcomes remain high even 10 to 20 years after the implantation and Autologous chondrocyte implantation has emerged as an effective and durable solution for the treatment of large full-thickness cartilage and osteochondral lesions of the knee joint.
Abstract: Background: The medium-term results of autologous chondrocyte implantation (ACI) have shown good to excellent outcomes for the majority of patients. However, no long-term results 10 to 20 years after the surgery have been reported.Hypothesis: Autologous chondrocyte implantation provides a durable solution to the treatment of full-thickness cartilage lesions of the knee, maintaining good clinical results even 10 to 20 years after implantation.Study Design: Case series; Level of evidence, 4.Methods: In this uncontrolled study, questionnaires with the Lysholm, Tegner-Wallgren, Brittberg-Peterson, modified Cincinnati (Noyes), and Knee Injury and Osteoarthritis Outcome Score (KOOS) scores were sent to 341 patients. Preoperative Lysholm, Tegner-Wallgren, and Brittberg-Peterson scores were also retrieved when possible from patients’ files. The patients were asked to grade their status during the past 10 years as better, worse, or unchanged. Finally, they were asked if they would do the operation again.Results: T...
TL;DR: It is reported that gut microbiota modulate the intestinal eCB system tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels, and shows that LPS acts as a master switch to control adipose tissue metabolism both in vivo and ex vivo by blocking cannabinoid‐driven adipogenesis.
Abstract: Obesity is characterised by altered gut microbiota, low-grade inflammation and increased endocannabinoid (eCB) system tone; however, a clear connection between gut microbiota and eCB signalling has yet to be confirmed. Here, we report that gut microbiota modulate the intestinal eCB system tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels. The impact of the increased plasma LPS levels and eCB system tone found in obesity on adipose tissue metabolism (e.g. differentiation and lipogenesis) remains unknown. By interfering with the eCB system using CB1 agonist and antagonist in lean and obese mouse models, we found that the eCB system controls gut permeability and adipogenesis. We also show that LPS acts as a master switch to control adipose tissue metabolism both in vivo and ex vivo by blocking cannabinoid-driven adipogenesis. These data indicate that gut microbiota determine adipose tissue physiology through LPS-eCB system regulatory loops and may have critical functions in adipose tissue plasticity during obesity.
TL;DR: In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8 and, consistent with the winner's curse, its effect size in the replication sample was much smaller.
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
TL;DR: From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.
Abstract: The mouse retina has been used extensively over the past decades to study both physiologic and pathologic angiogenesis. Over time, various mouse retina models have evolved into well-characterized and robust tools for in vivo angiogenesis research. This article is a review of the angiogenic development of the mouse retina and a discussion of some of the most widely used vascular disease models. From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.
University of Leicester1, University of Nottingham2, Queen Mary University of London3, Medical Research Council4, Imperial College London5, King's College London6, Western General Hospital7, Uppsala University8, Wellcome Trust Sanger Institute9, University of Bristol10, St George's, University of London11, University of Helsinki12, University of Jyväskylä13, National Institutes of Health14, University of Zurich15, University of Split16, University of Zagreb17, University of Edinburgh18, University of Greifswald19, University of Gothenburg20, University of Western Australia21, Sir Charles Gairdner Hospital22, University College London23, University of London24, Glenfield Hospital25, University of Dundee26, Southampton General Hospital27, National Institute for Health Research28, Pasteur Institute29, University of Basel30, AstraZeneca31, University of Tampere32, University of St Andrews33, Health Protection Agency34
TL;DR: Genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium offers mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
Abstract: Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
TL;DR: Functional and anatomical evidence for abnormal neuroimmune interactions has been found in patients with IBS and the link between immune alterations and severity of gastrointestinal symptoms and the positive effect of anti-inflammatory treatments in IBS further highlight the relevance of neuro immune interactions in this condition.
Abstract: IBS is one of the most common functional gastrointestinal disorders worldwide and is thought to be the result of disturbed neural function along the brain-gut axis. The mechanisms behind this disturbance are not clear, but important roles for low-grade inflammation and immunological alterations in the development of symptoms compatible with IBS have become evident. The development of long-standing gastrointestinal symptoms after infectious gastroenteritis and patients with IBD in remission frequently having functional gastrointestinal symptoms support this hypothesis. An increased innate immune activity in the intestinal mucosa and in blood is found in subpopulations of patients with IBS. Mast cells and monocytes seem to be particularly important. In addition, studies have demonstrated that IBS may be associated with an activated adaptive immune response. Increased epithelial barrier permeability and an abnormal gut flora might lead to increased activation of the intestinal immune system. Functional and anatomical evidence for abnormal neuroimmune interactions has been found in patients with IBS. The link between immune alterations and severity of gastrointestinal symptoms and the positive effect of anti-inflammatory treatments in IBS further highlight the relevance of neuroimmune interactions in this condition.
TL;DR: It was found that most pyrosequencing singletons were artifactual and contained a strongly elevated proportion of insertions compared with natural intra- and interspecific variation, which influenced the richness and community composition as recovered by pyro sequencing.
Abstract: • Compared with Sanger sequencing-based methods, pyrosequencing provides orders of magnitude more data on the diversity of organisms in their natural habitat, but its technological biases and relative accuracy remain poorly understood. • This study compares the performance of pyrosequencing and traditional sequencing for species' recovery of ectomycorrhizal fungi on root tips in a Cameroonian rain forest and addresses biases related to multi-template PCR and pyrosequencing analyses. • Pyrosequencing and the traditional method yielded qualitatively similar results, but there were slight, but significant, differences that affected the taxonomic view of the fungal community. We found that most pyrosequencing singletons were artifactual and contained a strongly elevated proportion of insertions compared with natural intra- and interspecific variation. The alternative primers, DNA extraction methods and PCR replicates strongly influenced the richness and community composition as recovered by pyrosequencing. • Pyrosequencing offers a powerful alternative for the identification of ectomycorrhizal fungi in pooled root samples, but requires careful selection of molecular tools. A well-populated backbone database facilitates the detection of biological and technical artifacts. The pyrosequencing pipeline is available at http://unite.ut.ee/454pipeline.tgz.
TL;DR: It is suggested that the single-item question on work ability could be used as a simple indicator for assessing the status and progress of work ability among women on long-term sick leave.
Abstract: Objectives This study investigated the association between the work ability index (WAI) and the single-item question on work ability among women working in human service organizations (HSO) currently on long-term sick leave. It also examined the association between the WAI and the single-item question in relation to sick leave, symptoms, and health. Predictive values of the WAI, the changed WAI, the single-item question and the changed single-item question were investigated for degree of sick leave, symptoms, and health.
Methods This cohort study comprised 324 HSO female workers on long-term (>60 days) sick leave, with follow-ups at 6 and 12 months. Participants responded to questionnaires. Data on work ability, sick leave, health, and symptoms were analyzed with regard to associations and predictability. Spearman correlation and mixed-model analysis were performed for repeated measurements over time.
Results The study showed a very strong association between the WAI and the single-item question among all participants. Both the WAI and the single-item question showed similar patterns of associations with sick leave, health, and symptoms. The predictive value for the degree of sick leave and health-related quality of life (HRQoL) was strong for both the WAI and the single-item question, and slightly less strong for vitality, neck pain, both self-rated general and mental health, and behavioral and current stress.
Conclusion This study suggests that the single-item question on work ability could be used as a simple indicator for assessing the status and progress of work ability among women on long-term sick leave.
TL;DR: In this paper, Prahalad and Ramaswamy analyzed co-creation as a relatively new and critical development within the field of innovation and provided examples of four building blocks by which it occurs: dialogue, access, transparency and risk.
Abstract: In 2004, Prahalad and Ramaswamy analyzed co-creation as a relatively new and critical development within the field of innovation. They provided examples of four building blocks by which co-creation occurs: dialogue, access, transparency and risk. In this article, we relate these elements to the phenomenon of branding, extending the building block framework, using the marketing concepts of brand community and brand co-creation. We use data from a longitudinal case study of the LEGO Group and its brand community LUGNET to derive propositions from our marketing-based reframing of co-creation. Our findings suggest a simplified model based on the dimensions of company/stakeholder engagement and organizational self-disclosure, which we recommend as central concerns to the developing theory of brand co-creation. We conclude by presenting the implications that our work suggests for brand management and brand governance, including the possibility that brands may allow society to regain control over massive international corporations lost during the recent period of globalization.
TL;DR: It is shown that the gut microbiota affects both host energy and lipid metabolism and highlights its role in the development of metabolic diseases.
University of Milan1, Harvard University2, Georgetown University3, University of California, Los Angeles4, University of Mainz5, Medical University of Graz6, Technische Universität München7, University of Düsseldorf8, Semmelweis University9, Sheba Medical Center10, University of Alberta11, Tel Aviv Sourasky Medical Center12, Goethe University Frankfurt13, University of Münster14, University of Zurich15, Lithuanian University of Health Sciences16, Royal Adelaide Hospital17, University of Gothenburg18, University of Grenoble19, Charité20, RWTH Aachen University21, University of Cincinnati22, Trinity College, Dublin23, University of Utah24, University of Jena25, McMaster University26, University of Colorado Denver27, Frankston Hospital28, Columbia University29, Jerini30
TL;DR: In patients with hereditary angioedema having acute attacks, a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificantbenefit of ic atibant in the other trial are found with regard to the primary end point.
Abstract: BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)
TL;DR: A standardized classification system will allow to clarify unambiguously the identity of any given osseointegrated surface and help to identify the biological outcomes of each surface characteristic.
TL;DR: It is concluded that a lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder.
TL;DR: Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well, and different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted.
Abstract: Reliable, valid, and easy-to-administer instruments to identify possible caseness and to provide proxies for clinical diagnoses are needed in epidemiological research on child and adolescent mental health. The aim of this study is to provide further validity data for a parent telephone interview focused on Autism - Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC), for which reliability and preliminary validation data have been previously reported. Parents of 91 children clinically diagnosed at a specialized Child Neuropsychiatric Clinic, 366 control children and 319 children for whom clinical diagnoses had been previously assigned were interviewed by the A-TAC over the phone. Interviewers were blind to clinical information. Different scores from the A-TAC were compared to the diagnostic outcome. Areas under ROC curves for interview scores as predictors of clinical diagnoses were around 0.95 for most disorders, including autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (AD/HD), tic disorders, developmental coordination disorders (DCD) and learning disorders, indicating excellent screening properties. Screening cut-off scores with sensitivities above 0.90 (0.95 for ASD and AD/HD) were established for most conditions, as well as cut-off scores to identify proxies to clinical diagnoses with specificities above 0.90 (0.95 for ASD and AD/HD). The previously reported validity of the A-TAC was supported by this larger replication study using broader scales from the A-TAC-items and a larger number of diagnostic categories. Short versions of algorithms worked as well as larger. Different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted. Data on the validity for mood problems and oppositional defiant/conduct problems are still lacking. Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well.
TL;DR: A proinflammatory state in adipose tissue can lead to local insulin resistance with an impaired inhibitory effect of insulin on the release of FFAs and endothelial dysfunction that clearly promotes cardiovascular diseases and type 2 diabetes.
Abstract: Metabolic syndrome is associated with dysfunctional adipose tissue that is most likely a consequence of the enlargement of adipocytes and infiltration of macrophages into adipose tissue. Obesity and ectopic lipid deposition are major risk factors for diseases ranging from insulin resistance to type 2 diabetes and atherosclerosis. Enlargement of adipocytes, due to impaired adipocyte differentiation, leads to a chronic state of inflammation in the adipocytes and adipose tissue with a reduction in the secretion of adiponectin and increase in the secretion of proinflammatory cytokines such as interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1. The secretion of cytokines like tumour necrosis factor (TNF)- α, mainly from macrophages, enhances local inflammation. These proinflammatory cytokines might also substantially affect cardiovascular function and morphology. Furthermore, a proinflammatory state in adipose tissue can lead to local insulin resistance with an impaired inhibitory effect of insulin on the release of FFAs and endothelial dysfunction that clearly promotes cardiovascular diseases and type 2 diabetes. The underlying mechanisms of ectopic fat accumulation in various tissues and the impact on metabolic syndrome and its association with insulin resistance are discussed.
TL;DR: The PRF protocol concentrated most platelets and leukocytes from a blood harvest into a single autologous fibrin biomaterial and offers reproducible results as long as the main production principles are respected.
Abstract: Background: Platelet-rich fibrin (PRF; Choukroun's technique) is a second-generation platelet concentrate for surgical use. This easy protocol allows the production of leukocyte- and platelet-rich fibrin clots and membranes starting from 10-ml blood samples. The purposes of this study were to determine the cell composition and three-dimensional organization of this autologous biomaterial and to evaluate the influence of different collection tubes (dry glass or glass-coated plastic tubes) and compression procedures (forcible or soft) on the final PRF-membrane architecture.Methods: After centrifugation, blood analyses were performed on the residual waste plasmatic layers after collecting PRF clots. The PRF clots and membranes were processed for examination by light microscopy and scanning electron microscopy.Results: Approximately 97% of the platelets and >50% of the leukocytes were concentrated in the PRF clot and showed a specific three-dimensional distribution, depending on the centrifugation forces. Pla...