Showing papers by "Newcastle University published in 2010"
University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
2,482 citations
TL;DR: A technique is developed, termed geographically weighted regression, which attempts to capture variation by calibrating a multiple regression model which allows different relationships to exist at different points in space by using Monte Carlo methods.
Abstract: Spatial nonstationarity is a condition in which a simple “global” model cannot explain the relationships between some sets of variables. The nature of the model must alter over space to reflect the structure within the data. In this paper, a technique is developed, termed geographically weighted regression, which attempts to capture this variation by calibrating a multiple regression model which allows different relationships to exist at different points in space. This technique is loosely based on kernel regression. The method itself is introduced and related issues such as the choice of a spatial weighting function are discussed. Following this, a series of related statistical tests are considered which can be described generally as tests for spatial nonstationarity. Using Monte Carlo methods, techniques are proposed for investigating the null hypothesis that the data may be described by a global model rather than a non-stationary one and also for testing whether individual regression coefficients are stable over geographic space. These techniques are demonstrated on a data set from the 1991 U.K. census relating car ownership rates to social class and male unemployment. The paper concludes by discussing ways in which the technique can be extended.
2,330 citations
TL;DR: This work proposes principles for deciding saturation in theory-based interview studies, and demonstrates these principles in two studies, based on the theory of planned behaviour, designed to identify three belief categories (Behavioural, Normative and Control).
Abstract: In interview studies, sample size is often justified by interviewing participants until reaching 'data saturation'. However, there is no agreed method of establishing this. We propose principles for deciding saturation in theory-based interview studies (where conceptual categories are pre-established by existing theory). First, specify a minimum sample size for initial analysis (initial analysis sample). Second, specify how many more interviews will be conducted without new ideas emerging (stopping criterion). We demonstrate these principles in two studies, based on the theory of planned behaviour, designed to identify three belief categories (Behavioural, Normative and Control), using an initial analysis sample of 10 and stopping criterion of 3. Study 1 (retrospective analysis of existing data) identified 84 shared beliefs of 14 general medical practitioners about managing patients with sore throat without prescribing antibiotics. The criterion for saturation was achieved for Normative beliefs but not for other beliefs or studywise saturation. In Study 2 (prospective analysis), 17 relatives of people with Paget's disease of the bone reported 44 shared beliefs about taking genetic testing. Studywise data saturation was achieved at interview 17. We propose specification of these principles for reporting data saturation in theory-based interview studies. The principles may be adaptable for other types of studies.
2,248 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
Benjamin F. Voight1, Benjamin F. Voight2, Laura J. Scott3, Valgerdur Steinthorsdottir4 +180 more•Institutions (53)
TL;DR: By combining genome-wide association data from 8,130 individuals with type 2 diabetes and 38,987 controls of European descent and following up previously unidentified meta-analysis signals, 12 new T2D association signals are identified with combined P < 5 × 10−8.
Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
1,785 citations
Pierre-and-Marie-Curie University1, University of British Columbia2, Bristol-Myers Squibb3, Yale University4, University of California, Los Angeles5, University of Virginia6, French Institute of Health and Medical Research7, University College London8, University of California, San Diego9, McGill University10, Goethe University Frankfurt11, University of Kentucky12, Tohoku University13, Newcastle University14, University of Lille Nord de France15, University of Nice Sophia Antipolis16, Brown University17, NewYork–Presbyterian Hospital18, Maastricht University Medical Centre19, VU University Amsterdam20
TL;DR: This paper aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities.
Abstract: Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.
1,776 citations
Newcastle University1, Children's Hospital of Philadelphia2, Case Western Reserve University3, Duke University4, Veterans Health Administration5, Cincinnati Children's Hospital Medical Center6, University of California, Davis7, University of Rochester8, Baylor College of Medicine9, Boston Children's Hospital10, Centers for Disease Control and Prevention11
TL;DR: These recommendations provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care.
Abstract: Duchenne muscular dystrophy (DMD) is a severe, progressive disease that aff ects 1 in 3600–6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation–University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.
1,664 citations
TL;DR: Analysis of outcomes of 5876 patients treated in Medical Research Council trials allows more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML.
1,651 citations
Michael R. Hoffmann1, Craig Hilton-Taylor2, Ariadne Angulo2, Monika Böhm3 +170 more•Institutions (81)
TL;DR: Though the threat of extinction is increasing, overall declines would have been worse in the absence of conservation, and current conservation efforts remain insufficient to offset the main drivers of biodiversity loss in these groups.
Abstract: Using data for 25,780 species categorized on the International Union for Conservation of Nature Red List, we present an assessment of the status of the world's vertebrates. One-fifth of species are classified as Threatened, and we show that this figure is increasing: On average, 52 species of mammals, birds, and amphibians move one category closer to extinction each year. However, this overall pattern conceals the impact of conservation successes, and we show that the rate of deterioration would have been at least one-fifth again as much in the absence of these. Nonetheless, current conservation efforts remain insufficient to offset the main drivers of biodiversity loss in these groups: agricultural expansion, logging, overexploitation, and invasive alien species.
1,333 citations
University of Milan1, University of Siena2, Marche Polytechnic University3, Sapienza University of Rome4, University of Nantes5, University of Pécs6, Umeå University7, Newcastle University8, University of Greifswald9, Ludwig Maximilian University of Munich10, University of Paris11, Case Western Reserve University12, University of Zagreb13, University of Florida14, Indiana University15, Leeds General Infirmary16, University of Liège17, University of Groningen18, Tel Aviv University19, Medical University of Warsaw20, University of Colorado Denver21, Lille University of Science and Technology22, Erasmus University Rotterdam23, University of Iowa24
TL;DR: This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants.
Abstract: The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infant's own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.
1,267 citations
TL;DR: An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies, which reflect the most relevant morphological and clinical features ofDCI.
Abstract: Background and Purpose—In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods—An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results—It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at au...
TL;DR: In this article, the synthesis of cyclic carbonates by the 100% atom economical reaction between epoxides and CO2 is reviewed in the context of reducing global emissions of waste CO 2 and converting waste CO2 into industrially useful chemical feedstocks.
University of North Carolina at Chapel Hill1, University of Texas Health Science Center at Houston2, University of Cambridge3, University of Pavia4, University of Milan5, Stanford University6, Kaiser Permanente7, National Institutes of Health8, University of Washington9, Wake Forest University10, Cedars-Sinai Medical Center11, Group Health Cooperative12, Lund University13, University of Michigan14, National Institute for Health and Welfare15, University of Helsinki16, Boston University17, University of Chicago18, International Agency for Research on Cancer19, Charles University in Prague20, Institut Gustave Roussy21, French Institute of Health and Medical Research22, University of Padua23, University of Glasgow24, Palacký University, Olomouc25, Trinity College, Dublin26, National and Kapodistrian University of Athens27, Newcastle University28, University of Aberdeen29, University of Turin30, Nofer Institute of Occupational Medicine31, Russian Academy32, University of Exeter33, Massachusetts Institute of Technology34, Harvard University35, Broad Institute36, VU University Amsterdam37, Erasmus University Rotterdam38, University of Virginia39, Virginia Commonwealth University40, University of Pennsylvania41, Duke University42, Tufts University43, University of Ioannina44
TL;DR: A meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium found the strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3, and three loci associated with number of cigarettes smoked per day were identified.
Abstract: Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
Newcastle University1, Children's Hospital of Philadelphia2, Case Western Reserve University3, Duke University4, Veterans Health Administration5, Cincinnati Children's Hospital Medical Center6, University of California, Davis7, University of Rochester8, Baylor College of Medicine9, Boston Children's Hospital10, Centers for Disease Control and Prevention11
TL;DR: A comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions are presented.
Abstract: Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.
TL;DR: The factors involved in the formation of these biofilms are described, including the initial adherence to the oral tissues and teeth, cooperation between bacterial species in the biofilm, signalling between the bacteria and its role in pathogenesis, and the transfer of DNA between bacteria.
Abstract: Growth of oral bacteria in situ requires adhesion to a surface because the constant flow of host secretions thwarts the ability of planktonic cells to grow before they are swallowed. Therefore, oral bacteria evolved to form biofilms on hard tooth surfaces and on soft epithelial tissues, which often contain multiple bacterial species. Because these biofilms are easy to study, they have become the paradigm of multispecies biofilms. In this Review we describe the factors involved in the formation of these biofilms, including the initial adherence to the oral tissues and teeth, cooperation between bacterial species in the biofilm, signalling between the bacteria and its role in pathogenesis, and the transfer of DNA between bacteria. In all these aspects distance between cells of different species is integral for oral biofilm growth.
TL;DR: This poster presents a meta-modelling procedure called “spot-spot analysis” that allows for the direct comparison of the response of the immune system to various types of carbohydrates and its role in disease.
TL;DR: It is suggested that the NPT can act as a sensitising tool, enabling researchers to think through issues of implementation while designing a complex intervention and its evaluation, and may improve trial design by highlighting potential problems with recruitment or data collection.
Abstract: The past decade has seen considerable interest in the development and evaluation of complex interventions to improve health. Such interventions can only have a significant impact on health and health care if they are shown to be effective when tested, are capable of being widely implemented and can be normalised into routine practice. To date, there is still a problematic gap between research and implementation. The Normalisation Process Theory (NPT) addresses the factors needed for successful implementation and integration of interventions into routine work (normalisation). In this paper, we suggest that the NPT can act as a sensitising tool, enabling researchers to think through issues of implementation while designing a complex intervention and its evaluation. The need to ensure trial procedures that are feasible and compatible with clinical practice is not limited to trials of complex interventions, and NPT may improve trial design by highlighting potential problems with recruitment or data collection, as well as ensuring the intervention has good implementation potential. The NPT is a new theory which offers trialists a consistent framework that can be used to describe, assess and enhance implementation potential. We encourage trialists to consider using it in their next trial.
TL;DR: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.
Abstract: Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin–producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS. Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases. Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H ( CFH ) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein ( MCP ) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH , C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations. Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.
New York University1, Bangor University2, Pompeu Fabra University3, University of Arkansas for Medical Sciences4, Hong Kong Polytechnic University5, University College London6, Alzheimer's Association7, Newcastle University8, Karolinska Institutet9, University of New South Wales10, Spanish National Research Council11, Cochrane Collaboration12, University of Washington13
TL;DR: NPTs emerge as a useful, versatile and potentially cost-effective approach to improve outcomes and QoL in ADRD for both the PWD and CG.
Abstract: Introduction: Nonpharmacological therapies (NPTs) can improve the quality of life (QoL) of people with Alzheimer’s disease (AD) and their carers. The objective of this study was to evaluate the best evidence on the effects of NPTs in AD and related disorders (ADRD) by performing a systematic review and meta-analysis of the entire field. Methods: Existing reviews and major electronic databases were searched for randomized controlled trials (RCTs). The deadline for study inclusion was September 15, 2008. Intervention categories and outcome domains were predefined by consensus. Two researchers working together detected 1,313 candidate studies of which 179 RCTs belonging to 26 intervention categories were selected. Cognitive deterioration had to be documented in all participants, and degenerative etiology
TL;DR: Creation of a platform of tools to provide information to doctors and patients should be the first step in giving patients choice about their treatment, say Glyn Elwyn and colleagues.
Abstract: Creation of a platform of tools to provide information to doctors and patients should be the first step in giving patients choice about their treatment, say Glyn Elwyn and colleagues.
TL;DR: There exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of ‘deep’ cellular senescence, and is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.
Abstract: Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of ‘deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFβ. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.
Nicholas John Craddock1, Matthew E. Hurles2, Niall Cardin3, Richard D. Pearson3 +232 more•Institutions (34)
TL;DR: A large, direct genome-wide study of association between CNVs and eight common human diseases concludes that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis ofcommon human diseases.
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
TL;DR: Surgeons must consider implant design, expected component size and acetabular component positioning in order to reduce early failures when performing large-bearing metal-on-metal hip resurfacing and replacement.
Abstract: Early failure associated with adverse reactions to metal debris is an emerging problem after hip resurfacing but the exact mechanism is unclear. We analysed our entire series of 660 metal-on-metal resurfacings (Articular Surface Replacement (ASR) and Birmingham Hip Resurfacing (BHR)) and large-bearing ASR total hip replacements, to establish associations with metal debris-related failures. Clinical and radiological outcomes, metal ion levels, explant studies and lymphocyte transformation tests were performed. A total of 17 patients (3.4%) were identified (all ASR bearings) with adverse reactions to metal debris, for which revision was required. This group had significantly smaller components, significantly higher acetabular component anteversion, and significantly higher whole concentrations of blood and joint chromium and cobalt ions than asymptomatic patients did (all p < 0.001). Post-revision lymphocyte transformation tests on this group showed no reactivity to chromium or cobalt ions. Explants from these revisions had greater surface wear than retrievals for uncomplicated fractures. The absence of adverse reactions to metal debris in patients with well-positioned implants usually implies high component wear. Surgeons must consider implant design, expected component size and acetabular component positioning in order to reduce early failures when performing large-bearing metal-on-metal hip resurfacing and replacement.
TL;DR: ARG from all classes of antibiotics tested have significantly increased since 1940, but especially within the tetracyclines, with some individual ARG being >15 times more abundant now than in the 1970s.
Abstract: Mass production and use of antibiotics and antimicrobials in medicine and agriculture have existed for over 60 years, and has substantially benefited public health and agricultural productivity throughout the world. However, there is growing evidence that resistance to antibiotics (AR) is increasing both in benign and pathogenic bacteria, posing an emerging threat to public and environmental health in the future. Although evidence has existed for years from clinical data of increasing AR, almost no quantitative environmental data exist that span increased industrial antibiotic production in the 1950s to the present; i.e., data that might delineate trends in AR potentially valuable for epidemiological studies. To address this critical knowledge gap, we speculated that AR levels might be apparent in historic soil archives as evidenced by antibiotic resistance gene (ARG) abundances over time. Accordingly, DNA was extracted from five long-term soil-series from different locations in The Netherlands that spanned 1940 to 2008, and 16S rRNA gene and 18 ARG abundances from different major antibiotic classes were quantified. Results show that ARG from all classes of antibiotics tested have significantly increased since 1940, but especially within the tetracyclines, with some individual ARG being >15 times more abundant now than in the 1970s. This is noteworthy because waste management procedures have broadly improved and stricter rules on nontherapeutic antibiotic use in agriculture are being promulgated. Although these data are local to The Netherlands, they suggest basal environmental levels of ARG still might be increasing, which has implications to similar locations around the world.
TL;DR: Evidence is provided that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem, the first evidence, to the authors' knowledge, that subtypes of medULLoblastomas have distinct cellular origins.
Abstract: Medulloblastomas are the most common malignant childhood brain tumours and are thought to arise from the cerebellum. There is substantial heterogeneity among medulloblastomas and some are thought to arise following aberrant Sonic Hedgehog pathway activation. It is now shown that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered WNT signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment.
TL;DR: A multisectoral approach to diabetes control and care is vital for expansion of socioculturally appropriate diabetes programmes in sub-Saharan African countries and the rate of diabetes-related morbidity and mortality in this region could grow substantially.
TL;DR: A meta-analysis of nine genome-wide association studies and a follow-up of 29 independent loci found three newly implicated loci to be associated with type 2 diabetes: GIPR, ADCY5 and VPS13C.
Abstract: Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2- h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
TL;DR: In this article, the authors investigated the efficacy of early interventions for social communication for the treatment of autism in children and found that dyadic social communication can reduce the severity of autism symptoms.
TL;DR: Whereas human and mouse monocyte subsets are far more broadly conserved than currently recognized, important differences between the species deserve consideration when models of human disease are studied in mice.
TL;DR: In this article, the concepts of adaptation and adaptability are developed in a framework based upon agents, mechanisms and sites, which can better capture the geographical diversity, variety and unevenness of resilience.
Abstract: The resilience of places in response to uncertain, volatile and rapid change has emerged as a focus of academic and policy attention. This paper aims to contribute to understanding and explaining the resilience of places. Drawing upon evolutionary Economic Geography, the concepts of adaptation and adaptability are developed in a framework based upon agents, mechanisms and sites. In contrast to equilibrium-based approaches, this approach can better capture the geographical diversity, variety and unevenness of resilience and address questions of what kind of resilience and for whom.