Showing papers by "Newcastle University published in 2007"
University of Bristol1, University of Oxford2, Wellcome Trust Centre for Human Genetics3, Churchill Hospital4, National Health Service5, University of London6, Imperial College London7, University of Oulu8, National Institutes of Health9, Medical Research Council10, Wellcome Trust Sanger Institute11, Newcastle University12, Royal London Hospital13, Queen Mary University of London14, University of Dundee15, Ninewells Hospital16
TL;DR: A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI).
Abstract: Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
4,184 citations
Istanbul University1, Stavanger University Hospital2, University of Bergen3, King's College London4, Newcastle University5, Pierre-and-Marie-Curie University6, Juntendo University7, University of New South Wales8, University of California, Los Angeles9, Mayo Clinic10, McGill University11, Rush University Medical Center12, Tel Aviv University13, French Institute of Health and Medical Research14, University of Louisville15, Icahn School of Medicine at Mount Sinai16, Innsbruck Medical University17, University of Lisbon18, University of Barcelona19
TL;DR: Clinical diagnostic criteria for probable and possible PD‐D are proposed, characterized by impairment in attention, memory, executive and visuo‐spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent.
Abstract: Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.
2,454 citations
TL;DR: In this paper, the authors applied a previously validated statistical model, Impact, to data on the use and effectiveness of specific cardiac treatments and on changes in risk factors between 1980 and 2000 among U.S. adults 25 to 84 years old.
Abstract: BACKGROUND Mortality from coronary heart disease in the United States has decreased substantially in recent decades. We conducted a study to determine how much of this decrease could be explained by the use of medical and surgical treatments as opposed to changes in cardiovascular risk factors. METHODS We applied a previously validated statistical model, IMPACT, to data on the use and effectiveness of specific cardiac treatments and on changes in risk factors between 1980 and 2000 among U.S. adults 25 to 84 years old. The difference between the observed and expected number of deaths from coronary heart disease in 2000 was distributed among the treatments and risk factors included in the analyses. RESULTS From 1980 through 2000, the age-adjusted death rate for coronary heart disease fell from 542.9 to 266.8 deaths per 100,000 population among men and from 263.3 to 134.4 deaths per 100,000 population among women, resulting in 341,745 fewer deaths from coronary heart disease in 2000. Approximately 47% of this decrease was attributed to treatments, including secondary preventive therapies after myocardial infarction or revascularization (11%), initial treatments for acute myocardial infarction or unstable angina (10%), treatments for heart failure (9%), revascularization for chronic angina (5%), and other therapies (12%). Approximately 44% was attributed to changes in risk factors, including reductions in total cholesterol (24%), systolic blood pressure (20%), smoking prevalence (12%), and physical inactivity (5%), although these reductions were partially offset by increases in the body-mass index and the prevalence of diabetes, which accounted for an increased number of deaths (8% and 10%, respectively). CONCLUSIONS Approximately half the decline in U.S. deaths from coronary heart disease from 1980 through 2000 may be attributable to reductions in major risk factors and approximately half to evidence-based medical therapies.
2,354 citations
TL;DR: There is a need for a move away from comparison studies into the provision of decision-making tools for planning and management that are robust to future uncertainties; with examination and understanding of uncertainties within the modelling system.
Abstract: There is now a large published literature on the strengths and weaknesses of downscaling methods for different climatic variables, in different regions and seasons. However, little attention is given to the choice of downscaling method when examining the impacts of climate change on hydrological systems. This review paper assesses the current downscaling literature, examining new developments in the downscaling field specifically for hydrological impacts. Sections focus on the downscaling concept; new methods; comparative methodological studies; the modelling of extremes; and the application to hydrological impacts.
Consideration is then given to new developments in climate scenario construction which may offer the most potential for advancement within the ‘downscaling for hydrological impacts’ community, such as probabilistic modelling, pattern scaling and downscaling of multiple variables and suggests ways that they can be merged with downscaling techniques in a probabilistic climate change scenario framework to assess the uncertainties associated with future projections. Within hydrological impact studies there is still little consideration given to applied research; how the results can be best used to enable stakeholders and managers to make informed, robust decisions on adaptation and mitigation strategies in the face of many uncertainties about the future. It is suggested that there is a need for a move away from comparison studies into the provision of decision-making tools for planning and management that are robust to future uncertainties; with examination and understanding of uncertainties within the modelling system. Copyright © 2007 Royal Meteorological Society
2,015 citations
TL;DR: The molecular mechanisms by which hydrogen peroxide is sensed and the increasing evidence that antioxidant enzymes play multiple, key roles as sensors and regulators of signal transduction in response to hydrogen peroxy are discussed.
1,464 citations
McMaster University1, University of Toronto2, Dalhousie University3, Pennsylvania State University4, Nationwide Children's Hospital5, University of Iowa6, University of Miami7, University of South Carolina8, University of Paris9, Pasteur Institute10, University of Gothenburg11, Icahn School of Medicine at Mount Sinai12, Stanford University13, Vanderbilt University14, Johns Hopkins University15, University of North Carolina at Chapel Hill16, University of California, Los Angeles17, University of Pennsylvania18, Washington University in St. Louis19, University of Chicago20, Harvard University21, Emory University22, George Washington University23, Yale University24, University of Utah25, University of Washington26, University of Pittsburgh27, University of California, Irvine28, Veterans Health Administration29, University of Rochester30, University of Toulouse31, German Cancer Research Center32, Goethe University Frankfurt33, National and Kapodistrian University of Athens34, University of Bologna35, Utrecht University36, Guy's Hospital37, King's College London38, University of Cambridge39, University of Manchester40, Newcastle University41, University of Oxford42, University of Illinois at Chicago43, University of Michigan44, Centre Hospitalier Universitaire de Toulouse45, McGill University46, Autism Speaks47
TL;DR: Linkage and copy number variation analyses implicate chromosome 11p12–p13 and neurexins, respectively, among other candidate loci, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
Abstract: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
1,338 citations
TL;DR: In this paper, the authors report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirm the previously reported association of AITD with TSHR and FCRL3.
Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
1,299 citations
TL;DR: Brief interventions consistently produced reductions in alcohol consumption, and the effect was clear in men at one year of follow up, but unproven in women.
Abstract: Excessive drinking contributes significantly to social problems, physical and psychological illness, injury and death Hidden effects include increased levels of violence, accidents and suicide Most alcohol-related harm is caused by excessive drinkers whose consumption exceeds recommended drinking levels, not the drinkers with severe alcohol dependency problems One way to reduce consumption levels in a community may be to provide a brief intervention in primary care over one to four sessions This is provided by healthcare workers such as general physicians, nurses or psychologists In general practice, patients are routinely asked about alcohol consumption during registration, general health checks and as part of health screening (using a questionnaire) They tend not to be seeking help for alcohol problems when presenting The intervention they are offered includes feedback on alcohol use and harms, identification of high risk situations for drinking and coping strategies, increased motivation and the development of a personal plan to reduce drinking It takes place within the time-frame of a standard consultation, 5 to 15 minutes for a general physician, longer for a nurseA total of 29 controlled trials from various countries were identified, in general practice (24 trials) or an emergency setting (five trials) Participants drank an average of 306 grams of alcohol (over 30 standard drinks) per week on entry to the trial Over 7000 participants with a mean age of 43 years were randomised to receive a brief intervention or a control intervention, including assessment only After one year or more, people who received the brief intervention drank less alcohol than people in the control group (average difference 38 grams/week, range 23 to 54 grams) For men (some 70% of participants), the benefit of brief intervention was a difference of 57 grams/week, range 25 to 89 grams (six trials) The benefit was not clear for women The benefits of brief intervention were similar in the normal clinical setting and in research settings with greater resources Longer counselling had little additional benefit
1,226 citations
University of Cambridge1, Wellcome Trust Centre for Human Genetics2, King's College London3, Western General Hospital4, University of Oxford5, Newcastle University6, University of Bristol7, St George's, University of London8, Wellcome Trust Sanger Institute9, University College London10, Guy's and St Thomas' NHS Foundation Trust11
TL;DR: A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci, and 37 SNPs from these and other loci were tested for association in an independent case-control sample.
Abstract: A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.
1,189 citations
National Institute for Biological Standards and Control1, University of Sheffield2, Karolinska Institutet3, Technion – Israel Institute of Technology4, Leeds Teaching Hospitals NHS Trust5, Monash University6, Hebrew University of Jerusalem7, Thermo Fisher Scientific8, National Institutes of Health9, University of Cambridge10, University of Kansas11, University of Toronto12, Masaryk University13, Academy of Sciences of the Czech Republic14, Uppsala University15, Stanford University16, Newcastle University17, Pierre-and-Marie-Curie University18, WiCell19, University of Helsinki20, King's College London21, Kyoto University22, Hudson Institute23
TL;DR: The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide and found that despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers ofhuman embryonic stem cells.
Abstract: The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
1,064 citations
University of Paris1, Newcastle University2, Rush University Medical Center3, Stavanger University Hospital4, University of Bergen5, King's College London6, Prince of Wales Medical Research Institute7, Mayo Clinic8, Pierre-and-Marie-Curie University9, University of California, Los Angeles10, McGill University11, Tel Aviv University12, French Institute of Health and Medical Research13, University of Louisville14, Juntendo University15, Icahn School of Medicine at Mount Sinai16, Innsbruck Medical University17, Instituto de Medicina Molecular18, University of Barcelona19, Istanbul University20
TL;DR: The main focus of this article is to operationalize the diagnosis of PD‐D and to propose pratical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment.
Abstract: A preceding article described the clinical features of Parkinson's disease dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and "possible" PD-D. The main focus of this article is to operationalize the diagnosis of PD-D and to propose practical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment. Level I is aimed primarily at the clinician with no particular expertise in neuropsychological methods, but who requires a simple, pragmatic set of tests that are not excessively time-consuming. Level I can be used alone or in concert with Level II, which is more suitable when there is the need to specify the pattern and the severity on the dementia of PD-D for clinical monitoring, research studies or pharmacological trials. Level II tests can also be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end of a Level I evaluation. Given the lack of evidence-based standards for some tests when applied in this clinical context, we have tried to make practical and unambiguous recommendations, based upon the available literature and the collective experience of the Task Force. We accept, however, that further validation of certain tests and modifications in the recommended cut off values will be required through future studies.
TL;DR: Almost half the decline in U.S. deaths from coronary heart disease from 1980 through 2000 may be attributable to reductions in major risk factors and approximately half to evidence-based medical therapies.
Abstract: Following a peak in deaths from coronary heart disease (CHD) in about 1968, age-adjusted rates have declined by half. Two factors may have made critical contributions: a substantial decrease in prevalence of major cardiovascular risk factors such as smoking, high cholesterol, and high blood pressure; and major breakthroughs in evidence-based treatments including coronary bypass graft surgery, coronary angioplasty, thrombolytic therapy, and stents. The investigators used a validated statistical model, IMPACT, in an attempt to identify those factors chiefly responsible for the impressive decline in CHD mortality. Data were available for U.S. adults 25 to 84 years of age covering the years 1980-2000. Between 1980 and 2000, the age-adjusted death rate for CHD fell from 543 to 267 deaths per 100,000 population among men, and from 263 to 134 per 100,000 population among women. The result was 341,745 fewer CHD deaths in 2000. The U.S. IMPACT model explained approximately 90% of the decline in CHD deaths. • About 47% of the decline in deaths from CHD was ascribed to treatments, including secondary preventive therapy following acute myocardial infarction (AMI) or revascularization (11%), initial treatments for AMI or unstable angina (10%), treatments for heart failure (9%), revascularization for chronic angina (5%), and other treatments (12%). • Approximately 44% of the decline in CHD deaths was attributed to changes in risk factors, including reductions in total cholesterol of 0.34 mmol/L; systolic blood pressure of 5.1 mm Hg; the prevalence of smoking by 11.7%; and physical inactivity by 5%. These reductions were, however, partly offset by increases in body mass index and the prevalence of diabetes. These effects accounted, respectively, for increases of 8% and 10% in CHD mortality. The proportional contributions of specific treatments and risk factor changes to the overall reduction in deaths from CHD in the year 2000 were relatively consistent. The contribution of treatments for AMI remained consistently smaller than that of secondary prevention or treatments for heart failure, regardless of whether best, minimum, or maximum estimates were compared. These findings suggest the need for comprehensive strategies to treat and prevent CHD. Efforts will be needed to maximize the coverage of effective treatments and to actively promote population-based prevention through reducing risk factors.
University of Aberdeen1, University of Oregon2, Newcastle University3, Natural Environment Research Council4, University of California, Berkeley5, University of Sheffield6, University of California, Merced7, University of Warwick8, Macaulay Institute9, Mansfield University of Pennsylvania10, University of York11
TL;DR: It is argued that the full potential of the ongoing revolution in microbial ecology will not be realized if research is not directed and driven by theory, and that the generality of established ecological theory must be tested using microbial systems.
Abstract: Microbial ecology is currently undergoing a revolution, with repercussions spreading throughout microbiology, ecology and ecosystem science. The rapid accumulation of molecular data is uncovering vast diversity, abundant uncultivated microbial groups and novel microbial functions. This accumulation of data requires the application of theory to provide organization, structure, mechanistic insight and, ultimately, predictive power that is of practical value, but the application of theory in microbial ecology is currently very limited. Here we argue that the full potential of the ongoing revolution will not be realized if research is not directed and driven by theory, and that the generality of established ecological theory must be tested using microbial systems.
TL;DR: It is demonstrated how different theories can be used to generate testable hypotheses regarding factors that influence the implementation of change, and it shows how different theoretical assumptions lead to different quality-improvement strategies.
Abstract: A consistent finding in articles on quality improvement in health care is that change is difficult to achieve. According to the research literature, the majority of interventions are targeted at health care professionals. But success in achieving change may be influenced by factors other than those relating to individual professionals, and theories may help explain whether change is possible. This article argues for a more systematic use of theories in planning and evaluating quality-improvement interventions in clinical practice. It demonstrates how different theories can be used to generate testable hypotheses regarding factors that influence the implementation of change, and it shows how different theoretical assumptions lead to different quality-improvement strategies.
TL;DR: The iron content of deep-sea sediments shows that the deep ocean was anoxic and ferruginous before and during the Gaskiers glaciation 580 million years ago and that it became oxic afterward.
Abstract: Because animals require oxygen, an increase in late-Neoproterozoic oxygen concentrations has been suggested as a stimulus for their evolution. The iron content of deep-sea sediments shows that the deep ocean was anoxic and ferruginous before and during the Gaskiers glaciation 580 million years ago and that it became oxic afterward. The first known members of the Ediacara biota arose shortly after the Gaskiers glaciation, suggesting a causal link between their evolution and this oxygenation event. A prolonged stable oxic environment may have permitted the emergence of bilateral motile animals some 25 million years later.
University of Zurich1, University of Adelaide2, National Institute of Standards and Technology3, Johns Hopkins University4, University of Illinois at Urbana–Champaign5, Lamont–Doherty Earth Observatory6, Texas A&M University7, Stockholm University8, Commonwealth Scientific and Industrial Research Organisation9, Rice University10, Chinese Academy of Sciences11, Binghamton University12, Ohio State University13, University of Denver14, University of Hawaii at Manoa15, University of Bonn16, Environment Canada17, Massachusetts Institute of Technology18, Chimie ParisTech19, Institut national de la recherche agronomique20, Martin Luther University of Halle-Wittenberg21, Spanish National Research Council22, Newcastle University23
TL;DR: In this paper, the authors conducted a comprehensive intercomparison of this type (multimethod, multilab, and multisample), focusing mainly on methods used for soil and sediment BC studies.
Abstract: Black carbon (BC), the product of incomplete combustion of fossil fuels and biomass (called elemental carbon (EC) in atmospheric sciences), was quantified in 12 different materials by 17 laboratories from different disciplines, using seven different methods. The materials were divided into three classes: (1) potentially interfering materials, (2) laboratory-produced BC-rich materials, and (3) BC-containing environmental matrices (from soil, water, sediment, and atmosphere). This is the first comprehensive intercomparison of this type (multimethod, multilab, and multisample), focusing mainly on methods used for soil and sediment BC studies. Results for the potentially interfering materials (which by definition contained no fire-derived organic carbon) highlighted situations where individual methods may overestimate BC concentrations. Results for the BC-rich materials (one soot and two chars) showed that some of the methods identified most of the carbon in all three materials as BC, whereas other methods identified only soot carbon as BC. The different methods also gave widely different BC contents for the environmental matrices. However, these variations could be understood in the light of the findings for the other two groups of materials, i.e., that some methods incorrectly identify non-BC carbon as BC, and that the detection efficiency of each technique varies across the BC continuum. We found that atmospheric BC quantification methods are not ideal for soil and sediment studies as in their methodology these incorporate the definition of BC as light-absorbing material irrespective of its origin, leading to biases when applied to terrestrial and sedimentary materials. This study shows that any attempt to merge data generated via different methods must consider the different, operationally defined analytical windows of the BC continuum detected by each technique, as well as the limitations and potential biases of each technique. A major goal of this ring trial was to provide a basis on which to choose between the different BC quantification methods in soil and sediment studies. In this paper we summarize the advantages and disadvantages of each method. In future studies, we strongly recommend the evaluation of all methods analyzing for BC in soils and sediments against the set of BC reference materials analyzed here.
TL;DR: The interim findings from this ongoing study were inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes.
Abstract: Background A recent meta-analysis raised concern regarding an increased risk of myocardial infarction and death from cardiovascular causes associated with rosiglitazone treatment of type 2 diabetes. Methods We conducted an unplanned interim analysis of a randomized, multicenter, open-label, noninferiority trial involving 4447 patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea, in which 2220 patients were assigned to receive add-on rosiglitazone (rosiglitazone group), and 2227 to receive a combination of metformin plus sulfonylurea (control group). The primary end point was hospitalization or death from cardiovascular causes. Results Because the mean follow-up was only 3.75 years, our interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.31...
Newcastle University1, J. Craig Venter Institute2, University of Maryland, College Park3, University of Glasgow4, Technical University of Denmark5, University of Calgary6, Natural History Museum7, Ghent University8, University of Dundee9, University of Sassari10, University of California, Los Angeles11, Children's Hospital Oakland Research Institute12, Charles University in Prague13, University of Iowa14, University of Düsseldorf15, University of California, San Francisco16, University of Queensland17, QIMR Berghofer Medical Research Institute18, Chang Gung University19, University of Strathclyde20
TL;DR: The genome sequence of the protist Trichomonas vaginalis predicts previously unknown functions for the hydrogenosome, which support a common evolutionary origin of this unusual organelle with mitochondria.
Abstract: We describe the genome sequence of the protist Trichomonas vaginalis, a sexually transmitted human pathogen. Repeats and transposable elements comprise about two-thirds of the similar to 160-megabase genome, reflecting a recent massive expansion of genetic material. This expansion, in conjunction with the shaping of metabolic pathways that likely transpired through lateral gene transfer from bacteria, and amplification of specific gene families implicated in pathogenesis and phagocytosis of host proteins may exemplify adaptations of the parasite during its transition to a urogenital environment. The genome sequence predicts previously unknown functions for the hydrogenosome, which support a common evolutionary origin of this unusual organelle with mitochondria.
TL;DR: It seems that elastic extracellular matrix (ECM) components have a crucial role in controlling TGFβ signalling, while soluble and membrane bound forms of TGF β co-receptors add further layers of regulation.
Abstract: The intracellular mechanism of transforming growth factor-beta (TGFbeta) signalling via kinase receptors and SMAD effectors is firmly established, but recent studies of human cardiovascular syndromes such as Marfan syndrome and pre-eclampsia have refocused attention on the importance of regulating the availability of active extracellular TGFbeta. It seems that elastic extracellular matrix (ECM) components have a crucial role in controlling TGFbeta signalling, while soluble and membrane bound forms of TGFbeta co-receptors add further layers of regulation. Together, these extracellular interactions determine the final bioavailability of TGFbeta to vascular cells, and dysregulation is associated with an increasing number of vascular pathologies.
TL;DR: The ELF panel has good diagnostic accuracy in an independent validation cohort of patients with NAFLD and the addition of established simple markers augments the diagnostic performance across different stages of fibrosis, which will potentially allow superior stratification of patients for emerging therapeutic strategies.
International Agency for Research on Cancer1, University of Mainz2, University of Tampere3, Institut Gustave Roussy4, Columbia University5, Health Protection Agency6, National Institute for Occupational Safety and Health7, United States Atomic Energy Commission8, Australian Nuclear Science and Technology Organisation9, Chalk River Laboratories10, New Generation University College11, University of Ottawa12, Radiation and Nuclear Safety Authority13, Institut de radioprotection et de sûreté nucléaire14, International Atomic Energy Agency15, National Board of Health and Welfare16, American University of Beirut17, Vilnius University18, Newcastle University19, University of North Carolina at Chapel Hill20, Autonomous University of Madrid21, Électricité de France22, Semmelweis University23
TL;DR: This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date, and shows a strong healthy worker survivor effect in these cohorts.
Abstract: Cardis, E., Vrijheid, M., Blettner, M., Gilbert, E., Hakama, M., Hill, C., Howe, G., Kaldor, J., Muirhead, C. R., Schubauer-Berigan, M., Yoshimura, T., Bermann, F., Cowper, G., Fix, J., Hacker, C., Heinmiller, B., Marshall, M., Thierry-Chef, I., Utterback, D., Ahn, Y-O., Amoros, E., Ashmore, P., Auvinen, A., Bae, J-M., Bernar, J. S., Biau, A., Combalot, E., Deboodt, P., Diez Sacristan, A., Eklof, M., Engels, H., Engholm, G., Gulis, G., Habib, R. R., Holan, K., Hyvonen, H., Kerekes, A., Kurtinaitis, J., Malker, H., Martuzzi, M., Mastauskas, A., Monnet, A., Moser, M., Pearce, M. S., Richardson, D. B., Rodriguez-Artalejo, F., Rogel, A., Tardy, H., Telle-Lamberton, M., Turai, I., Usel, M. and Veress, K. The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: Estimates of Radiation-Related Cancer Risks. Radiat. Res. 167, 396– 416 (2007). A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low d...
TL;DR: The Normalization Process Model is broken down to show that it is consistent and adequate in generating accurate description, systematic explanation, and the production of rational knowledge claims about the workability and integration of complex interventions.
Abstract: The Normalization Process Model is a theoretical model that assists in explaining the processes by which complex interventions become routinely embedded in health care practice. It offers a framework for process evaluation and also for comparative studies of complex interventions. It focuses on the factors that promote or inhibit the routine embedding of complex interventions in health care practice. A formal theory structure is used to define the model, and its internal causal relations and mechanisms. The model is broken down to show that it is consistent and adequate in generating accurate description, systematic explanation, and the production of rational knowledge claims about the workability and integration of complex interventions. The model explains the normalization of complex interventions by reference to four factors demonstrated to promote or inhibit the operationalization and embedding of complex interventions (interactional workability, relational integration, skill-set workability, and contextual integration). The model is consistent and adequate. Repeated calls for theoretically sound process evaluations in randomized controlled trials of complex interventions, and policy-makers who call for a proper understanding of implementation processes, emphasize the value of conceptual tools like the Normalization Process Model.
TL;DR: It is shown that Sox9 maintains pancreatic progenitors by stimulating their proliferation, survival, and persistence in an undifferentiated state, and the finding that SOX9 regulates the Notch-effector HES1 suggests a NotCh-dependent mechanism and establishes a possible genetic link between SOX factors and Notch.
Abstract: The factors necessary to maintain organ-specific progenitor cells are poorly understood and yet of extreme clinical importance. Here, we identify the transcription factor SOX9 as the first specific marker and maintenance factor of multipotential progenitors during pancreas organogenesis. In the developing pancreas, SOX9 expression is restricted to a mitotically active, Notch-responsive subset of PDX1+ pluripotent progenitors and is absent from committed endocrine precursors or differentiated cells. Similar to Notch mutations, organ-specific Sox9 inactivation in mice causes severe pancreatic hypoplasia resulting from depletion of the progenitor cell pool. We show that Sox9 maintains pancreatic progenitors by stimulating their proliferation, survival, and persistence in an undifferentiated state. Our finding that SOX9 regulates the Notch-effector HES1 suggests a Notch-dependent mechanism and establishes a possible genetic link between SOX factors and Notch. These findings will be of major significance for the development of in vitro protocols for cell replacement therapies.
TL;DR: In this article, the authors reviewed standards and literature for technical requirements, as well as the performance of asphalt pavements constructed using such recycled materials (waste glass, steel slag, tyres and plastics).
Abstract: The construction and maintenance of UK roads consume large amounts of quarried aggregates. The use of secondary (recycled), instead of primary (virgin), materials helps easing landfill pressures and reducing demand of extraction. However, concerns over inferior road performance and additional costs have hindered the widespread use of secondary aggregates in such applications. This is especially the case in surface layers of asphalt pavements that may represent a value application for recycled solid waste materials (SWM). Waste glass, steel slag, tyres and plastics are selected for this study, which reviews standards and literature for technical requirements, as well as the performance of asphalt pavements constructed using such recycled materials. Waste arising and management indicates that although there is a large potential for supplying secondary materials, a few factors have effectively depressed such recycling activities. Such barriers are described here and may also apply to the secondary use of other SWM. After identifying and quantifying such barriers a brief discussion suggests ways of their removal.
TL;DR: Gas adsorption experiments have been carried out on a copper benzene tricarboxylate metal-organic framework material and Chemiluminescence and platelet aggregometry experiments indicate that the amount of NO recovered on exposure of the resulting complex to water is enough to be biologically active, completely inhibiting platelet aggregation in platelet rich plasma.
Abstract: Gas adsorption experiments have been carried out on a copper benzene tricarboxylate metal-organic framework material, HKUST-1. Hydrogen adsorption at 1 and 10 bar (both 77 K) gives an adsorption capacity of 11.16 mmol H2 per g of HKUST-1 (22.7 mg g(-)1, 2.27 wt %) at 1 bar and 18 mmol per g (36.28 mg g(-)1, 3.6 wt %) at 10 bar. Adsorption of D2 at 1 bar (77 K) is between 1.09 (at 1 bar) and 1.20(at <100 mbar) times the H2 values depending on the pressure, agreeing with the theoretical expectations. Gravimetric adsorption measurements of NO on HKUST-1 at 196 K (1 bar) gives a large adsorption capacity of approximately 9 mmol g(-1), which is significantly greater than any other adsorption capacity reported on a porous solid. At 298 K the adsorption capacity at 1 bar is just over 3 mmol g(-1). Infra red experiments show that the NO binds to the empty copper metal sites in HKUST-1. Chemiluminescence and platelet aggregometry experiments indicate that the amount of NO recovered on exposure of the resulting complex to water is enough to be biologically active, completely inhibiting platelet aggregation in platelet rich plasma.
TL;DR: The findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB and the diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.
Abstract: Summary Background Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand 123 I-2β-carbometoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ( 123 I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included. Methods We did a phase III study in which we used a 123 I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0·80) and specificity (0·85) targets and prespecified lower thresholds (sensitivity 0·65, specificity 0·73) using one-sided binomial tests with a significance level of α=0·025. Findings Abnormal scans had a mean sensitivity of 77·7% for detecting clinical probable DLB, with specificity of 90·4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85·7% was achieved for overall diagnostic accuracy, 82·4% for positive predictive value, and 87·5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's κ=0·87). The procedure was well tolerated with few adverse events. Interpretation A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with 123 I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.
Sergey Nejentsev1, Joanna M. M. Howson1, Neil Walker1, Jeffrey S. Szeszko1 +218 more•Institutions (26)
TL;DR: In this article, the major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune.
Abstract: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
Universidade Federal de Santa Catarina1, University of California, Santa Barbara2, University of Hawaii3, Smithsonian Tropical Research Institute4, Universidade Federal do Espírito Santo5, United States Geological Survey6, University of the Algarve7, Newcastle University8, University of the Azores9, Federal Fluminense University10, University of La Laguna11, University of California, Santa Cruz12
TL;DR: Both historical events and relatively recent dispersal have had a strong influence on Atlantic tropical marine biodiversity and have contributed to the biogeographical patterns observed today; however, examples of the latter process outnumber those of the former.
Abstract: Aim To understand why and when areas of endemism (provinces) of the tropical Atlantic Ocean were formed, how they relate to each other, and what processes have contributed to faunal enrichment.
Location Atlantic Ocean.
Methods The distributions of 2605 species of reef fishes were compiled for 25 areas of the Atlantic and southern Africa. Maximum-parsimony and distance analyses were employed to investigate biogeographical relationships among those areas. A collection of 26 phylogenies of various Atlantic reef fish taxa was used to assess patterns of origin and diversification relative to evolutionary scenarios based on spatio-temporal sequences of species splitting produced by geological and palaeoceanographic events. We present data on faunal (species and genera) richness, endemism patterns, diversity buildup (i.e. speciation processes), and evaluate the operation of the main biogeographical barriers and/or filters.
Results Phylogenetic (proportion of sister species) and distributional (number of shared species) patterns are generally concordant with recognized biogeographical provinces in the Atlantic. The highly uneven distribution of species in certain genera appears to be related to their origin, with highest species richness in areas with the greatest phylogenetic depth. Diversity buildup in Atlantic reef fishes involved (1) diversification within each province, (2) isolation as a result of biogeographical barriers, and (3) stochastic accretion by means of dispersal between provinces. The timing of divergence events is not concordant among taxonomic groups. The three soft (non-terrestrial) inter-regional barriers (mid-Atlantic, Amazon, and Benguela) clearly act as ‘filters’ by restricting dispersal but at the same time allowing occasional crossings that apparently lead to the establishment of new populations and species. Fluctuations in the effectiveness of the filters, combined with ecological differences among provinces, apparently provide a mechanism for much of the recent diversification of reef fishes in the Atlantic.
Main conclusions Our data set indicates that both historical events (e.g. Tethys closure) and relatively recent dispersal (with or without further speciation) have had a strong influence on Atlantic tropical marine biodiversity and have contributed to the biogeographical patterns we observe today; however, examples of the latter process outnumber those of the former.
Drexel University1, University of Pennsylvania2, Stavanger University Hospital3, University of Bergen4, Hammersmith Hospital5, University of Paris6, Istanbul University7, Columbia University8, University of California, San Diego9, Washington University in St. Louis10, Rush University Medical Center11, Harvard University12, National Institutes of Health13, VU University Amsterdam14, University of Tokyo15, Yokohama City University16, Newcastle University17, Icahn School of Medicine at Mount Sinai18, University of Rochester19
TL;DR: The authors agreed to endorse “Lewy body disorders” as the umbrella term for PD, PDD, and DLB to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of α-synuclein metabolism.
Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.
TL;DR: The development of a weather generator for use in climate impact assessments of agricultural and water system management, which produces internally consistent series of meteorological variables including: rainfall, temperature, humidity, wind, sunshine, as well as derivation of potential evapotranspiration.
Abstract: This paper describes the development of a weather generator for use in climate impact assessments of agricultural and water system management. The generator produces internally consistent series of meteorological variables including: rainfall, temperature, humidity, wind, sunshine, as well as derivation of potential evapotranspiration. The system produces series at a daily time resolution, using two stochastic models in series: first, for rainfall which produces an output series which is then used for a second model generating the other variables dependent on rainfall. The series are intended for single sites defined nationally across the UK at a 5km resolution, but can be generated to be representative across small catchments (<1000km2). Scenarios can be generated for the control period (1961-1990) based on observed data, as well as for the UK Climate Impacts Programme (UKCIP02) scenarios for three time slices (2020s, 2050s and 2080s). Future scenarios are generated by fitting the models to observations which have been perturbed by application of change factors derived from the UKCIP02 mean projected changes in that variable. These change factors are readily updated, as new scenarios become available, and with suitable calibration data the approach could be extended to any geographical region.