Showing papers by "John Radcliffe Hospital published in 2011"
Clinical Trial Service Unit1, University College London2, North Bristol NHS Trust3, University of Würzburg4, The George Institute for Global Health5, Children's Hospital at Westmead6, Peking Union Medical College7, Sultanah Aminah Hospital8, University of British Columbia9, National Institutes of Health10, Brigham and Women's Hospital11, University of Minnesota12, University of Otago13, University of Picardie Jules Verne14, University of Copenhagen15, Chiang Mai University16, Oslo University Hospital17, Charles University in Prague18, Medical University of Silesia19, Utrecht University20, University Medical Center Groningen21, University of Helsinki22, John Radcliffe Hospital23
TL;DR: Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
2,123 citations
TL;DR: It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells.
Abstract: Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease.
1,508 citations
TL;DR: The authors bring together the results from these pharmacological, neurophysiological, and imaging studies to describe their current knowledge of the physiological effects of tDCS, and the theoretical framework for how tDCS affects motor learning is proposed.
Abstract: Since the rediscovery of transcranial direct current stimulation (tDCS) about 10 years ago, interest in tDCS has grown exponentially. A noninvasive stimulation technique that induces robust excitability changes within the stimulated cortex, tDCS is increasingly being used in proof-of-principle and stage IIa clinical trials in a wide range of neurological and psychiatric disorders. Alongside these clinical studies, detailed work has been performed to elucidate the mechanisms underlying the observed effects. In this review, the authors bring together the results from these pharmacological, neurophysiological, and imaging studies to describe their current knowledge of the physiological effects of tDCS. In addition, the theoretical framework for how tDCS affects motor learning is proposed.
1,353 citations
Karlstad University1, Dresden University of Technology2, Karolinska University Hospital3, Mental Health Services4, Phillips University5, University of Florence6, Karolinska Institutet7, John Radcliffe Hospital8, King's College London9, London School of Economics and Political Science10, Lund University11, Harvard University12, University of Basel13, Norwegian University of Science and Technology14, University of Zurich15, Umeå University16, University of Cambridge17, University of Lausanne18, University of Sassari19, European Monitoring Centre for Drugs and Drug Addiction20, Aalborg University21, Cliniques Universitaires Saint-Luc22, Maastricht University Medical Centre23, Radboud University Nijmegen24, Stockholm School of Economics25
TL;DR: The present report presents much improved cost estimates for the total cost of disorders of the brain in Europe in 2010, covering 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items.
1,325 citations
Mayo Clinic1, New York University2, University of Hamburg3, George Washington University4, University of Girona5, Johns Hopkins University6, St George's, University of London7, Harvard University8, University of Ottawa9, Hospital for Sick Children10, University of Miami11, Paris Descartes University12, University College London13, University of Sydney14, Cincinnati Children's Hospital Medical Center15, John Radcliffe Hospital16, University of Amsterdam17, Indiana University18
TL;DR: This international consensus statement provides the state of genetic testing for the channelopathy and cardiomyopathies and summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of geneticTesting for these potentially heritable cardiac conditions.
Abstract: This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations.
Writing recommendations for genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.1
The most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts' opinions).
A Class I recommendation ( “is recommended” ) was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40% and signal/noise ratio >10; Table 3), AND/OR when …
1,147 citations
TL;DR: By combining NTA with fluorescence measurement it is demonstrated that vesicles can be labeled with specific antibody-conjugated quantum dots, allowing their phenotype to be determined, demonstrating that NTA is far more sensitive than conventional flow cytometry.
1,081 citations
TL;DR: This work attempts to identify common themes in experiments with human participants and with animal models which suggest roles that the areas play in learning about reward associations, selecting reward goals, choosing actions to obtain reward, and monitoring the potential value of switching to alternative courses of action.
957 citations
TL;DR: It is shown that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion.
Abstract: The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) can be proteolytically activated by cathepsins B and L upon viral uptake into target cell endosomes. In contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave SARS S. We along with others could previously show that the type II transmembrane protease TMPRSS2 activates the influenza virus hemagglutinin and the human metapneumovirus F protein by cleavage. Here, we assessed whether SARS S is proteolytically processed by TMPRSS2. Western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibition of antibody-mediated neutralization, most likely because SARS S fragments function as antibody decoys. trans-cleavage activated SARS S on effector cells for fusion with target cells and allowed efficient SARS S-driven viral entry into targets treated with a lysosomotropic agent or a cathepsin inhibitor. Finally, ACE2, the cellular receptor for SARS-CoV, and TMPRSS2 were found to be coexpressed by type II pneumocytes, which represent important viral target cells, suggesting that SARS S is cleaved by TMPRSS2 in the lung of SARS-CoV-infected individuals. In summary, we show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion.
926 citations
TL;DR: This issue is examined in childhood acute lymphoblastic leukaemia in which the ETV6–RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or ‘driver’ copy number alterations.
Abstract: Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6–RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or ‘driver’ copy number alterations By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγnull mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo These data have implications for cancer genomics and for the targeted therapy of cancer Genome-wide analysis of cancer cells in individual patients has revealed extensive genetic heterogeneity Two groups have now mapped genetic homogeneity in patients with acute lymphoblastic leukaemia (ALL) Mel Greaves and colleagues obtained mutational profiles of large numbers of single cells from 60 individuals with ETV6–RUNX1-positive ALL, while John Dick and colleagues profile BCR-ABL1-positive ALL Both groups deduce the evolutionary path by which different subclones emerge during disease progression Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insight into the heterogeneity of these functional subpopulations at the genetic level This work has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells Analysing single cells from human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample, the evolutionary path by which different subclones have emerged, and ongoing dynamic changes associated with relapse Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells
780 citations
Queen Mary University of London1, King's College London2, Medical Research Council3, University of Cambridge4, South London and Maudsley NHS Foundation Trust5, University of Cumbria6, John Radcliffe Hospital7, Royal Free Hospital8, Frenchay Hospital9, Western General Hospital10, University of Edinburgh11
TL;DR: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition.
748 citations
TL;DR: The global and regional distributions of individual subtypes and recombinants are broadly stable, although CRFs may play an increasing role in the HIV pandemic.
Abstract: Objective
To estimate the global and regional distribution of HIV-1 subtypes and recombinants between 2000 and 2007.
TL;DR: This study demonstrates the importance of exosomes in both the release of alpha synuclein and its transmission between cells and suggests that factors associated with PD pathology accelerate this process.
TL;DR: Increased numbers of innate lymphoid cells in patients with inflammatory bowel disease are found to be associated with better prognosis and decreased likelihood of long-term disease progression.
Abstract: Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23–driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23–responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3− cells in IBD. IL17A and IL17F expression is restricted to CD56− ILCs, whereas IL-23 induces IL22 and IL26 in the CD56+ ILC compartment. Furthermore, we observed a significant and selective increase in CD127+CD56− ILCs in the inflamed intestine in Crohn’s disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23–responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.
TL;DR: GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.
TL;DR: It is proposed that the levels of beta oscillations provide a measure of the likelihood that a new voluntary action will need to be actuated, and that the resulting modulation of beta activity is predictive, enabling the appropriate prospective resourcing and preparation of potential actions.
University of California, San Diego1, Mayo Clinic2, Rambam Health Care Campus3, University of Western Ontario4, Keio University5, Leiden University Medical Center6, St. Michael's Hospital7, University of Melbourne8, University Hospital of Lausanne9, University of Copenhagen10, Akershus University Hospital11, Harvard University12, University of Kiel13, Innsbruck Medical University14, John Radcliffe Hospital15, Katholieke Universiteit Leuven16, University of Milan17, French Institute of Health and Medical Research18, university of lille19
TL;DR: The methods to develop an instrument that can measure cumulative bowel damage, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection are outlined.
Abstract: Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage.
TL;DR: The new specialty of immunotherapy-responsive CNS disorders is likely to expand further as more antibody targets are discovered, and antibody assays can help with diagnosis.
Abstract: Summary Several CNS disorders associated with specific antibodies to ion channels, receptors, and other synaptic proteins have been recognised over the past 10 years, and can be often successfully treated with immunotherapies. Antibodies to components of voltage-gated potassium channel complexes (VGKCs), NMDA receptors (NMDARs), AMPA receptors (AMPARs), GABA type B receptors (GABA B Rs), and glycine receptors (GlyRs) can be identified in patients and are associated with various clinical presentations, such as limbic encephalitis and complex and diffuse encephalopathies. These diseases can be associated with tumours, but they are more often non-paraneoplastic, and antibody assays can help with diagnosis. The new specialty of immunotherapy-responsive CNS disorders is likely to expand further as more antibody targets are discovered. Recent findings raise many questions about the classification of these diseases, the relation between antibodies and specific clinical phenotypes, the relative pathological roles of serum and intrathecal antibodies, the mechanisms of autoantibody generation, and the development of optimum treatment strategies.
TL;DR: It is found that SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
TL;DR: Together, these results suggest complementary valuation processes across PFC areas: OFC neurons dynamically evaluate current choices relative to recent choice values, whereas ACC neurons encode choice predictions and prediction errors using a common valuation currency reflecting the integration of multiple decision parameters.
Abstract: Damage to prefrontal cortex (PFC) impairs decision-making, but the underlying value computations that might cause such impairments remain unclear. Here we report that value computations are doubly dissociable among PFC neurons. Although many PFC neurons encoded chosen value, they used opponent encoding schemes such that averaging the neuronal population extinguished value coding. However, a special population of neurons in anterior cingulate cortex (ACC), but not in orbitofrontal cortex (OFC), multiplexed chosen value across decision parameters using a unified encoding scheme and encoded reward prediction errors. In contrast, neurons in OFC, but not ACC, encoded chosen value relative to the recent history of choice values. Together, these results suggest complementary valuation processes across PFC areas: OFC neurons dynamically evaluate current choices relative to recent choice values, whereas ACC neurons encode choice predictions and prediction errors using a common valuation currency reflecting the integration of multiple decision parameters.
TL;DR: The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities.
TL;DR: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver‐related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality.
TL;DR: The implantation of the ACP device is a feasible method for percutaneous occlusion of the LAA, and the initial experience with the Amplatzer Cardiac Plug in humans is detailed.
Abstract: In most patients with atrial fibrillation (AF) and stroke, there is thrombotic embolization from the left atrial appendage (LAA). Percutaneous closure of the LAA is a novel alternative for the treatment of patients with AF at a high risk of stroke, in whom long-term anticoagulation therapy is not possible or not desired. This study details the initial experience with the Amplatzer Cardiac Plug (ACP) in humans.
TL;DR: It is suggested that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy.
TL;DR: Breast cancer radiotherapy has, at least until recently, increased the risk of developing ischaemic heart disease, pericarditis and valvular disease and women with ischaemia heart disease before breast cancer diagnosis may have incurred higher risks than others.
TL;DR: Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss, and Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort.
Abstract: Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss. Age-related cataract is a cause of blindness on a global scale involving genetic and environmental influences. With ageing, lens proteins undergo non-enzymatic, post-translational modification and the accumulation of fluorescent chromophores, increasing susceptibility to oxidation and cross-linking and increased light-scatter. Because the human lens grows throughout life, the lens core is exposed for a longer period to such influences and the risk of oxidative damage increases in the fourth decade when a barrier to the transport of glutathione forms around the lens nucleus. Consequently, as the lens ages, its transparency falls and the nucleus becomes more rigid, resisting the change in shape necessary for accommodation. This is the basis of presbyopia. In some individuals, the steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to the formation of a brown nuclear cataract. The process is homogeneous and the affected lens fibres retain their gross morphology. Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort. Unlike nuclear cataract, progression is intermittent, stepwise and non-uniform.
TL;DR: In resource-limited settings, malaria control programmes should consider use of text messaging to improve health workers' case-management practices and correct artemether-lumefantrine management improved.
TL;DR: Morphology and aneuploidy are linked at the blastocyst stage, however, the association is weak, and consequently, morphologic analysis cannot be relied on to ensure transfer of chromosomally normal embryos.
TL;DR: An analysis of the RBC-spleen dynamic interactions during P falciparum infection reflects both data and hypotheses, and provides a framework on which a more complete immunologic understanding of malaria pathogenesis may be elaborated.
TL;DR: Key barriers included difficulty accessing surgical services due to distance, poor roads, and lack of suitable transport; lack of local resources and expertise; direct and indirect costs related to surgical care; and fear of undergoing surgery and anesthesia.
Abstract: There is increasing evidence that lack of facilities, equipment, and expertise in district hospitals across many low- and middle-income countries constitutes a major barrier to accessing surgical care. However, what is less clear, is the extent to which people perceive barriers when trying to access surgical care. PubMed and EMBASE were searched using key words (“access” and “surgery,” “barrier” and “surgery,” “barrier” and “access”), MeSH headings (“health services availability,” “developing countries,” “rural population”), and the subject heading “health care access.” Articles were included if they were qualitative and applied to illnesses where the treatment is primarily surgical. Key barriers included difficulty accessing surgical services due to distance, poor roads, and lack of suitable transport; lack of local resources and expertise; direct and indirect costs related to surgical care; and fear of undergoing surgery and anesthesia. The significance of cultural, financial, and structural barriers pertinent to surgery and their role in wider health care issues are discussed. Immediate action to improve financial and geographic accessibility along with investment in district hospitals is likely to make a significant impact on overcoming access and barrier issues. Further research is needed to identify issues that need to be addressed to close the gap between the care needed and that provided.
TL;DR: An extensive geo-database of surveys is collated, forming the evidence-base for a multi-locus Bayesian geostatistical model to generate global frequency maps of the common Duffy alleles to refine the global cartography of thecommon Duffy variants.
Abstract: Blood group variants are characteristic of population groups, and can show conspicuous geographic patterns. Interest in the global prevalence of the Duffy blood group variants is multidisciplinary, but of particular importance to malariologists due to the resistance generally conferred by the Duffy-negative phenotype against Plasmodium vivax infection. Here we collate an extensive geo-database of surveys, forming the evidence-base for a multi-locus Bayesian geostatistical model to generate global frequency maps of the common Duffy alleles to refine the global cartography of the common Duffy variants. We show that the most prevalent allele globally was FY*A, while across sub- saharan Africa the predominant allele was the silent FY*B ES variant, commonly reaching fixation across stretches of the continent. The maps presented not only represent the first spatially and genetically comprehensive description of variation at this locus, but also constitute an advance towards understanding the transmission patterns of the neglected P. vivax malaria parasite.