Showing papers by "University of Münster published in 2012"
Johns Hopkins University1, University of Barcelona2, St George's, University of London3, Taipei Veterans General Hospital4, Maastricht University5, Washington University in St. Louis6, Imperial College London7, University of Virginia8, Virginia Commonwealth University9, Thomas Jefferson University10, Beaumont Hospital11, University of Bordeaux12, Leipzig University13, University of Oklahoma14, University of Michigan15, Royal Melbourne Hospital16, University College Dublin17, Korea University18, University of Münster19, University of Birmingham20, University of Western Ontario21, Cleveland Clinic22, Harvard University23, University of Pennsylvania24, Northwestern University25, Université de Montréal26, Mayo Clinic27, Icahn School of Medicine at Mount Sinai28, University of California, Los Angeles29, National Yang-Ming University30, Loyola University Chicago31
TL;DR: This 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure.
Abstract: During the past decade, catheter ablation of atrial fibrillation (AF) has evolved rapidly from an investigational procedure to its current status as a commonly performed ablation procedure in many major hospitals throughout the world. Surgical ablation of AF, using either standard or minimally invasive techniques, is also performed in many major hospitals throughout the world.
In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society.1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons and the American College of Cardiology. Since the publication of the 2007 document, there has been much learned about AF ablation, and the indications for these procedures have changed. Therefore the purpose of this 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation, including definitions relevant to this topic.
This statement summarizes the opinion of the Task Force members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF. This statement is not intended to recommend or promote catheter ablation of AF. Rather the ultimate judgment regarding care of a particular patient …
2,754 citations
University of Pennsylvania1, Harvard University2, Broad Institute3, National Institutes of Health4, Boston University5, Lund University6, University of Copenhagen7, University of Texas Health Science Center at Houston8, deCODE genetics9, Queen Mary University of London10, University of Lübeck11, Glenfield Hospital12, University of Leicester13, University of Oxford14, University of Cambridge15, University of Ottawa16, University of Iceland17, Population Health Research Institute18, McGill University19, Vanderbilt University20, University of Missouri–Kansas City21, University of Münster22, University of Verona23, Queen's University Belfast24, MedStar Washington Hospital Center25, GlaxoSmithKline26, University of Helsinki27, Karolinska Institutet28, University of Mainz29, Utrecht University30, University of Groningen31, University of Michigan32, Centro Nacional de Investigaciones Cardiovasculares33, United States Department of Agriculture34, University of North Carolina at Chapel Hill35, University of Regensburg36, Katholieke Universiteit Leuven37, University of Edinburgh38, University of Kiel39, University of Leeds40, Aarhus University41, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico42, University of Washington43, Wellcome Trust Sanger Institute44
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10
1,878 citations
Columbia University1, University of Amsterdam2, University of California, Los Angeles3, University of Coimbra4, University of Zurich5, University of Mainz6, University of Münster7, University of Nantes8, Weizmann Institute of Science9, Shanghai Jiao Tong University10, University of Bologna11, Max Planck Society12, Purdue University13, Rice University14
TL;DR: A search for particle dark matter with the XENON100 experiment, operated at the Laboratori Nazionali del Gran Sasso for 13 months during 2011 and 2012, has yielded no evidence for dark matter interactions.
Abstract: We report on a search for particle dark matter with the XENON100 experiment, operated at the Laboratori Nazionali del Gran Sasso (LNGS) for 13 months during 2011 and 2012. XENON100 features an ultra-low electromagnetic background of (5.3\pm0.6)\times10^-3 events (kg day keVee)^-1 in the energy region of interest. A blind analysis of 224.6 live days \times 34 kg exposure has yielded no evidence for dark matter interactions. The two candidate events observed in the pre-defined nuclear recoil energy range of 6.6-30.5 keVnr are consistent with the background expectation of (1.0 \pm 0.2) events. A Profile Likelihood analysis using a 6.6-43.3 keVnr energy range sets the most stringent limit on the spin-independent elastic WIMP-nucleon scattering cross section for WIMP masses above 8 GeV/c^2, with a minimum of 2 \times 10^-45 cm^2 at 55 GeV/c^2 and 90% confidence level.
1,624 citations
TL;DR: In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.
Abstract: The use of coordinating moieties as directing groups for the functionalization of aromatic CH bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of CH activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivatives. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted CH activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.
1,419 citations
University of Pennsylvania1, Johns Hopkins University2, Mayo Clinic3, University of Barcelona4, St George's, University of London5, Maastricht University6, Cleveland Clinic7, University of Virginia8, Baylor University9, Virginia Commonwealth University10, Thomas Jefferson University11, Beaumont Hospital12, University of Bordeaux13, Leipzig University14, University of Oklahoma15, University of Michigan16, Royal Melbourne Hospital17, University College Dublin18, Korea University19, University of Birmingham20, University of Münster21, University of Western Ontario22, Imperial College London23, Harvard University24, Northwestern University25, National Yang-Ming University26, Washington University in St. Louis27, Université de Montréal28, Icahn School of Medicine at Mount Sinai29, University of California, Los Angeles30, Loyola University Chicago31
TL;DR: A report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), was published in this paper.
1,271 citations
TL;DR: This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
Abstract: The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
1,063 citations
TL;DR: The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes, suggesting a strong bias in present clinical syndrome descriptions.
964 citations
TL;DR: The present article addresses the radical trifluoromethylation of alkenes and arenes mainly focussing on recent achievements, however, important earlier work in this field is also covered.
Abstract: This Minireview highlights recent developments in radical trifluoromethylation reactions. The trifluoromethyl group belongs to the privileged moieties in medicinal chemistry. Many drugs and drug candidates contain a trifluoromethyl substituent. Also in agrochemicals, the CF3 moiety often appears. The present article addresses the radical trifluoromethylation of alkenes and arenes mainly focussing on recent achievements. However, important earlier work in this field is also covered.
835 citations
Alisa K. Manning1, Alisa K. Manning2, Alisa K. Manning3, Robert A. Scott +240 more•Institutions (69)
TL;DR: Six previously unknown loci associated with fasting insulin at P < 5 × 10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals are presented.
Abstract: Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
811 citations
TL;DR: The present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.
797 citations
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
TL;DR: Diagnostic criteria for vestibular migraine are presented, jointly formulated by the Committee for Classification of Vestibular Disorders of the Bárány Society and the Migraine Classification Subcommittee of the International Headache Society, and will appear in an appendix of the third edition of the ICHD.
Abstract: This paper presents diagnostic criteria for vestibular migraine, jointly formulated by the Committee for Classification of Vestibular Disorders of the Barany Society and the Migraine Classification Subcommittee of the International Headache Society (IHS) The classification includes vestibular migraine and probable vestibular migraine Vestibular migraine will appear in an appendix of the third edition of the International Classification of Headache Disorders (ICHD) as a first step for new entities, in accordance with the usual IHS procedures Probable vestibular migraine may be included in a later version of the ICHD, when further evidence has been accumulated The diagnosis of vestibular migraine is based on recurrent vestibular symptoms, a history of migraine, a temporal association between vestibular symptoms and migraine symptoms and exclusion of other causes of vestibular symptoms Symptoms that qualify for a diagnosis of vestibular migraine include various types of vertigo as well as head motion-induced dizziness with nausea Symptoms must be of moderate or severe intensity Duration of acute episodes is limited to a window of between 5 minutes and 72 hours
University of Turin1, Masaryk University2, University of Münster3, Sapienza University of Rome4, Monash University5, Medical University of Vienna6, Medical University of Warsaw7, University of Tübingen8, Casa Sollievo della Sofferenza9, University of Bologna10, Medical University of Białystok11, Ankara University12, Charles University in Prague13, Dresden University of Technology14, University of Ulm15, Celgene16, National and Kapodistrian University of Athens17
TL;DR: MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age.
Abstract: The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P <0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P = 0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P = 0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. Conclusions MPR-R significantly prolonged progression-free survival in patients with newly di agnosed multiple myeloma who were ineligible for transplantation, with the great est benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.)
TL;DR: Using a consistent schema for nomenclature of the Stx toxins and stx genes by phylogenetic sequence-based relatedness of the holotoxin proteins, a typing approach should obviate the need to bioassay each newly described toxin and that predicts important biological characteristics.
Abstract: When Shiga toxin-producing Escherichia coli (STEC) strains emerged as agents of human disease, two types of toxin were identified: Shiga toxin type 1 (Stx1) (almost identical to Shiga toxin produced by Shigella dysenteriae type 1) and the immunologically distinct type 2 (Stx2). Subsequently, numerous STEC strains have been characterized that express toxins with variations in amino acid sequence, some of which confer unique biological properties. These variants were grouped within the Stx1 or Stx2 type and often assigned names to indicate that they were not identical in sequence or phenotype to the main Stx1 or Stx2 type. A lack of specificity or consistency in toxin nomenclature has led to much confusion in the characterization of STEC strains. Because serious outcomes of infection have been attributed to certain Stx subtypes and less so with others, we sought to better define the toxin subtypes within the main Stx1 and Stx2 types. We compared the levels of relatedness of 285 valid sequence variants of Stx1 and Stx2 and identified common sequences characteristic of each of three Stx/Stx1 and seven Stx2 subtypes. A novel, simple PCR subtyping method was developed, independently tested on a battery of 48 prototypic STEC strains, and improved at six clinical and research centers to test the reproducibility, sensitivity, and specificity of the PCR. Using a consistent schema for nomenclature of the Stx toxins and stx genes by phylogenetic sequence-based relatedness of the holotoxin proteins, we developed a typing approach that should obviate the need to bioassay each newly described toxin and that predicts important biological characteristics.
TL;DR: This work demonstrates the generation of single-mode coherent auto-oscillations in a device that combines local injection of a pure spin current with enhanced spin-wave radiation losses, and suggests a new route for the implementation of nanoscale microwave sources for next-generation integrated electronics.
Abstract: The dynamical processes associated with the magnetization of a material can be drastically altered by the application of a spin current. This study now demonstrates the feasibility of selectively exciting coherent auto-oscillation modes in magnetic nanostructures.
TL;DR: Data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.
Abstract: Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4(me2)) across the genome, but it did increase H3K4(me2) and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.
Heidelberg University1, Charité2, Ludwig Maximilian University of Munich3, University of Düsseldorf4, University of Würzburg5, Ruhr University Bochum6, University of Regensburg7, Technische Universität München8, University of Ulm9, University of Erlangen-Nuremberg10, Goethe University Frankfurt11, University of Tübingen12, Hannover Medical School13, University of Münster14, Leipzig University15, University of Rostock16, University of Göttingen17
TL;DR: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
Abstract: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Seropositive patients were found to be predominantly female (p 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
TL;DR: It is shown that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication, and it is proposed that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
Abstract: Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
Free University of Berlin1, Max Planck Society2, University of Colorado Boulder3, University of Oxford4, Royal Berkshire NHS Foundation Trust5, University of Ioannina6, Harvard University7, Mayo Clinic8, University of Miami9, German Center for Neurodegenerative Diseases10, University of Tübingen11, Boston University12, Emory University13, University of British Columbia14, Indiana University15, Wadsworth Center16, University College London17, VU University Amsterdam18, University of Lübeck19, University of Chicago20, Centre national de la recherche scientifique21, University of Toulouse22, National Institutes of Health23, Kobe University24, deCODE genetics25, University of Washington26, University of Münster27, Centers for Disease Control and Prevention28, University of Mainz29
TL;DR: This study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Abstract: More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson’s disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ,27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Metaanalyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P,5610 28 ) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3 ,P ARK16,SNCA, STK39 ,a ndSYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P=1.3610 28 ). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
University of Cologne1, Charles University in Prague2, Heidelberg University3, Masaryk University4, University of Tübingen5, University of Ulm6, Charité7, Ludwig Maximilian University of Munich8, University of Würzburg9, University of Hamburg10, University of Duisburg-Essen11, Leipzig University12, University of Münster13, University of Salzburg14, University Hospital Regensburg15, Saarland University16
TL;DR: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen, and should be the treatment of choice for advanced stage Hodgkin's lymphoma.
TL;DR: It is shown that a combination of transcription factors induces mouse fibroblasts to directly acquire a neural stem cell identity-which is term as induced neural stem cells (iNSCs).
University of Cambridge1, University of Toronto2, University of Pennsylvania3, University of Southampton4, University of Helsinki5, University of Southern California6, QIMR Berghofer Medical Research Institute7, Columbia University8, National Institutes of Health9, Mayo Clinic10, Leipzig University11, Claude Bernard University Lyon 112, University of Melbourne13, University of Utah14, Cancer Prevention Institute of California15, Vilnius University16, University of Latvia17, University of Copenhagen18, Complutense University of Madrid19, University of Turin20, University of Florence21, Sapienza University of Rome22, German Cancer Research Center23, Memorial Hospital of South Bend24, Erasmus University Rotterdam25, Utrecht University26, Royal Devon and Exeter Hospital27, Churchill Hospital28, University Hospital of Wales29, University College London30, Fox Chase Cancer Center31, University of Kansas32, University of Cologne33, Technische Universität München34, Dresden University of Technology35, University of Kiel36, University of Düsseldorf37, Heidelberg University38, University of Ulm39, Hannover Medical School40, University of Münster41, Charité42, University of Würzburg43, University of Paris44, Georgetown University45, Laval University46, University of Padua47, Peter MacCallum Cancer Centre48, University of Chicago49, Harvard University50, University of Delaware51, American Cancer Society52, Medical University of Vienna53, Ohio State University54, University of Southern Denmark55, University of Pisa56, Karolinska Institutet57, Lund University58, City of Hope National Medical Center59, University of California, San Francisco60, Roswell Park Cancer Institute61, Cedars-Sinai Medical Center62
TL;DR: Pathologic characteristics of BRCA1 and BRCa2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.
Abstract: BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 1-14. ©2011 AACR.
TL;DR: A semi-empirical counterpoise-type correction for basis set superposition error (BSSE) in molecular systems is presented, and an atom pair-wise potential corrects for the inter- and intra- molecular BSSE in supermolecular Hartree-Fock (HF) or density functional theory (DFT) calculations.
Abstract: A semi-empirical counterpoise-type correction for basis set superposition error (BSSE) in molecular systems is presented. An atom pair-wise potential corrects for the inter- and intra-molecular BSSE in supermolecular Hartree-Fock (HF) or density functional theory (DFT) calculations. This geometrical counterpoise (gCP) denoted scheme depends only on the molecular geometry, i.e., no input from the electronic wave-function is required and hence is applicable to molecules with ten thousands of atoms. The four necessary parameters have been determined by a fit to standard Boys and Bernadi counterpoise corrections for Hobza’s S66×8 set of non-covalently bound complexes (528 data points). The method’s target are small basis sets (e.g., minimal, split-valence, 6-31G*), but reliable results are also obtained for larger triple-ζ sets. The intermolecular BSSE is calculated by gCP within a typical error of 10%‐30% that proves sufficient in many practical applications. The approach is suggested as a quantitative correction in production work and can also be routinely applied to estimate the magnitude of the BSSE beforehand. The applicability for biomolecules as the primary target is tested for the crambin protein, where gCP removes intramolecular BSSE effectively and yields conformational energies comparable to def2-TZVP basis results. Good mutual agreement is also found with Jensen’s ACP(4) scheme, estimating the intramolecular BSSE in the phenylalanineglycine-phenylalanine tripeptide, for which also a relaxed rotational energy profile is presented. A variety of minimal and double-ζ basis sets combined with gCP and the dispersion corrections DFTD3 and DFT-NL are successfully benchmarked on the S22 and S66 sets of non-covalent interactions. Outstanding performance with a mean absolute deviation (MAD) of 0.51 kcal/mol (0.38 kcal/mol after D3-refit) is obtained at the gCP-corrected HF-D3/(minimal basis) level for the S66 benchmark. The gCP-corrected B3LYP-D3/6-31G* model chemistry yields MAD=0.68 kcal/mol, which represents a huge improvement over plain B3LYP/6-31G* (MAD=2.3 kcal/mol). Application of gCPcorrected B97-D3 and HF-D3 on a set of large protein-ligand complexes prove the robustness of the method. Analytical gCP gradients make optimizations of large systems feasible with small basis sets, as demonstrated for the inter-ring distances of 9-helicene and most of the complexes in Hobza’s S22 test set. The method is implemented in a freely available FORTRAN program obtainable from the author’s website. © 2012 American Institute of Physics .[ http://dx.doi.org/10.1063/1.3700154]
TL;DR: Combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV- 1-infected individuals.
Abstract: Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.
TL;DR: The use of Mtwo and Reciproc instruments resulted in better canal cleanliness in the apical part compared with ProTaper and WaveOne, and all instruments maintained the original canal curvature well and were safe to use.
Abstract: Burklein S, Hinschitza K, Dammaschke T, Schafer E. Shaping ability and cleaning effectiveness of two single-file systems in severely curved root canals of extracted teeth: Reciproc and WaveOne versus Mtwo and ProTaper. Interna- tional Endodontic Journal. Aim To compare shaping ability and cleaning effec- tiveness of two reciprocating single-file systems with Mtwo and ProTaper rotary instruments during the preparation of curved root canals in extracted teeth. Methodology A total of 80 root canals with curva- tures ranging between 25� and 39� were divided into four groups of 20 canals. Based on radiographs taken prior to instrumentation, the groups were balanced with respect to the angle and the radius of canal curvature. Canals were prepared to the following apical sizes: Mtwo: size 35 using the single-length technique; ProTaper: F3, instruments were used in a modified crown-down manner; Reciproc and WaveOne: size 25. Using pre- and post-instrumentation radiographs, straightening of the canal curvatures was determined with a computer image analysis program. Preparation time and instrument failures were also recorded. These data were analysed statistically using anova and Student-Newman-Keuls test. The amounts of debris and smear layer were quantified on the basis of a numerical evaluation scale and were analysed statisti- cally using the Kruskal-Wallis test. Results During preparation no file fractured. All instruments maintained the original canal curvature well with no significant differences between the differ- ent files (P = 0.382). Instrumentation with Reciproc was significantly faster than with all other instruments (P 0.05), while ProTaper showed significantly more residual debris (P 0.05). Conclusions Under the conditions of this study, all instruments maintained the original canal curvature well and were safe to use. The use of Mtwo and Reciproc instruments resulted in better canal cleanli- ness in the apical part compared with ProTaper and WaveOne.
UCL Institute of Neurology1, University of Münster2, Leiden University3, French Institute of Health and Medical Research4, University of British Columbia5, University of London6, University of Iowa7, Central Manchester University Hospitals NHS Foundation Trust8, University of Oxford9, University of Ulm10, Monash University11
TL;DR: On the basis of longitudinal effect size, several objective outcome measures for clinical trials in participants with early HD are recommended and Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes.
Abstract: Summary Background TRACK-HD is a prospective observational biomarker study in premanifest and early Huntington's disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials. Methods We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes. Findings Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants. Interpretation On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group. Funding CHDI/HighQ Foundation Inc.
TL;DR: A meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease identifies novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
University of Paris1, Pierre-and-Marie-Curie University2, Leeds Teaching Hospitals NHS Trust3, Leiden University4, University College Dublin5, Medical University of Vienna6, University of Crete7, Ruhr University Bochum8, Charité9, University of Barcelona10, Rikshospitalet–Radiumhospitalet11, Katholieke Universiteit Leuven12, University of Leeds13, University of California, San Diego14, Maastricht University15, University of Münster16, Royal National Hospital for Rheumatic Diseases17, University of Glasgow18, University of Rochester19, University of Amsterdam20, Sapienza University of Rome21, Oregon Health & Science University22
TL;DR: These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion.
Abstract: Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-infl ammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extraarticular manifestations of PsA. Five overarching principles and a research agenda were defi ned. Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.
Johns Hopkins University1, University of Barcelona2, St George's, University of London3, Maastricht University4, Washington University in St. Louis5, Imperial College London6, University of Virginia7, Baylor University8, Virginia Commonwealth University9, Thomas Jefferson University10, Beaumont Hospital11, University of Bordeaux12, Leipzig University13, University of Oklahoma14, University of Michigan15, Royal Melbourne Hospital16, University College Dublin17, Korea University18, University of Birmingham19, University of Münster20, University of Western Ontario21, Cleveland Clinic22, Harvard University23, University of Pennsylvania24, Northwestern University25, Université de Montréal26, Mayo Clinic27, Icahn School of Medicine at Mount Sinai28, University of California, Los Angeles29, National Yang-Ming University30, Loyola University Chicago31
TL;DR: This is a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA).
Abstract: This is a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). This is endorsed by the governing bodies of the ACC Foundation, the AHA, the ECAS, the EHRA, the STS, the APHRS, and the HRS.
St George's, University of London1, University of Oxford2, University of Newcastle3, University of Edinburgh4, University of Maryland, Baltimore5, University of Texas Health Science Center at Houston6, Erasmus University Rotterdam7, Ludwig Maximilian University of Munich8, University of Iceland9, deCODE genetics10, National Institutes of Health11, University of Washington12, Imperial College London13, Boston University14, University of Virginia15, Fred Hutchinson Cancer Research Center16, Utrecht University17, Autonomous University of Barcelona18, Medical University of Graz19, University of Glasgow20, University of Münster21, National University of Ireland, Galway22, University of Cambridge23, Jagiellonian University24, Katholieke Universiteit Leuven25, Lund University26, University of Copenhagen27, University of Kiel28, University of Dundee29, Instituto Nacional de Saúde Dr. Ricardo Jorge30, Instituto de Medicina Molecular31, Brigham and Women's Hospital32, University Medical Center Utrecht33, Broad Institute34, Karolinska Institutet35, University of Pennsylvania36, McMaster University37, University of Mississippi38, Harvard University39, Group Health Research Institute40, University of Mississippi Medical Center41, Mayo Clinic42
TL;DR: The results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations validated are specific to a stroke subtype, and this finding has two implications.
Abstract: Summary Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.