Showing papers by "University of Amsterdam published in 2009"
TL;DR: This article showed that baseline estimation errors are directly reflected in the observed PCR efficiency values and are thus propagated exponentially in the estimated starting concentrations as well as 'fold-difference' results.
Abstract: Despite the central role of quantitative PCR (qPCR) in the quantification of mRNA transcripts, most analyses of qPCR data are still delegated to the software that comes with the qPCR apparatus This is especially true for the handling of the fluorescence baseline This article shows that baseline estimation errors are directly reflected in the observed PCR efficiency values and are thus propagated exponentially in the estimated starting concentrations as well as 'fold-difference' results Because of the unknown origin and kinetics of the baseline fluorescence, the fluorescence values monitored in the initial cycles of the PCR reaction cannot be used to estimate a useful baseline value An algorithm that estimates the baseline by reconstructing the log-linear phase downward from the early plateau phase of the PCR reaction was developed and shown to lead to very reproducible PCR efficiency values PCR efficiency values were determined per sample by fitting a regression line to a subset of data points in the log-linear phase The variability, as well as the bias, in qPCR results was significantly reduced when the mean of these PCR efficiencies per amplicon was used in the calculation of an estimate of the starting concentration per sample
2,652 citations
University of Paris-Sud1, French Institute of Health and Medical Research2, Institut Gustave Roussy3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, University of Gothenburg11, Boston Children's Hospital12, University of Freiburg13, University of California, San Francisco14, Buck Institute for Research on Aging15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Howard Hughes Medical Institute25, Yale University26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, University of Göttingen45, Stony Brook University46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells
2,218 citations
Woolcock Institute of Medical Research1, University of Otago2, University of Cape Town3, Creighton University4, University of Arizona5, University of Groningen6, University of Edinburgh7, McMaster University8, Imperial College London9, University of Leicester10, University of Amsterdam11, University of Washington12, University of Aberdeen13, University of Pittsburgh14
TL;DR: New definitions for asthma control, severity, and exacerbations are developed, based on current treatment principles and clinical and research relevance, to provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.
Abstract: Background: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.Purpose: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.Methods: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.Results: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge ...
1,642 citations
TL;DR: In this article, a life-designing model for career intervention endorses five presuppositions about people and their work lives: contextual possibilities, dynamic processes, non-linear progression, multiple perspectives, and personal patterns.
1,428 citations
Book•
30 Jan 2009TL;DR: What constitutes a distributed operating system and how it is distinguished from a computer network are discussed, and several examples of current research projects are examined in some detail.
Abstract: Distributed operating systems have many aspects in common with centralized ones, but they also differ in certain ways This paper is intended as an introduction to distributed operating systems, and especially to current university research about them After a discussion of what constitutes a distributed operating system and how it is distinguished from a computer network, various key design issues are discussed Then several examples of current research projects are examined in some detail, namely, the Cambridge Distributed Computing System, Amoeba, V, and Eden
1,327 citations
TL;DR: Recent studies revealing that regional and global climatic change may benefit various species of harmful cyanobacteria by increasing their growth rates, dominance, persistence, geographic distributions and activity are reviewed.
Abstract: Cyanobacteria are the Earth's oldest known oxygen-evolving photosynthetic microorganisms, and they have had major impacts on shaping our current atmosphere and biosphere. Their long evolutionary history has enabled cyanobacteria to develop survival strategies and persist as important primary producers during numerous geochemical and climatic changes that have taken place on Earth during the past 3.5 billion years. Today, some cyanobacterial species form massive surface growths or 'blooms' that produce toxins, cause oxygen depletion and alter food webs, posing a major threat to drinking and irrigation water supplies, fishing and recreational use of surface waters worldwide. These harmful cyanobacteria can take advantage of anthropogenically induced nutrient over-enrichment (eutrophication), and hydrologic modifications (water withdrawal, reservoir construction). Here, we review recent studies revealing that regional and global climatic change may benefit various species of harmful cyanobacteria by increasing their growth rates, dominance, persistence, geographic distributions and activity. Future climatic change scenarios predict rising temperatures, enhanced vertical stratification of aquatic ecosystems, and alterations in seasonal and interannual weather patterns (including droughts, storms, floods); these changes all favour harmful cyanobacterial blooms in eutrophic waters. Therefore, current mitigation and water management strategies, which are largely based on nutrient input and hydrologic controls, must also accommodate the environmental effects of global warming.
1,266 citations
TL;DR: Together, the effects of individual mediators on neuronal function and plasticity are integrated, and emerging evidence suggests that there is crosstalk between them that enables fine-tuned responses to diverse challenges.
Abstract: The impact of stress on brain function is increasingly recognized. Various substances are released in response to stress and can influence distinct neuronal circuits, but the functional advantages of having such a diversity of stress mediators remain unclear. Individual neurotransmitter, neuropeptide and steroid stress mediators have specific spatial and temporal niches, but these niches also overlap. In addition, the effects of individual mediators on neuronal function and plasticity are integrated, and emerging evidence suggests that there is crosstalk between them. Together, this results in the stress instruments producing an orchestrated 'symphony' that enables fine-tuned responses to diverse challenges.
1,240 citations
TL;DR: Team process variables were more strongly related to creativity and innovation measured at the team than the individual level, and displayed considerably stronger relationships with self-report measures of innovation compared with independent ratings and objective criteria.
Abstract: This article presents a meta-analysis of team-level antecedents of creativity and innovation in the workplace. Using a general input-process-output model, the authors examined 15 team-level variables researched in primary studies published over the last 30 years and their relation to creativity and innovation. An exhaustive search of the international innovation literature resulted in a final sample (k) of 104 independent studies. Results revealed that team process variables of support for innovation, vision, task orientation, and external communication displayed the strongest relationships with creativity and innovation (rhos between 0.4 and 0.5). Input variables (i.e., team composition and structure) showed weaker effect sizes. Moderator analyses confirmed that relationships differ substantially depending on measurement method (self-ratings vs. independent ratings of innovation) and measurement level (individual vs. team innovation). Team variables displayed considerably stronger relationships with self-report measures of innovation compared with independent ratings and objective criteria. Team process variables were more strongly related to creativity and innovation measured at the team than the individual level. Implications for future research and pragmatic ramifications for organizational practice are discussed in conclusion.
1,218 citations
TL;DR: The role of CLR signalling in regulating adaptive immunity and immunopathogenesis is described and how this knowledge can be harnessed for the development of innovative vaccination approaches is discussed.
Abstract: C-type lectin receptors (CLRs) expressed by dendritic cells are crucial for tailoring immune responses to pathogens. Following pathogen binding, CLRs trigger distinct signalling pathways that induce the expression of specific cytokines which determine T cell polarization fates. Some CLRs can induce signalling pathways that directly activate nuclear factor-kappaB, whereas other CLRs affect signalling by Toll-like receptors. Dissecting these signalling pathways and their effects on host immune cells is essential to understand the molecular mechanisms involved in the induction of adaptive immune responses. In this Review we describe the role of CLR signalling in regulating adaptive immunity and immunopathogenesis and discuss how this knowledge can be harnessed for the development of innovative vaccination approaches.
1,182 citations
TL;DR: A review of modern research on the psychology of emotion regulation can be found in this paper, where the authors classified emotion-regulation strategies in terms of their targets and functions and relevant empirical work is reviewed.
Abstract: The present article reviews modern research on the psychology of emotion regulation. Emotion regulation determines the offset of emotional responding and is thus distinct from emotional sensitivity, which determines the onset of emotional responding. Among the most viable categories for classifying emotion-regulation strategies are the targets and functions of emotion regulation. The emotion-generating systems that are targeted in emotion regulation include attention, knowledge, and bodily responses. The functions of emotion regulation include satisfying hedonic needs, supporting specific goal pursuits, and facilitating the global personality system. Emotion-regulation strategies are classified in terms of their targets and functions and relevant empirical work is reviewed. Throughout this review, emotion regulation emerges as one of the most far-ranging and influential processes at the interface of cognition and emotion.
1,162 citations
Boston Children's Hospital1, Vrije Universiteit Brussel2, University of California, San Francisco3, Nationwide Children's Hospital4, University of Illinois at Urbana–Champaign5, University of Amsterdam6, University of Naples Federico II7, Great Ormond Street Hospital8, University of Mississippi Medical Center9
TL;DR: This document serves as an update of the North American and European societies for Pediatric Gastroenterology, Hepatology, and Nutrition 2009 clinical guidelines for the diagnosis and management of gastroesophageal reflux disease in infants and children and is intended to be applied in daily practice and as a basis for clinical trials.
Abstract: Objective: T o de v elop a North American Society for Pediatric Ga str oen te rol og y , He pat olo gy , and Nut ri tio n (N ASP GH AN) and Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n (ES PGH AN ) int er nat io nal con se ns us on th e di agn os is an d ma nag em ent of gas tr oes op hag eal refl ux and gas tr oes op hag eal re flu x di sea se in th e ped ia tr ic po pu la tio n. Methods: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which de v eloped these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-av ailable e vidence from PubMed, Cumulati ve Index to Nursing and Allied Health Literature, and bibliographies. The committee con v ened in face-to-face meetings 3 times. Consensus was achie v ed for all recommendations through nominal group technique, a structured, quantitati v e method. Articles were e v aluated using the Oxford Centre for Evidence-based Medicine Le vels of Evidence. Using the Oxford Grades of Recommendation, the quality of e vidence of each of the recommendations made by the committee was determined and is summarized in appendices. Results: More than 600 articles were re vie wed for this work. The document provides e vidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population. Conclusions: Th is do cum ent is int end ed to be us ed in dai ly pra cti ce fo r th e de v el op me nt of fut ure cli ni cal pra ct ic e gu ide lin es and as a bas is for cli ni cal tr ia ls . JP GN 49 :49 8 – 54 7, 20 09 . Ke y Wo rd s: Cli nic al pra ct ic e gu id el ine s — Di agn os tic te sts — Ga str oes op hag ea l refl ux (GE R) — Ga str oes op hag ea l refl ux di sea se (GE RD ) — The rap eut ic mod al iti es. # 20 09 by Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n and No rt h Am er ica n So ci ety for Pe dia tri c Ga str oen te rol og y , Hep at ol og y , an d Nu tr iti on
TL;DR: The strongest links were found for parental monitoring, psychological control, and negative aspects of support such as rejection and hostility, accounting for up to 11% of the variance in delinquency.
Abstract: This meta-analysis of 161 published and unpublished manuscripts was conducted to determine whether the association between parenting and delinquency exists and what the magnitude of this linkage is. The strongest links were found for parental monitoring, psychological control, and negative aspects of support such as rejection and hostility, accounting for up to 11% of the variance in delinquency. Several effect sizes were moderated by parent and child gender, child age, informant on parenting, and delinquency type, indicating that some parenting behaviors are more important for particular contexts or subsamples. Although both dimensions of warmth and support seem to be important, surprisingly very few studies focused on parenting styles. Furthermore, fewer than 20% of the studies focused on parenting behavior of fathers, despite the fact that the effect of poor support by fathers was larger than poor maternal support, particularly for sons. Implications for theory and parenting are discussed.
TL;DR: In this paper, the authors demonstrate that emotional expressions affect observers' behavior by triggering inferential processes and/or affective reactions in them, and propose a new framework that can account for existing findings and guide future research.
Abstract: The idea that emotions regulate social interaction is increasingly popular. But exactly how do emotions do this? To address this question, I draw on research on the interpersonal effects of emotions on behavior in personal relationships, parent–child interactions, conflict, negotiation, and leadership, and propose a new framework that can account for existing findings and guide future research: the emotions as social information (EASI) model. I demonstrate that emotional expressions affect observers' behavior by triggering inferential processes and/or affective reactions in them. The predictive strength of these two processes—which may inspire different behaviors—depends on the observer's information processing and on social-relational factors. Examples of moderators that determine the relative predictive strength of inferences and affective reactions include power, need for cognitive closure, time pressure, display rules, and the appropriateness and target of the emotional expression, which are all discu...
University of Toronto1, University of Turin2, Imperial College London3, Leicester General Hospital4, John Radcliffe Hospital5, Université de Montréal6, University of Washington7, LSU Health Sciences Center Shreveport8, Leiden University9, Columbia University10, Case Western Reserve University11, Mayo Clinic12, University of Amsterdam13, Vanderbilt University14, Western Infirmary15, German Cancer Research Center16, Johns Hopkins University17, St. Vincent's Health System18, Scott & White Hospital19, University of Florida20, University of North Carolina at Chapel Hill21, University of Alabama at Birmingham22, Jikei University School of Medicine23, The Chinese University of Hong Kong24, Nanjing University25, Austral University of Chile26, Juntendo University27, Peking University28, Erasmus University Rotterdam29, Wakayama Medical University30
TL;DR: In this article, a new classification for IgA nephropathy is presented by an international consensus working group and the goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease.
University of Milano-Bicocca1, University of Paris2, University of Brescia3, University of Bologna4, University of Lausanne5, Queen Mary University of London6, Ghent University7, University of Barcelona8, University of Glasgow9, Istanbul University10, Katholieke Universiteit Leuven11, Hannover Medical School12, University of Manchester13, University of Oslo14, Joseph Fourier University15, Gdańsk Medical University16, University of Copenhagen17, University of Münster18, University of Valencia19, Complutense University of Madrid20, University of Erlangen-Nuremberg21, Maastricht University22, University of Amsterdam23, University of Milan24
TL;DR: The objective of this study was to establish a baseline for the design of a systematic literature review of this type of treatment for high blood pressure using a simple, straightforward, and scalable procedure.
Abstract: Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit
TL;DR: A previously uncharacterized IL-22-producing human helper T cell population that coexpressed the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10 is described, which may be important in skin homeostasis and pathology.
Abstract: Interleukin 22 (IL-22) is a member of the IL-10 cytokine family that is involved in inflammatory and wound healing processes. Originally considered a T helper type 1 (T(H)1)-associated cytokine, IL-22 has since been shown to be produced mainly by IL-17-producing helper T cells (T(H)-17 cells). Here we describe a previously uncharacterized IL-22-producing human helper T cell population that coexpressed the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10. These cells were distinct from both T(H)-17 cells and T(H)1 cells. Downregulation of either the aryl hydrocarbon receptor (AHR) or the transcription factor RORC by RNA-mediated interference affected IL-22 production, whereas IL-17 production was affected only by downregulation of RORC by RNA-mediated interference. AHR agonists substantially altered the balance of IL-22- versus IL-17-producing cells. This subset of IL-22-producing cells may be important in skin homeostasis and pathology.
University College Dublin1, Massachusetts Institute of Technology2, Broad Institute3, University of Aveiro4, University of Aberdeen5, Boston University6, University of Minnesota7, Duke University8, Imperial College London9, Stanford University10, University of Exeter11, Leibniz Association12, University of Amsterdam13, Wellcome Trust Sanger Institute14, University of Illinois at Urbana–Champaign15, Stony Brook University16, Newcastle University17, University of Iowa18, University of Sheffield19, University of Texas Health Science Center at Houston20
TL;DR: There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence in Candida albicans species.
Abstract: Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.
TL;DR: For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin, and these reductions were predictive of event rates irrespective of the lipid endpoint used.
TL;DR: An interactive diagram is developed with the aim to display all of the currently known anatomical connections of the rat parahippocampal–hipp hippocampal network and discuss the functional implications of some relatively underexposed connections.
Abstract: Converging evidence suggests that each parahippocampal and hippocampal subregion contributes uniquely to the encoding, consolidation and retrieval of declarative memories, but their precise roles remain elusive. Current functional thinking does not fully incorporate the intricately connected networks that link these subregions, owing to their organizational complexity; however, such detailed anatomical knowledge is of pivotal importance for comprehending the unique functional contribution of each subregion. We have therefore developed an interactive diagram with the aim to display all of the currently known anatomical connections of the rat parahippocampal-hippocampal network. In this Review, we integrate the existing anatomical knowledge into a concise description of this network and discuss the functional implications of some relatively underexposed connections.
TL;DR: In this article, a scale to measure computer and videogame addiction was developed and validated in two independent samples of adolescent gamers (N = 352 and N = 369) using a second-order factor model.
Abstract: The aim of this study was to develop and validate a scale to measure computer and videogame addiction. Inspired by earlier theories and research on game addiction, we created 21 items to measure seven underlying criteria (i.e., salience, tolerance, mood modification, relapse, withdrawal, conflict, and problems). The dimensional structure of the scale was investigated in two independent samples of adolescent gamers (N = 352 and N = 369). In both samples, a second-order factor model described our data best. The 21-item scale, as well as a shortened 7-item version, showed high reliabilities. Furthermore, both versions showed good concurrent validity across samples, as indicated by the consistent correlations with usage, loneliness, life satisfaction, social competence, and aggression.
TL;DR: The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapyplus 3 years of androgens suppression in the treatment of locally advanced prostate cancer.
Abstract: Background The combination of radiotherapy plus long-term medical suppression of androgens (≥2 years) improves overall survival in patients with locally advanced prostate cancer We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer Methods We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 25 years of further treatment with a luteinizing hormone–releasing hormone agonist (long-term suppression) An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 135 for overall survival, with a one-sided alpha level of 005 An interim analysis showed futility, and the results are presented with an a
University of Virginia1, San Diego State University2, Uppsala University3, Sun Yat-sen University4, University of Sydney5, University of Warsaw6, University of Porto7, City University of New York8, Humboldt University of Berlin9, Iwate Prefectural University10, Transilvania University of Brașov11, University of Amsterdam12, Eötvös Loránd University13, University of Padua14, Harvard University15, University of Washington16
TL;DR: It is suggested that implicit stereotypes and sex differences in science participation and performance are mutually reinforcing, contributing to the persistent gender gap in science engagement.
Abstract: About 70% of more than half a million Implicit Association Tests completed by citizens of 34 countries revealed expected implicit stereotypes associating science with males more than with females. We discovered that nation-level implicit stereotypes predicted nation-level sex differences in 8th-grade science and mathematics achievement. Self-reported stereotypes did not provide additional predictive validity of the achievement gap. We suggest that implicit stereotypes and sex differences in science participation and performance are mutually reinforcing, contributing to the persistent gender gap in science engagement.
University of Oxford1, Imperial College London2, Université de Montréal3, University of Washington4, University of Turin5, Leicester General Hospital6, LSU Health Sciences Center Shreveport7, Leiden University8, University of Toronto9, Columbia University10, Case Western Reserve University11, Mayo Clinic12, University of Amsterdam13, Vanderbilt University14, Western Infirmary15, German Cancer Research Center16, Johns Hopkins University17, St. Vincent's Health System18, Scott & White Hospital19, University of Florida20, University of North Carolina at Chapel Hill21, University of Alabama at Birmingham22, Jikei University School of Medicine23, The Chinese University of Hong Kong24, Nanjing University25, Austral University of Chile26, Juntendo University27, Peking University28, Erasmus University Rotterdam29, Wakayama Medical University30
TL;DR: A unique approach for the pathological classification of a glomerular disease, IgA nephropathy, is developed, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility.
TL;DR: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional doses, without additional toxic effects.
Abstract: BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)
TL;DR: Oral administration of the β-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24 h later and prevented the return of fear.
Abstract: Animal studies have shown that fear memories can change when recalled, a process referred to as reconsolidation. We found that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24 h later and prevented the return of fear. Disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders.
TL;DR: In this article, the state of the literature on the consequences of online communication technologies (e.g., instant messaging) for adolescents' social connectedness and well-being is discussed.
Abstract: Adolescents are currently the defining users of the Internet. They spend more time online than adults do, and they use the Internet for social interaction more often than adults do. This article discusses the state of the literature on the consequences of online communication technologies (e.g., instant messaging) for adolescents' social connectedness and well-being. Whereas several studies in the 1990s suggested that Internet use is detrimental, recent studies tend to report opposite effects. We first explain why the results of more recent studies diverge from those of earlier studies. Then, we discuss a viable hypothesis to explain the recent findings: the Internet-enhanced self-disclosure hypothesis. Finally, we discuss some contingent factors that may deserve special attention in future research.
TL;DR: Recording neuron ensembles in the rat medial prefrontal cortex to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts found that learning influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network.
Abstract: Slow-wave sleep (SWS) is important for memory consolidation. During sleep, neural patterns reflecting previously acquired information are replayed. One possible reason for this is that such replay exchanges information between hippocampus and neocortex, supporting consolidation. We recorded neuron ensembles in the rat medial prefrontal cortex (mPFC) to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts. In general, reactivation of learning-related patterns occurred in distinct, highly synchronized transient bouts, mostly simultaneous with hippocampal sharp wave/ripple complexes (SPWRs), when hippocampal ensemble reactivation and cortico-hippocampal interaction is enhanced. During sleep following learning of a new rule, mPFC neural patterns that appeared during response selection replayed prominently, coincident with hippocampal SPWRs. This was learning dependent, as the patterns appeared only after rule acquisition. Therefore, learning, or the resulting reliable reward, influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network.
TL;DR: Investigation of the contribution of microRNA-146a, identified in the pilot expression profiling step, to the pathogenesis of systemic lupus erythematosus revealed a negative regulator of innate immunity, which provides potential novel strategies for therapeutic intervention.
Abstract: Objective
MicroRNA have recently been identified as regulators that modulate target gene expression and are involved in shaping the immune response. This study was undertaken to investigate the contribution of microRNA-146a (miR-146a), which was identified in the pilot expression profiling step, to the pathogenesis of systemic lupus erythematosus (SLE).
Methods
TaqMan microRNA assays of peripheral blood leukocytes were used for comparison of expression levels of microRNA between SLE patients and controls. Transfection and stimulation of cultured cells were conducted to determine the biologic function of miR-146a. Bioinformatics prediction and validation by reporter gene assay and Western blotting were performed to identify miR-146a targets.
Results
Profiling of 156 miRNA in SLE patients revealed the differential expression of multiple microRNA, including miR-146a, a negative regulator of innate immunity. Further analysis showed that underexpression of miR-146a negatively correlated with clinical disease activity and with interferon (IFN) scores in patients with SLE. Of note, overexpression of miR-146a reduced, while inhibition of endogenous miR-146a increased, the induction of type I IFNs in peripheral blood mononuclear cells (PBMCs). Furthermore, miR-146a directly repressed the transactivation downstream of type I IFN. At the molecular level, miR-146a could target IFN regulatory factor 5 and STAT-1. More importantly, introduction of miR-146a into the patients' PBMCs alleviated the coordinate activation of the type I IFN pathway.
Conclusion
The microRNA miR-146a is a negative regulator of the IFN pathway. Underexpression of miR-146a contributes to alterations in the type I IFN pathway in lupus patients by targeting the key signaling proteins. The findings provide potential novel strategies for therapeutic intervention.
TL;DR: IgG4 by itself is unlikely to be a cause of allergic symptoms, but the presence of allergen‐specific IgG4 indicates that anti‐inflammatory, tolerance‐inducing mechanisms have been activated.
Abstract: Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as 'Fab-arm exchange', results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.