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News Article | February 15, 2017
Site: www.eurekalert.org

-- Largest imaging study of ADHD to date identifies differences in five regions of the brain, with greatest differences seen in children rather than adults. Attention-deficit hyperactivity disorder (ADHD) is associated with the delayed development of five brain regions and should be considered a brain disorder, according to a study published in The Lancet Psychiatry. The study is the largest to look at the brain volumes of people with ADHD, involving more than 3200 people. The authors say the findings could help improve understanding of the disorder, and might be important in challenging beliefs that ADHD is a label for difficult children or the result of poor parenting. ADHD symptoms include inattention and/or hyperactivity and acting impulsively. The disorder affects more than one in 20 (5.3%) under-18 year olds, and two-thirds of those diagnosed continue to experience symptoms as adults. Previous studies have linked differences in brain volume with the disorder, but small sample sizes mean results have been inconclusive. Areas thought to be involved in ADHD are located in the basal ganglia - a part of the brain that controls emotion, voluntary movement and cognition - and research has previously found that the caudate and putamen regions within the ganglia are smaller in people with ADHD. The new international study measured differences in the brain structure of 1713 people with a diagnosis of ADHD and 1529 people without, all aged between four and 63 years old. All 3242 people had an MRI scan to measure their overall brain volume, and the size of seven regions of the brain that were thought to be linked to ADHD - the pallidum, thalamus, caudate nucleus, putamen, nucleus accumbens, amygdala and hippocampus. The researchers also noted whether those with ADHD had ever taken psychostimulant medication, for example Ritalin. The study found that overall brain volume and five of the regional volumes were smaller in people with ADHD - the caudate nucleus, putamen, nucleus accumbens, amygdala and hippocampus. "These differences are very small - in the range of a few percent - so the unprecedented size of our study was crucial to help identify these. Similar differences in brain volume are also seen in other psychiatric disorders, especially major depressive disorder." said lead author Dr Martine Hoogman, Radboud University Medical Center, Nijmegen, The Netherlands. [1] The differences observed were most prominent in the brains of children with ADHD, but less obvious in adults with the disorder. Based on this, the researchers propose that ADHD is a disorder of the brain, and suggest that delays in the development of several brain regions are characteristic of ADHD. Besides the caudate nucleus and putamen, for which previous studies have already shown links to ADHD, researchers were able to conclusively link the amygdala, nucleus accumbens and hippocampus to ADHD. The researchers hypothesise that the amygdala is associated with ADHD through its role in regulating emotion, and the nucleus accumbens may be associated with the motivation and emotional problems in ADHD via its role in reward processing. The hippocampus' role in the disorder might act through its involvement in motivation and emotion. At the time of their MRI scan, 455 people with ADHD were receiving psychostimulant medication, and looking back further, 637 had had the medication in their lifetime. The different volumes of the five brain regions involved in ADHD were present whether or not people had taken medication, suggesting the differences in brain volumes are not a result of psychostimulants. "The results from our study confirm that people with ADHD have differences in their brain structure and therefore suggest that ADHD is a disorder of the brain," added Dr Hoogman. "We hope that this will help to reduce stigma that ADHD is 'just a label' for difficult children or caused by poor parenting. This is definitely not the case, and we hope that this work will contribute to a better understanding of the disorder." [1] While the study included large numbers of people of all ages, its design means that it cannot determine how ADHD develops throughout life. Therefore, longitudinal studies tracking people with ADHD from childhood to adulthood to see how the brain differences change over time will be an important next step in the research. Writing in a linked Comment Dr Jonathan Posner, Columbia University, USA, said: "[This] is the largest study of its kind and well powered to detect small effect sizes. Large sample sizes are particularly important in the study of ADHD because of the heterogeneity of the disorder both in the biological cause and clinical manifestation... This study represents an important contribution to the field by providing robust evidence to support the notion of ADHD as a brain disorder with substantial effects on the volumes of subcortical nuclei. Future meta-analyses and mega-analyses will need to investigate medication effects as well as the developmental course of volumetric differences in this disorder." The study was funded by the National Institutes of Health. The study is part of the ENIGMA Consortium, where researchers are also studying the structure of the brain in other psychiatric disorders, allowing researchers to define differences and similarities between the disorders. It was conducted by scientists from Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, University of Southern California, University of Groningen, QIMR Berghofer Medical Research Institute, University Medical Center Utrecht, National Human Genome Research Institute, Asociación para la Innovación en Análisis, Gestión y Procesamiento de Datos Científicos y Tecnológicos, University Hospital Aachen, JARA Translational Brain Medicine, Research Center Juelich, Harvard Medical School, The Broad Institute, University of Bergen, Cincinnati Children's Hospital Medical Center, University of California, UC San Diego, University of Tübingen, University of Würzburg, University of Dublin, NYU Langone Medical Center, King's College London, Heidelberg University, Federal University of Rio de Janeiro, University of Zurich, Child Mind Institute, Nathan Kline Institute for Psychiatric Research, Otto-von-Guericke-University, Maastricht University, University Hospital Frankfurt, Haukeland University Hospital, Child and Adolescent Mental Health Center, Beth Israel Deaconess Medical Center, Karakter Child and Adolescent Psychiatry, VU University Amsterdam, Universitat Autònoma de Barcelona, Fundació IMIM, Hospital Universitari Vall d'Hebron, SUNY Upstate Medical University, National Institute of Mental Health. [1] Quote direct from author and cannot be found in the text of the Article. IF YOU WISH TO PROVIDE A LINK FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(17)30049-4/fulltext

News Article | February 15, 2017
Site: www.eurekalert.org

Vitamin D supplements protect against acute respiratory infections including colds and flu, according to a study led by Queen Mary University of London (QMUL) Vitamin D supplements protect against acute respiratory infections including colds and flu, according to a study led by Queen Mary University of London (QMUL). The study provides the most robust evidence yet that vitamin D has benefits beyond bone and muscle health, and could have major implications for public health policy, including the fortification of foods with vitamin D to tackle high levels of deficiency in the UK. The results, published in the BMJ, are based on a new analysis of raw data from around 11,000 participants in 25 clinical trials conducted in 14 countries including the UK, USA, Japan, India, Afghanistan, Belgium, Italy, Australia and Canada. Individually, these trials yielded conflicting results, with some reporting that vitamin D protected against respiratory infections, and others showing no effect. Lead researcher Professor Adrian Martineau from QMUL said: "This major collaborative research effort has yielded the first definitive evidence that vitamin D really does protect against respiratory infections. Our analysis of pooled raw data from each of the 10,933 trial participants allowed us to address the thorny question of why vitamin D 'worked' in some trials, but not in others. "The bottom line is that the protective effects of vitamin D supplementation are strongest in those who have the lowest vitamin D levels, and when supplementation is given daily or weekly rather than in more widely spaced doses. "Vitamin D fortification of foods provides a steady, low-level intake of vitamin D that has virtually eliminated profound vitamin D deficiency in several countries. By demonstrating this new benefit of vitamin D, our study strengthens the case for introducing food fortification to improve vitamin D levels in countries such as the UK where profound vitamin D deficiency is common." Vitamin D - the 'sunshine vitamin' - is thought to protect against respiratory infections by boosting levels of antimicrobial peptides - natural antibiotic-like substances - in the lungs. Results of the study fit with the observation that colds and 'flu are commonest in winter and spring, when levels of vitamin D are at their lowest. They may also explain why vitamin D protects against asthma attacks, which are commonly triggered by respiratory viruses. Daily or weekly supplementation halved the risk of acute respiratory infection in people with the lowest baseline vitamin D levels, below 25 nanomoles per litre (nmol/L). However, people with higher baseline vitamin D levels also benefited, although the effect was more modest (10 per cent risk reduction). Overall, the reduction in risk of acute respiratory infection induced by vitamin D was on a par with the protective effect of injectable 'flu vaccine against 'flu-like illnesses. Acute respiratory infections are a major cause of global morbidity and mortality. Upper respiratory infections such as colds and 'flu are the commonest reason for GP consultations and days off work. Acute lower respiratory infections such as pneumonia are less common, but caused an estimated 2.65 million deaths worldwide in 2013. Vitamin D supplementation is safe and inexpensive, so reductions in acute respiratory infections brought about by vitamin D supplementation could be highly cost-effective. The study was conducted by a consortium of 25 investigators from 21 institutions worldwide* and funded by the National Institute for Health Research. Joel Winston, Public Relations Manager (School of Medicine and Dentistry) Queen Mary University of London j.winston@qmul.ac.uk Tel: +44 (0)20 7882 7943 / +44 (0)7970 096 188 * Institutions involved in the research: Edmond and Lily Safra Children's Hospital (Tel Hashomer, Israel), Geisel School of Medicine at Dartmouth (NH, USA), Harvard School of Public Health (Boston, MA, USA), Jikei University School of Medicine (Tokyo, Japan), Karolinska Institutet (Stockholm, Sweden), Massachusetts General Hospital (Boston, MA, USA), McMaster University (Hamilton, Ontario, Canada), Medical University of Lodz (Poland), QIMR Berghofer Medical Research Institute (Queensland, Australia), Queen Mary University of London (UK), The Pennsylvania State University (Hershey, PA, USA), Università degli Studi di Milano (Milan, Italy), Universitair ziekenhuis Leuven (Belgium), University of Auckland (New Zealand), University of Birmingham (UK), University of Colorado School of Medicine (Aurora, CO, USA), University of Delhi (India), University of Otago (Christchurch, New Zealand), University of Tampere (Finland), University of Tasmania (Australia), Winthrop University Hospital (Mineola, NY, USA). Research paper: 'Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of individual participant data'. Martineau et al. BMJ 2017 Queen Mary University of London (QMUL) is one of the UK's leading universities, and one of the largest institutions in the University of London, with 23,120 students from more than 155 countries. A member of the Russell Group, we work across the humanities and social sciences, medicine and dentistry, and science and engineering, with inspirational teaching directly informed by our research. In the most recent national assessment of the quality of research, we were placed ninth in the UK (REF 2014). As well as our main site at Mile End - which is home to one of the largest self-contained residential campuses in London - we have campuses at Whitechapel, Charterhouse Square, and West Smithfield dedicated to the study of medicine, and a base for legal studies at Lincoln's Inn Fields. We have a rich history in London with roots in Europe's first public hospital, St Barts; England's first medical school, The London; one of the first colleges to provide higher education to women, Westfield College; and the Victorian philanthropic project, the People's Palace at Mile End. Today, as well as retaining these close connections to our local community, we are known for our international collaborations in both teaching and research. QMUL has an annual turnover of £350m, a research income worth £125m (2014/15), and generates employment and output worth £700m to the UK economy each year. The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. The NIHR is the research arm of the NHS. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government's strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world. For further information, visit the NIHR website (http://www. ).

News Article | February 16, 2017
Site: www.eurekalert.org

An immune system proteinase called granzyme A appears to promote arthritic inflammation in mice infected with chikungunya virus, scientists report in a new PLOS Pathogens study. The study also suggested that granzyme A could serve as a potential target for new drugs to treat chikungunya and related viral arthritides in people. Chikungunya virus is transmitted by mosquitoes, with a recent epidemic causing millions of cases globally. While it is rarely fatal, chikungunya can cause severe, chronic polyarthritis (inflammation in multiple joints) and/or polyarthralgia (pain in multiple joints). Current standard anti-inflammatory drug treatment can relieve these symptoms, but they are often not particularly effective. To aid research into potential new treatments, Jane Wilson and Natalie Prow of QIMR Berghofer Medical Research Institute, Australia, and colleagues exploited an adult wild-type mouse model of chikungunya virus infection and diseases previously developed by the group. In the new study, they use RNA-Seq technology to examine in detail the mouse inflammatory responses to infection. They found that genes activated in the mouse model closely mirrored genes known to be activated in infected humans, providing a level of validation of the model. Particularly prominent in the RNA-Seq analysis was the up-regulation of a number of granzymes, a group of proteinases secreted by immune cells that were originally thought to be involved in killing (via apoptosis) virus infected cells or other target cells. However, an emerging consensus supported by the new PLOS Pathogens study, is that some granzymes (particularly granzyme A and K) have a role in promoting inflammation. Exploring further, the scientists showed that mice missing the granzyme A gene, when infected with chikungunya virus, experienced dramatically less foot swelling and arthritis. Furthermore, treating mice with a granzyme A inhibitor also significantly reduced foot swelling and arthritis. They also found elevated granzyme A levels in blood samples taken from non-human primates infected with chikungunya, as well as from human chikungunya patients. Overall the findings suggest that granzyme A could serve as a potential drug target for anti-inflammatory treatments for chikungunya -- and perhaps also for other inflammatory diseases. Further research will be needed to explore this potential and determine how well the new findings can be extended from mice to humans. In your coverage please use this URL to provide access to the freely available article in PLOS Pathogens: http://dx. Citation: Wilson JAC, Prow NA, Schroder WA, Ellis JJ, Cumming HE, Gearing LJ, et al. (2017) RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation. PLoS Pathog 13(2): e1006155. doi:10.1371/journal.ppat.1006155 Funding: The work was primarily funded by the National Health and Medical Research Council (NHMRC), Australia (grant APP613622) . JACW was awarded an Australian Postgraduate Award scholarship by the School of Medicine, University of Queensland. NAP was in part supported by an Advance Queensland Research Fellowship from the Queensland government. AS is a principal research fellow with the NHMRC. BSL3 equipment was funded by the Queensland Tropical Health Alliance. The NHP studies were funded by (i) "Programme d'Investissements d'Avenir" (PIA) under Grant ANR-11-INBS-0008 funding the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France) infrastructure and (ii) the Integrated Chikungunya Research (ICRES) project of the European Union FP7 project grant agreement no. 261202. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.

Fornito A.,Monash University | Zalesky A.,University of Melbourne | Breakspear M.,QIMR Berghofer Medical Research Institute | Breakspear M.,Royal Brisbane and Womens Hospital
Nature Reviews Neuroscience | Year: 2015

Pathological perturbations of the brain are rarely confined to a single locus; instead, they often spread via axonal pathways to influence other regions. Patterns of such disease propagation are constrained by the extraordinarily complex, yet highly organized, topology of the underlying neural architecture; the so-called connectome. Thus, network organization fundamentally influences brain disease, and a connectomic approach grounded in network science is integral to understanding neuropathology. Here, we consider how brain-network topology shapes neural responses to damage, highlighting key maladaptive processes (such as diaschisis, transneuronal degeneration and dedifferentiation), and the resources (including degeneracy and reserve) and processes (such as compensation) that enable adaptation. We then show how knowledge of network topology allows us not only to describe pathological processes but also to generate predictive models of the spread and functional consequences of brain disease. © 2015 Macmillan Publishers Limited. All rights reserved.

Rossjohn J.,Monash University | Rossjohn J.,University of Cardiff | Gras S.,Monash University | Miles J.J.,University of Cardiff | And 4 more authors.
Annual Review of Immunology | Year: 2015

The Major Histocompatibility Complex (MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I-like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system. © 2015 by Annual Reviews. All rights reserved.

Martinet L.,QIMR Berghofer Medical Research Institute | Martinet L.,Institute National Of La Sante Et Of La Recherche Medicale Unite Mixte Of Recherche 1037 | Smyth M.J.,QIMR Berghofer Medical Research Institute | Smyth M.J.,University of Queensland
Nature Reviews Immunology | Year: 2015

Natural killer (NK) cells are innate lymphocytes that are crucial for the control of infections and malignancies. NK cells express a variety of inhibitory and activating receptors that facilitate fine discrimination between damaged and healthy cells. Among them, a family of molecules that bind nectin and nectin-like proteins has recently emerged and has been shown to function as an important regulator of NK cell functions. These molecules include CD226, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), CD96, and cytotoxic and regulatory T cell molecule (CRTAM). In this Review, we focus on the recent advances in our understanding of how these receptors regulate NK cell biology and of their roles in pathologies such as cancer, infection and autoimmunity. © 2015 Macmillan Publishers Limited. All rights reserved.

Mittal D.,QIMR Berghofer Medical Research Institute | Gubin M.M.,University of Washington | Schreiber R.D.,University of Washington | Smyth M.J.,QIMR Berghofer Medical Research Institute | Smyth M.J.,University of Queensland
Current Opinion in Immunology | Year: 2014

The principles of cancer immunoediting have set the foundations for understanding the dual host-protective and tumor sculpting actions of immunity on cancer and establishing the basis for novel individualized cancer immunotherapies. During cancer immunoediting, the host immune system shapes tumor fate in three phases through the activation of innate and adaptive immune mechanisms. In the first phase, Elimination, transformed cells are destroyed by a competent immune system. Sporadic tumor cells that manage to survive immune destruction may then enter an Equilibrium phase where editing occurs. The Escape phase represents the third and final phase of the process, where immunologically sculpted tumors begin to grow progressively, become clinically apparent and establish an immunosuppressive tumor microenvironment. This review focuses on important recent developments that have enhanced our understanding of each phase of the cancer immunoediting process, summarizes the discovery of new predictive and prognostic biomarkers and discusses development of novel and objectively effective cancer immunotherapies. © 2014 Elsevier Ltd.

Nyholt D.R.,QIMR Berghofer Medical Research Institute
Bioinformatics | Year: 2014

The genomics era provides opportunities to assess the genetic overlap across phenotypes at the measured genotype level; however, current approaches require individual-level genome-wide association (GWA) single nucleotide polymorphism (SNP) genotype data in one or both of a pair of GWA samples. To facilitate the discovery of pleiotropic effects and examine genetic overlap across two phenotypes, I have developed a user-friendly web-based application called SECA to perform SNP effect concordance analysis using GWA summary results. The method is validated using publicly available summary data from the Psychiatric Genomics Consortium. © 2014 The Author 2014.

Cloonan N.,QIMR Berghofer Medical Research Institute
BioEssays | Year: 2015

Despite a library full of literature on miRNA biology, core issues relating to miRNA target detection, biological effect, and mode of action remain controversial. This essay proposes that the predominant mechanism of direct miRNA action is translational inhibition, whereas the bulk of miRNA effects are mRNA based. It explores several issues confounding miRNA target detection, and discusses their impact on the dominance of "miRNA seed" dogma and the exploration of non-canonical binding sites. Finally, it makes comparisons between miRNA target prediction and transcription factor binding prediction, and questions the value of characterizing miRNA binding sites based on which miRNA nucleotides are paired with an mRNA. © 2015 The Author. Bioessays published by WILEY Periodicals, Inc.

Whitfield J.B.,QIMR Berghofer Medical Research Institute
Clinical Biochemist Reviews | Year: 2014

Many biochemical traits are recognised as risk factors, which contribute to or predict the development of disease. Only a few are in widespread use, usually to assist with treatment decisions and motivate behavioural change. The greatest effort has gone into evaluation of risk factors for cardiovascular disease and/or diabetes, with substantial overlap as 'cardiometabolic' risk. Over the past few years many genome-wide association studies (GWAS) have sought to account for variation in risk factors, with the expectation that identifying relevant polymorphisms would improve our understanding or prediction of disease; others have taken the direct approach of genomic case-control studies for the corresponding diseases. Large GWAS have been published for coronary heart disease and Type 2 diabetes, and also for associated biomarkers or risk factors including body mass index, lipids, C-reactive protein, urate, liver function tests, glucose and insulin. Results are not encouraging for personal risk prediction based on genotyping, mainly because known risk loci only account for a small proportion of risk. Overlap of allelic associations between disease and marker, as found for low density lipoprotein cholesterol and heart disease, supports a causal association, but in other cases genetic studies have cast doubt on accepted risk factors. Some loci show unexpected effects on multiple markers or diseases. An intriguing feature of risk factors is the blurring of categories shown by the correlation between them and the genetic overlap between diseases previously thought of as distinct. GWAS can provide insight into relationships between risk factors, biomarkers and diseases, with potential for new approaches to disease classification.

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