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Showing papers by "University of Iowa published in 2014"


Journal ArticleDOI
05 Feb 2014-JAMA
TL;DR: Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.
Abstract: Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

7,119 citations


Journal ArticleDOI
Stephan Ripke1, Stephan Ripke2, Benjamin M. Neale2, Benjamin M. Neale1  +351 moreInstitutions (102)
24 Jul 2014-Nature
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

6,809 citations


Journal ArticleDOI
Andrew R. Wood1, Tõnu Esko2, Jian Yang3, Sailaja Vedantam4  +441 moreInstitutions (132)
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

1,872 citations


Journal ArticleDOI
TL;DR: A new statistical model and computer program, replicate MATS (rMATS), designed for detection of differential alternative splicing from replicate RNA-Seq data, which uses a hierarchical model to simultaneously account for sampling uncertainty in individual replicates and variability among replicates.
Abstract: Ultra-deep RNA sequencing (RNA-Seq) has become a powerful approach for genome-wide analysis of pre-mRNA alternative splicing. We previously developed multivariate analysis of transcript splicing (MATS), a statistical method for detecting differential alternative splicing between two RNA-Seq samples. Here we describe a new statistical model and computer program, replicate MATS (rMATS), designed for detection of differential alternative splicing from replicate RNA-Seq data. rMATS uses a hierarchical model to simultaneously account for sampling uncertainty in individual replicates and variability among replicates. In addition to the analysis of unpaired replicates, rMATS also includes a model specifically designed for paired replicates between sample groups. The hypothesis-testing framework of rMATS is flexible and can assess the statistical significance over any user-defined magnitude of splicing change. The performance of rMATS is evaluated by the analysis of simulated and real RNA-Seq data. rMATS outperformed two existing methods for replicate RNA-Seq data in all simulation settings, and RT-PCR yielded a high validation rate (94%) in an RNA-Seq dataset of prostate cancer cell lines. Our data also provide guiding principles for designing RNA-Seq studies of alternative splicing. We demonstrate that it is essential to incorporate biological replicates in the study design. Of note, pooling RNAs or merging RNA-Seq data from multiple replicates is not an effective approach to account for variability, and the result is particularly sensitive to outliers. The rMATS source code is freely available at rnaseq-mats.sourceforge.net/. As the popularity of RNA-Seq continues to grow, we expect rMATS will be useful for studies of alternative splicing in diverse RNA-Seq projects.

1,546 citations


Journal ArticleDOI
Feng Yue1, Feng Yue2, Yong Cheng3, Alessandra Breschi, Jeff Vierstra4, Weisheng Wu1, Weisheng Wu5, Tyrone Ryba6, Tyrone Ryba7, Richard Sandstrom4, Zhihai Ma3, Carrie A. Davis8, Benjamin D. Pope7, Yin Shen2, Dmitri D. Pervouchine, Sarah Djebali, Robert E. Thurman4, Rajinder Kaul4, Eric Rynes4, Anthony Kirilusha9, Georgi K. Marinov9, Brian A. Williams9, Diane Trout9, Henry Amrhein9, Katherine I. Fisher-Aylor9, Igor Antoshechkin9, Gilberto DeSalvo9, Lei Hoon See8, Meagan Fastuca8, Jorg Drenkow8, Chris Zaleski8, Alexander Dobin8, Pablo Prieto, Julien Lagarde, Giovanni Bussotti, Andrea Tanzer10, Olgert Denas11, Kanwei Li11, M. A. Bender4, M. A. Bender12, Miaohua Zhang12, Rachel Byron12, Mark Groudine4, Mark Groudine12, David McCleary2, Long Pham2, Zhen Ye2, Samantha Kuan2, Lee Edsall2, Yi-Chieh Wu13, Matthew D. Rasmussen13, Mukul S. Bansal13, Manolis Kellis14, Manolis Kellis13, Cheryl A. Keller1, Christapher S. Morrissey1, Tejaswini Mishra1, Deepti Jain1, Nergiz Dogan1, Robert S. Harris1, Philip Cayting3, Trupti Kawli3, Alan P. Boyle5, Alan P. Boyle3, Ghia Euskirchen3, Anshul Kundaje3, Shin Lin3, Yiing Lin3, Camden Jansen15, Venkat S. Malladi3, Melissa S. Cline16, Drew T. Erickson3, Vanessa M. Kirkup16, Katrina Learned16, Cricket A. Sloan3, Kate R. Rosenbloom16, Beatriz Lacerda de Sousa17, Kathryn Beal, Miguel Pignatelli, Paul Flicek, Jin Lian18, Tamer Kahveci19, Dongwon Lee20, W. James Kent16, Miguel Santos17, Javier Herrero21, Cedric Notredame, Audra K. Johnson4, Shinny Vong4, Kristen Lee4, Daniel Bates4, Fidencio Neri4, Morgan Diegel4, Theresa K. Canfield4, Peter J. Sabo4, Matthew S. Wilken4, Thomas A. Reh4, Erika Giste4, Anthony Shafer4, Tanya Kutyavin4, Eric Haugen4, Douglas Dunn4, Alex Reynolds4, Shane Neph4, Richard Humbert4, R. Scott Hansen4, Marella F. T. R. de Bruijn22, Licia Selleri23, Alexander Y. Rudensky24, Steven Z. Josefowicz24, Robert M. Samstein24, Evan E. Eichler4, Stuart H. Orkin25, Dana N. Levasseur26, Thalia Papayannopoulou4, Kai Hsin Chang4, Arthur I. Skoultchi27, Srikanta Gosh27, Christine M. Disteche4, Piper M. Treuting4, Yanli Wang1, Mitchell J. Weiss, Gerd A. Blobel28, Xiaoyi Cao2, Sheng Zhong2, Ting Wang29, Peter J. Good30, Rebecca F. Lowdon29, Rebecca F. Lowdon30, Leslie B. Adams30, Leslie B. Adams31, Xiao Qiao Zhou30, Michael J. Pazin30, Elise A. Feingold30, Barbara J. Wold9, James Taylor11, Ali Mortazavi15, Sherman M. Weissman18, John A. Stamatoyannopoulos4, Michael Snyder3, Roderic Guigó, Thomas R. Gingeras8, David M. Gilbert7, Ross C. Hardison1, Michael A. Beer20, Bing Ren2 
20 Nov 2014-Nature
TL;DR: The mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types as mentioned in this paper.
Abstract: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases

1,335 citations


Journal ArticleDOI
TL;DR: MaNGA (Mapping Nearby Galaxies at Apache Point Observatory) as mentioned in this paper employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers).
Abstract: We present an overview of a new integral field spectroscopic survey called MaNGA (Mapping Nearby Galaxies at Apache Point Observatory), one of three core programs in the fourth-generation Sloan Digital Sky Survey (SDSS-IV) that began on 2014 July 1. MaNGA will investigate the internal kinematic structure and composition of gas and stars in an unprecedented sample of 10,000 nearby galaxies. We summarize essential characteristics of the instrument and survey design in the context of MaNGA's key science goals and present prototype observations to demonstrate MaNGA's scientific potential. MaNGA employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers). Two dual-channel spectrographs provide simultaneous wavelength coverage over 3600-10300 A at R ~ 2000. With a typical integration time of 3 hr, MaNGA reaches a target r-band signal-to-noise ratio of 4-8 (A–1 per 2'' fiber) at 23 AB mag arcsec–2, which is typical for the outskirts of MaNGA galaxies. Targets are selected with M * 109 M ☉ using SDSS-I redshifts and i-band luminosity to achieve uniform radial coverage in terms of the effective radius, an approximately flat distribution in stellar mass, and a sample spanning a wide range of environments. Analysis of our prototype observations demonstrates MaNGA's ability to probe gas ionization, shed light on recent star formation and quenching, enable dynamical modeling, decompose constituent components, and map the composition of stellar populations. MaNGA's spatially resolved spectra will enable an unprecedented study of the astrophysics of nearby galaxies in the coming 6 yr.

1,104 citations


Journal ArticleDOI
TL;DR: A new term is recommended, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time.
Abstract: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

1,016 citations



Journal ArticleDOI
TL;DR: Clinical Practice Guidelines for the Management of Hypertension in the Community as mentioned in this paper A Statement by the American Society of hypertension and the International Society of Hyperpharmension (ISH).
Abstract: Clinical Practice Guidelines for the Management of Hypertension in the Community A Statement by the American Society of Hypertension and the International Society of Hypertension

920 citations



Journal ArticleDOI
TL;DR: A systematic review and pooled analysis of individual patient data from prospective cohort studies and a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status found the PHASES score is an easily applicable aid for prediction of the risk of rupture of incidental intracranialAneurysms.
Abstract: Summary Background The decision of whether to treat incidental intracranial saccular aneurysms is complicated by limitations in current knowledge of their natural history. We combined individual patient data from prospective cohort studies to determine predictors of aneurysm rupture and to construct a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status. Methods We did a systematic review and pooled analysis of individual patient data from 8382 participants in six prospective cohort studies with subarachnoid haemorrhage as outcome. We analysed cumulative rupture rates with Kaplan-Meier curves and assessed predictors with Cox proportional-hazard regression analysis. Findings Rupture occurred in 230 patients during 29 166 person-years of follow-up. The mean observed 1-year risk of aneurysm rupture was 1·4% (95% CI 1·1–1·6) and the 5-year risk was 3·4% (2·9–4·0). Predictors were age, hypertension, history of subarachnoid haemorrhage, aneurysm size, aneurysm location, and geographical region. In study populations from North America and European countries other than Finland, the estimated 5-year absolute risk of aneurysm rupture ranged from 0·25% in individuals younger than 70 years without vascular risk factors with a small-sized ( 20 mm) posterior circulation aneurysm. By comparison with populations from North America and European countries other than Finland, Finnish people had a 3·6-times increased risk of aneurysm rupture and Japanese people a 2·8-times increased risk. Interpretation The PHASES score is an easily applicable aid for prediction of the risk of rupture of incidental intracranial aneurysms. Funding Netherlands Organisation for Health Research and Development.

Journal ArticleDOI
TL;DR: In this paper, the authors present results for the equation of state in ($2+1$)-flavor QCD using the highly improved staggered quark action and lattices with temporal extent.
Abstract: We present results for the equation of state in ($2+1$)-flavor QCD using the highly improved staggered quark action and lattices with temporal extent ${N}_{\ensuremath{\tau}}=6$, 8, 10, and 12. We show that these data can be reliably extrapolated to the continuum limit and obtain a number of thermodynamic quantities and the speed of sound in the temperature range 130--400 MeV. We compare our results with previous calculations and provide an analytic parameterization of the pressure, from which other thermodynamic quantities can be calculated, for use in phenomenology. We show that the energy density in the crossover region, $145\text{ }\text{ }\mathrm{MeV}\ensuremath{\le}T\ensuremath{\le}163\text{ }\text{ }\mathrm{MeV}$, defined by the chiral transition, is ${\ensuremath{\epsilon}}_{c}=(0.18--0.5)\text{ }\text{ }\mathrm{GeV}/{\mathrm{fm}}^{3}$, i.e., $(1.2--3.1)\text{ }{\ensuremath{\epsilon}}_{\text{nuclear}}$. At high temperatures, we compare our results with resummed and dimensionally reduced perturbation theory calculations. As a byproduct of our analyses, we obtain the values of the scale parameters ${r}_{0}$ from the static quark potential and ${w}_{0}$ from the gradient flow.

Journal ArticleDOI
Jacy R Crosby1, Gina M. Peloso2, Gina M. Peloso3, Paul L. Auer4, David R. Crosslin5, Nathan O. Stitziel6, Leslie A. Lange7, Yingchang Lu8, Zheng-Zheng Tang7, He Zhang9, George Hindy10, Nicholas G. D. Masca11, Kathleen Stirrups12, Stavroula Kanoni12, Ron Do3, Ron Do2, Goo Jun9, Youna Hu9, Hyun Min Kang9, Chenyi Xue9, Anuj Goel13, Martin Farrall13, Stefano Duga14, Pier Angelica Merlini, Rosanna Asselta14, Domenico Girelli15, Oliviero Olivieri15, Nicola Martinelli15, Wu Yin16, Dermot F. Reilly16, Elizabeth K. Speliotes9, Caroline S. Fox17, Kristian Hveem18, Oddgeir L. Holmen19, Majid Nikpay20, Deborah N. Farlow2, Themistocles L. Assimes21, Nora Franceschini7, Jennifer G. Robinson22, Kari E. North7, Lisa W. Martin23, Mark A. DePristo2, Namrata Gupta2, Stefan A. Escher10, Jan-Håkan Jansson24, Natalie R. van Zuydam25, Colin N. A. Palmer25, Nicholas J. Wareham26, Werner Koch27, Thomas Meitinger27, Annette Peters, Wolfgang Lieb28, Raimund Erbel, Inke R. König29, Jochen Kruppa29, Franziska Degenhardt30, Omri Gottesman8, Erwin P. Bottinger8, Christopher J. O'Donnell17, Bruce M. Psaty31, Bruce M. Psaty5, Christie M. Ballantyne32, Christie M. Ballantyne33, Gonçalo R. Abecasis9, Jose M. Ordovas34, Jose M. Ordovas35, Olle Melander10, Hugh Watkins13, Marju Orho-Melander10, Diego Ardissino, Ruth J. F. Loos8, Ruth McPherson20, Cristen J. Willer9, Jeanette Erdmann29, Alistair S. Hall36, Nilesh J. Samani11, Panos Deloukas37, Panos Deloukas38, Panos Deloukas12, Heribert Schunkert27, James G. Wilson39, Charles Kooperberg40, Stephen S. Rich41, Russell P. Tracy42, Danyu Lin7, David Altshuler3, David Altshuler2, Stacey Gabriel2, Deborah A. Nickerson5, Gail P. Jarvik5, L. Adrienne Cupples43, L. Adrienne Cupples26, Alexander P. Reiner40, Alexander P. Reiner5, Eric Boerwinkle32, Sekar Kathiresan2, Sekar Kathiresan3 
TL;DR: Rare mutations that disrupt AP OC3 function were associated with lower levels of plasma triglycerides and APOC3, and carriers of these mutations were found to have a reduced risk of coronary heart disease.
Abstract: Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10 − 20 ), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8×10 − 10 ). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4×10 − 6 ). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

Journal ArticleDOI
TL;DR: This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs.
Abstract: This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs.

Journal ArticleDOI
TL;DR: This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quInolone action against their enzyme targets, and suggests approaches to designing new drugs that display improved activity against resistant strains.
Abstract: Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone–enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains.

Journal ArticleDOI
TL;DR: The natural history of HD is described, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features, and potential future roles of these biomarkers in clinical trials are reviewed.
Abstract: Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.

Journal ArticleDOI
Paul M. Thompson1, Jason L. Stein2, Sarah E. Medland3, Derrek P. Hibar1  +329 moreInstitutions (96)
TL;DR: The ENIGMA Consortium has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected.
Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Journal ArticleDOI
TL;DR: Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of hypertension as mentioned in this paper, which is based on guidelines from the National Institute of Neurological Disorders and Strochastic Hemorrhage.
Abstract: Clinical practice guidelines for the management of hypertension in the community a statement by the American society of hypertension and the International society of hypertension

Journal ArticleDOI
TL;DR: The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart.
Abstract: In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. While ischaemic events dominate the cardiac complications of diabetes, it is widely recognised that the risk for developing heart failure is also increased in the absence of overt myocardial ischaemia and hypertension or is accelerated in the presence of these comorbidities. These diabetes-associated changes in myocardial structure and function have been called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed to contribute to the development of diabetic cardiomyopathy following analysis of various animal models of type 1 or type 2 diabetes and in genetically modified mouse models. The steady increase in reports presenting novel mechanistic data on this subject expands the list of potential underlying mechanisms. The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart.

Book ChapterDOI
TL;DR: Converging evidence now strongly suggest that deficits in BDNF signaling contribute to the pathogenesis of several major diseases and disorders such as Huntington's disease, Alzheimer's disease and depression, and manipulating BDNF pathways represents a viable treatment approach to a variety of neurological and psychiatric disorders.
Abstract: Among all neurotrophins, brain-derived neurotrophic factor (BDNF) stands out for its high level of expression in the brain and its potent effects on synapses. It is now widely accepted that the main function of BDNF in the adult brain is to regulate synapses, with structural and functional effects ranging from short-term to long-lasting, on excitatory or inhibitory synapses, in many brain regions. The diverse effects of BDNF on brain synapses stem from its complex downstream signaling cascades, as well as the diametrically opposing effects of the pro- and mature form through distinct receptors, TrkB and p75NTR. Many aspects of BDNF cell biology are regulated by neuronal activity. The synergistic interactions between neuronal activity and synaptic plasticity by BDNF make it an ideal and essential regulator of cellular processes that underlie cognition and other complex behaviors. Indeed, numerous studies firmly established that BDNF plays a critical role in hippocampal long-term potentiation (LTP), a long-term enhancement of synaptic efficacy thought to underlie learning and memory. Converging evidence now strongly suggest that deficits in BDNF signaling contribute to the pathogenesis of several major diseases and disorders such as Huntington’s disease, Alzheimer’s disease, and depression. Thus, manipulating BDNF pathways represents a viable treatment approach to a variety of neurological and psychiatric disorders.

Journal ArticleDOI
TL;DR: Perinatal mental illness is a significant complication of pregnancy and the postpartum period and early detection and effective management of perinatal psychiatric disorders are critical for the welfare of women and their offspring.
Abstract: Perinatal mental illness is a significant complication of pregnancy and the postpartum period. These disorders include depression, anxiety disorders, and postpartum psychosis, which usually manifests as bipolar disorder. Perinatal depression and anxiety are common, with prevalence rates for major and minor depression up to almost 20% during pregnancy and the first 3 months postpartum. Postpartum blues are a common but lesser manifestation of postpartum affective disturbance. Perinatal psychiatric disorders impair a woman's function and are associated with suboptimal development of her offspring. Risk factors include past history of depression, anxiety, or bipolar disorder, as well psychosocial factors, such as ongoing conflict with the partner, poor social support, and ongoing stressful life events. Early symptoms of depression, anxiety, and mania can be detected through screening in pregnancy and the postpartum period. Early detection and effective management of perinatal psychiatric disorders are critical for the welfare of women and their offspring.

Journal ArticleDOI
S. Chatrchyan, Khachatryan1, Albert M. Sirunyan, Armen Tumasyan  +2384 moreInstitutions (207)
26 May 2014
TL;DR: In this paper, a description of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices is provided.
Abstract: A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For tt events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of p_T > 0.9GeV is 94% for pseudorapidities of |η| < 0.9 and 85% for 0.9 < |η| < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of p_T = 100GeV emitted at |η| < 1.4, the resolutions are approximately 2.8% in p_T, and respectively, 10μm and 30μm in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10–12μm in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung.

Journal ArticleDOI
TL;DR: The NLRP3 inflammasome is the most thoroughly studied of the inflammaome complexes that have been described thus far, perhaps owing to its disparate assortment of agonists.
Abstract: Inflammasomes continue to generate interest in an increasing number of disciplines owing to their unique ability to integrate a myriad of signals from pathogen- and damage-associated molecular patterns into a proinflammatory response This potent caspase-1-dependent process is capable of activating the innate immune system, initiating pyroptosis (an inflammatory form of programmed cell death), and shaping adaptive immunity The NLRP3 inflammasome is the most thoroughly studied of the inflammasome complexes that have been described thus far, perhaps owing to its disparate assortment of agonists This review highlights our current understanding of the mechanisms of both priming and activation of the NLRP3 inflammasome

Journal ArticleDOI
TL;DR: In this paper, the authors presented the results of a project with the European Research Council and EPLANET (European Union) with the objective of supporting the development of a research network in the field of nuclear energy.
Abstract: Austrian Federal Ministry of Science and Research and the Austrian Science Fund; the Belgian Fonds de la Recherche Scientifique and Fonds voor Wetenschappelijk Onderzoek; the Brazilian Funding Agencies (CNPq, CAPES, FAPERJ, and FAPESP); the Bulgarian Ministry of Education and Science; CERN; the Chinese Academy of Sciences, Ministry of Science and Technology, and National Natural Science Foundation of China; the Colombian Funding Agency (COLCIENCIAS); the Croatian Ministry of Science, Education and Sport, and the Croatian Science Foundation; the Research Promotion Foundation, Cyprus; the Ministry of Education and Research, Recurrent Financing Contract No. SF0690030s09 and European Regional Development Fund, Estonia; the Academy of Finland, Finnish Ministry of Education and Culture, and Helsinki Institute of Physics; the Institut National de Physique Nucleaire et de Physique des Particules/CNRS and Commissariat a l’Energie Atomique et aux Energies Alternatives/CEA, France; the Bundesministerium fur Bildung und Forschung, Deutsche Forschungsgemeinschaft, and Helmholtz-Gemeinschaft Deutscher Forschungszentren, Germany; the General Secretariat for Research and Technology, Greece; the National Scientific Research Foundation and National Innovation Office, Hungary; the Department of Atomic Energy and the Department of Science and Technology, India; the Institute for Studies in Theoretical Physics and Mathematics, Iran; the Science Foundation, Ireland; the Istituto Nazionale di Fisica Nucleare, Italy; the Korean Ministry of Education, Science and Technology and the World Class University program of NRF, Republic of Korea; the Lithuanian Academy of Sciences; the Mexican Funding Agencies (CINVESTAV, CONACYT, SEP, and UASLP-FAI); the Ministry of Business, Innovation and Employment, New Zealand; the Pakistan Atomic Energy Commission; the Ministry of Science and Higher Education and the National Science Centre, Poland; the Fundacao para a Ciencia e a Tecnologia, Portugal; JINR, Dubna, the Ministry of Education and Science of the Russian Federation, the Federal Agency of Atomic Energy of the Russian Federation, Russian Academy of Sciences, and the Russian Foundation for Basic Research; the Ministry of Education, Science and Technological Development of Serbia; the Secretaria de Estado de Investigacion, Desarrollo e Innovacion and Programa Consolider-Ingenio 2010, Spain; the Swiss Funding Agencies (ETH Board, ETH Zurich, PSI, SNF, UniZH, Canton Zurich, and SER); the National Science Council, Taipei; the Thailand Center of Excellence in Physics, the Institute for the Promotion of Teaching Science and Technology of Thailand, Special Task Force for Activating Research and the National Science and Technology Development Agency of Thailand; the Scientific and Technical Research Council of Turkey and the Turkish Atomic Energy Authority; the Science and Technology Facilities Council, United Kingdom; the U.S. Department of Energy and the U.S. National Science Foundation.Individuals have received support from the Marie-Curie program and the European Research Council and EPLANET (European Union); the Leventis Foundation; the A. P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation a la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Council of Science and Industrial Research, India; the Compagnia di San Paolo (Torino); the HOMING PLUS programme of Foundation for Polish Science, cofinanced by EU, Regional Development Fund; and the Thalis and Aristeia programmes cofinanced by EU-ESF and the Greek NSRF.

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TL;DR: Both independently predict problematic daily-life impulsive behaviors, such as substance use, gambling, and delinquency; their joint use has incremental predictive power over the use of either type of measure alone and furthers the understanding of these important, problematic behaviors.
Abstract: Impulsivity is considered a personality trait affecting behavior in many life domains, from recreational activities to important decision making When extreme, it is associated with mental health problems, such as substance use disorders, as well as with interpersonal and social difficulties, including juvenile delinquency and criminality Yet, trait impulsivity may not be a unitary construct We review commonly used self-report measures of personality trait impulsivity and related constructs (eg, sensation seeking), plus the opposite pole, control or constraint A meta-analytic principal-components factor analysis demonstrated that these scales comprise 3 distinct factors, each of which aligns with a broad, higher order personality factor-Neuroticism/Negative Emotionality, Disinhibition versus Constraint/Conscientiousness, and Extraversion/Positive Emotionality/Sensation Seeking Moreover, Disinhibition versus Constraint/Conscientiousness comprise 2 correlated but distinct subfactors: Disinhibition versus Constraint and Conscientiousness/Will versus Resourcelessness We also review laboratory tasks that purport to measure a construct similar to trait impulsivity A meta-analytic principal-components factor analysis demonstrated that these tasks constitute 4 factors (Inattention, Inhibition, Impulsive Decision-Making, and Shifting) Although relations between these 2 measurement models are consistently low to very low, relations between both trait scales and laboratory behavioral tasks and daily-life impulsive behaviors are moderate That is, both independently predict problematic daily-life impulsive behaviors, such as substance use, gambling, and delinquency; their joint use has incremental predictive power over the use of either type of measure alone and furthers our understanding of these important, problematic behaviors Future use of confirmatory methods should help to ascertain with greater precision the number of and relations between impulsivity-related components

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TL;DR: The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies and can be harmonized with the DSM-5 criteria.
Abstract: Author(s): Sachdev, Perminder; Kalaria, Raj; O'Brien, John; Skoog, Ingmar; Alladi, Suvarna; Black, Sandra E; Blacker, Deborah; Blazer, Dan G; Chen, Christopher; Chui, Helena; Ganguli, Mary; Jellinger, Kurt; Jeste, Dilip V; Pasquier, Florence; Paulsen, Jane; Prins, Niels; Rockwood, Kenneth; Roman, Gustavo; Scheltens, Philip; Internationlal Society for Vascular Behavioral and Cognitive Disorders | Abstract: BackgroundSeveral sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.MethodsParticipants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force.ResultsCognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized.ConclusionsThe proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.

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TL;DR: In this paper, the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported using the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods.
Abstract: Observation of the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported. The analysis uses the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods. The data samples correspond to integrated luminosities of 5.1 inverse femtobarns at sqrt(s) = 7 TeV and 19.7 inverse femtobarns at 8 TeV. A clear signal is observed in the diphoton channel at a mass close to 125 GeV with a local significance of 5.7 sigma, where a significance of 5.2 sigma is expected for the standard model Higgs boson. The mass is measured to be 124.70 +/- 0.34 GeV = 124.70 +/- 0.31 (stat) +/- 0.15 (syst) GeV, and the best-fit signal strength relative to the standard model prediction is 1.14 +0.26/-0.23 = 1.14 +/- 0.21 (stat) +0.09/-0.05 (syst) +0.13/-0.09 (theo). Additional measurements include the signal strength modifiers associated with different production mechanisms, and hypothesis tests between spin-0 and spin-2 models.

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01 Dec 2014-Diabetes
TL;DR: It is shown that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding, compatible with the concept that FGF 21 functions physiologically as an insulin sensitizer under conditions of acute refeeded and overfeeding.
Abstract: Fibroblast growth factor (FGF)21 is an endocrine hormone that is expressed in multiple tissues and functions physiologically to maintain energy homeostasis. FGF21 is being pursued as a therapeutic target for diabetes and obesity because of its rapid and potent effects on improving insulin sensitivity. However, whether FGF21 enhances insulin sensitivity under physiologic conditions remains unclear. Here, we show that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding. After a prolonged fast, FGF21 acts as an insulin sensitizer to overcome the peripheral insulin resistance induced by fasting, thereby maximizing glucose uptake. Likewise, FGF21 is produced from the liver during overfeeding and mitigates peripheral insulin resistance. DIO FGF21 liver-specific knockout, but not FGF21 adipose-specific knockout, mice have increased insulin resistance and decreased brown adipose tissue–mediated glucose disposal. These data are compatible with the concept that FGF21 functions physiologically as an insulin sensitizer under conditions of acute refeeding and overfeeding.

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01 Jan 2014-JAMA
TL;DR: Benefit of alpha tocopherol in mild to moderate AD is suggested by slowing functional decline and decreasing caregiver burden.
Abstract: Importance Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. Objective To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. Design, Setting, and Participants Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. Interventions Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Main Outcomes and Measures Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. Results Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). Conclusions and Relevance Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. Trial Registration clinicaltrials.gov Identifier:NCT00235716

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TL;DR: Research to date suggests that the DSM-5 trait model provides reasonable coverage of personality pathology but also suggest areas for continued refinement, which provides a way of evolving psychopathology classification on the basis of research evidence as opposed to clinical authority.
Abstract: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) represents a watershed moment in the history of official psychopathology classification systems because it is the first DSM to feature an empirically based model of maladaptive personality traits. Attributes of patients with personality disorders were discussed by the DSM-5 Personality and Personality Disorders Work Group and then operationalized and refined in the course of an empirical project that eventuated in the construction of the Personality Inventory for DSM-5 (PID-5). We review research to date on the DSM-5 trait model, with a primary aim of discussing how this kind of research could serve to better tether the DSM to data as it continues to evolve. For example, studies to date suggest that the DSM-5 trait model provides reasonable coverage of personality pathology but also suggest areas for continued refinement. This kind of research provides a way of evolving psychopathology classification on the basis of res...