Arts & Sciences Brown School McKelvey School Medicine

WashU weekly Neuroscience publications

“Widely Metastatic Choroid Plexus Carcinoma Associated with Novel TP53 Somatic Mutation” (2018) World Neurosurgery

Widely Metastatic Choroid Plexus Carcinoma Associated with Novel TP53 Somatic Mutation
(2018) World Neurosurgery, 119, pp. 233-236. 

Baksh, B.S.a , Sinha, N.b , Salehi, A.a , Han, R.H.a , Miller, B.A.a d , Dahiya, S.b , Gauvain, K.M.c , Limbrick, D.D., Jr.a

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
b Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States
c Division of Hematology-Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
d Department of Neurosurgery, University of Kentucky Hospital, 800 Rose St., Lexington, KY 40536, United States

Abstract
Background: Choroid plexus carcinoma (CPC) is a rare, malignant tumor occurring more commonly in children than adults. This case report describes the clinical course of a 3-year-old boy with a rare case of metastatic CPC with a novel TP53 mutation. Case Description: A 3-year-old boy presented with postconcussive symptoms after a fall. Computed tomography and magnetic resonance imaging revealed lesions in the suprasellar cistern, left lateral ventricle, and cauda equina. The tumor was diagnosed as choroid plexus carcinoma with a novel TP53 V216M somatic mutation. The patient underwent resection of the left lateral ventricle lesion. Conclusion: We describe a case of CPC with highly metastatic characteristics and a novel TP53 mutation. Our report implicates TP53 in the pathogenesis of pediatric CPC, and we emphasize that CPC in children should prompt careful consideration of TP53 status to inform prognosis and clinical treatment. © 2018 Elsevier Inc.

Author Keywords
Choroid plexus carcinoma;  Metastatic;  Pediatric brain tumor;  TP53

Document Type: Article
Source: Scopus

“Interactions of the immune and sensory nervous systems in atopy” (2018) FEBS Journal

Interactions of the immune and sensory nervous systems in atopy
(2018) FEBS Journal, 285 (17), pp. 3138-3151. 

Oetjen, L.K.a b , Kim, B.S.a b c d

a Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States
b Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
A striking feature underlying all atopic disorders, such as asthma, atopic dermatitis, and food allergy, is the presence of pathologic sensory responses, reflexes, and behaviors. These symptoms, exemplified by chronic airway irritation and cough, chronic itch and scratching, as well as gastrointestinal discomfort and dysfunction, are often cited as the most debilitating aspects of atopic disorders. Emerging studies have highlighted how the immune system shapes the scope and intensity of sensory responses by directly modulating the sensory nervous system. Additionally, factors produced by neurons have demonstrated novel functions in propagating atopic inflammation at barrier surfaces. In this review, we highlight new studies that have changed our understanding of atopy through advances in characterizing the reciprocal interactions between the immune and sensory nervous systems. © 2018 Federation of European Biochemical Societies

Author Keywords
allergy;  asthma;  atopic dermatitis;  atopy;  cytokine;  neuroimmunology;  sensory nervous system

Document Type: Review
Source: Scopus

“Validation of diffusion tensor imaging measures of nigrostriatal neurons in macaques” (2018) PLoS ONE

Validation of diffusion tensor imaging measures of nigrostriatal neurons in macaques
(2018) PLoS ONE, 13 (9), art. no. e0202201, . 

Shimony, J.S.a b , Rutlin, J.a , Karimi, M.c , Tian, L.c , Snyder, A.Z.a c , Loftin, S.K.c , Norris, S.A.c , Perlmutter, J.S.a b c d e

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
e Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective Interpretation of diffusion MRI in the living brain requires validation against gold standard histological measures. We compared diffusion values of the nigrostriatal tract to PET and histological results in non-human primates (NHPs) with varying degrees of unilateral nigrostriatal injury induced by MPTP, a toxin selective for dopaminergic neurons. Methods Sixteen NHPs had MRI and PET scans of three different presynaptic radioligands and blinded video-based motor ratings before and after unilateral carotid artery infusion of variable doses of MPTP. Diffusion measures of connections between midbrain and striatum were calculated. Then animals were euthanized to quantify striatal dopamine concentration, stereologic measures of striatal tyrosine hydroxylase (TH) immunostained fiber density and unbiased stereologic counts of TH stained nigral cells. Results Diffusion measures correlated with MPTP dose, nigral TH-positive cell bodies and striatal TH-positive fiber density but did not correlate with in vitro nigrostriatal terminal field measures or in vivo PET measures of striatal uptake of presynaptic markers. Once nigral TH cell count loss exceeded 50% the stereologic terminal field measures reached a near zero floor effect but the diffusion measures continued to correlate with nigral cell counts. Conclusion Diffusion measures in the nigrostriatal tract correlate with nigral dopamine neurons and striatal fiber density, but have the same relationship to terminal field measures as a previous report of striatal PET measures of presynaptic neurons. These diffusion measures have the potential to act as non-invasive index of the severity of nigrostriatal injury. Diffusion imaging of the nigrostriatal tract could potentially have diagnostic value in humans with Parkinson disease or related disorders. © 2018 Shimony et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus
Access Type: Open Access

“GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia” (2018) Nature Neuroscience

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia
(2018) Nature Neuroscience, 21 (9), pp. 1161-1170. 

Pasman, J.A.a , Verweij, K.J.H.a b , Gerring, Z.c , Stringer, S.d , Sanchez-Roige, S.e , Treur, J.L.f , Abdellaoui, A.b , Nivard, M.G.g , Baselmans, B.M.L.g , Ong, J.-S.c , Ip, H.F.g , van der Zee, M.D.g , Bartels, M.g , Day, F.R.h , Fontanillas, P.i , Elson, S.L.i , de Wit, H.j , Davis, L.K.k , MacKillop, J.l , Derringer, J.L.m , Branje, S.J.T.n , Hartman, C.A.o , Heath, A.C.p , van Lier, P.A.C.q , Madden, P.A.F.p , Mägi, R.r , Meeus, W.n , Montgomery, G.W.s , Oldehinkel, A.J.o , Pausova, Z.t , Ramos-Quiroga, J.A.u v w x , Paus, T.y z , Ribases, M.u v w , Kaprio, J.aa , Boks, M.P.M.ab , Bell, J.T.ac , Spector, T.D.ac , Gelernter, J.ad , Boomsma, D.I.g , Martin, N.G.c , MacGregor, S.c , Perry, J.R.B.h , Palmer, A.A.e ae , Posthuma, D.d , Munafò, M.R.f af , Gillespie, N.A.c ag , Derks, E.M.c , Vink, J.M.a , the 23andMe Research Teamah , The Substance Use Disorders Working Group of the Psychiatric Genomics Consortiumah , International Cannabis Consortiumai

a Behavioural Science Institute, Radboud University, Nijmegen, Netherlands
b Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, Netherlands
c Genetic Epidemiology, Statistical Genetics, and Translational Neurogenomics Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
d Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
e Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
f MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
g Department of Biological Psychology/Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
h MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
i 23andMe, Inc., Mountain View, CA, United States
j Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
k Vanderbilt Genetics Institute; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, United States
l Peter Boris Centre for Addictions Research and Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University/St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada
m Department of Psychology, University of Illinois Urbana-Champaign, Champaign, IL, United States
n Department of Youth and Family, Utrecht University, Utrecht, Netherlands
o Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
p Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
q Department of Developmental Psychology and EMGO Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
r Estonian Genome Center, University of Tartu, Tartu, Estonia
s Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
t Hospital for Sick Children, Toronto, ON, Canada
u Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
v Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain
w Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain
x Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
y Rotman Research Institute, Baycrest, Toronto, ON, Canada
z Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada
aa Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland
ab Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
ac Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
ad Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
ae Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States
af UK Centre for Tobacco and Alcohol Studies and School of Experimental Psychology, University of Bristol, Bristol, United Kingdom
ag Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health–related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health. © 2018, The Author(s).

Document Type: Article
Source: Scopus

“Phase 2 trial of ibudilast in progressive multiple sclerosis” (2018) New England Journal of Medicine

Phase 2 trial of ibudilast in progressive multiple sclerosis
(2018) New England Journal of Medicine, 379 (9), pp. 846-855. 

Fox, R.J.a , Coffey, C.S.g , Conwit, R.h , Cudkowicz, M.E.i , Gleason, T.a , Goodman, A.m , Klawiter, E.C.j , Matsuda, K.u , McGovern, M.i , Naismith, R.T.x , Ashokkumar, A.i , Barnes, J.g , Ecklund, D.g , Klingner, E.g , Koepp, M.g , Long, J.D.g , Natarajan, S.a , Thornell, B.i , Yankey, J.g , Bermel, R.A.a , Debbins, J.P.y , Huang, X.b , Jagodnik, P.a , Lowe, M.J.b , Nakamura, K.c , Narayanan, S.z , Sakaie, K.E.b , Thoomukuntla, B.c , Zhou, X.aa , Krieger, S.n , Alvarez, E.ab , Apperson, M.v , Bashir, K.ac , Cohen, B.A.ad , Coyle, P.K.r , Delgado, S.ae , Dewitt, L.D.af , Flores, A.ag , Giesser, B.S.w , Goldman, M.D.ah , Jubelt, B.s , Lava, N.ai , Lynch, S.G.aj , Moses, H.ak , Ontaneda, D.a , Perumal, J.S.c o , Racke, M.d e , Repovic, P.l , Riley, C.S.p , Severson, C.k , Shinnar, S.q , Suski, V.al , Weinstock-Guttman, B.t , Yadav, V.am , Zabeti, A.f

a Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave., JJ36, Cleveland, OH 44195, United States
b Imaging Institute, United States
c Department of Biomedical Engineering, United States
d Cleveland Clinic, Cleveland, United States
e Ohio State University, Columbus, United States
f University of Cincinnati, Cincinnati, United States
g Data Coordinating Center, Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), University of Iowa, Iowa City, United States
h National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
i Clinical Coordinating Center, NeuroNEXT, Massachusetts General Hospital, Neurological Clinical Research Institute, United States
j Department of Neurology, Massachusetts General Hospital, Harvard Medical School, United States
k Brigham and Women’s Hospital, Boston, United States
l Swedish Medical Center at Seattle, Seattle, United States
m University of Rochester Medical Center, Rochester, United States
n Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, United States
o Weill Cornell Medical College, United States
p Columbia University Medical Center, United States
q Montefiore Medical Center, Albert Einstein College of Medicine, United States
r State University of New York (SUNY) at Stony Brook, Stony Brook, United States
s SUNY Upstate Medical University, Syracuse, United States
t SUNY at Buffalo, Buffalo, United States
u MediciNova, San Diego, United States
v University of California at Davis, Sacramento, United States
w University of California at Los Angeles, Los Angeles, CA, United States
x Washington University School of Medicine, St. Louis, United States
y Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
z NeuroRx Research, Montreal, United States
aa School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
ab University of Colorado Denver, Aurora, United States
ac University of Alabama at Birmingham, Birmingham, United States
ad Feinberg School of Medicine, Northwestern University, Chicago, United States
ae University of Miami Miller School of Medicine, Miami, United States
af University of Utah, Salt Lake City, United States
ag University of Texas, Southwestern Medical Center, Dallas, United States
ah University of Virginia at Charlottesville, Charlottesville, United States
ai Emory University, Atlanta, United States
aj University of Kansas Medical Center, Kansas City, United States
ak Vanderbilt University, Nashville, United States
al University of Pittsburgh Medical Center, Pittsburgh, United States
am Oregon Health and Science University, Portland, United States

Abstract
BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (=100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.) right © 2018 Massachusetts Medical Society.

Document Type: Article
Source: Scopus

“Trial designs for chemotherapy-induced peripheral neuropathy prevention” (2018) Neurology

Trial designs for chemotherapy-induced peripheral neuropathy prevention
(2018) Neurology, 91 (9), pp. 403-413. Cited 1 time.

Gewandter, J.S.a , Brell, J.b , Cavaletti, G.c , Dougherty, P.M.a d , Evans, S.e , Howie, L.f , McDermott, M.P.a , O’Mara, A.g , Gordon Smith, A.h , Dastros-Pitei, D.i , Gauthier, L.R.j , Haroutounian, S.k , Jarpe, M.l , Katz, N.P.m n , Loprinzi, C.o , Richardson, P.p , Lavoie-Smith, E.M.r , Wen, P.Y.p , Turk, D.C.s , Dworkin, R.H.a , Freeman, R.q

a University of RochesterNY, United States
b MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, United States
c University of Milano-Bicocca, Monza, Italy
d MD Anderson Cancer Center, Houston, TX, United States
e Milkin Institute School of Public Health, George Washington University, Washington, DC, United States
f Division of Oncology Products, US Food and Drug Administration, Silver Spring, United States
g National Institutes of Health, Bethesda, MD, United States
h Virginia Commonwealth University, Richmond, United States
i Mundipharma R and D Limited, Cambridge, United Kingdom
j Université LavalQC, Canada
k Washington University, St. Louis, MO, United States
l Regenacy Pharmaceuticals, Boston, United States
m Analgesic Solutions, Natick, United States
n Tufts University, Boston, MA, United States
o Mayo Clinic, Rochester, MN, United States
p Dana-Farber/Brigham and Women’s Cancer Center, United States
q Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
r University of Michigan, Ann Arbor, United States
s University of Washington, Seattle, United States

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)-Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies. © 2018 American Academy of Neurology.

Document Type: Review
Source: Scopus

“Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels” (2018) Alzheimer’s Research and Therapy

Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels
(2018) Alzheimer’s Research and Therapy, 10 (1), art. no. 86, . 

Maxwell, T.J.a , Corcoran, C.b , Del-Aguila, J.L.c , Budde, J.P.c , Deming, Y.c , Cruchaga, C.c , Goate, A.M.d e , Kauwe, J.S.K.f

a Computational Biology Institute, George Washington University, 45085 University Drive, Ashburn, VA 20148, United States
b Department of Mathematics and Statistics, Utah State University, 3900 Old Main Hill, Logan, UT 84322, United States
c Department of Psychiatry, Washington University, School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, United States
d Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, ICAHN 10-52, New York, NY 10029, United States
e Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, ICAHN 10-52, New York, NY 10029, United States
f Department of Biology, Brigham Young University, 4146 LSB, Provo, UT 84602, United States

Abstract
Background: A relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus. Relationship quantitative trait loci (rQTL) are often involved in gene-by-gene (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G. Methods: We performed genome-wide association studies to identify rQTL between tau and Aβ42 and ptau and Aβ42 with over 3000 individuals using age, gender, series, APOE ϵ2, APOE ϵ4, and two principal components for population structure as covariates. Each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model. Parametric bootstrapping was used to assess significance. Results: We found four significant tau/Aβ42 rQTL from three unique locations and six ptau/Aβ42 rQTL from five unique locations. G×G screens with these rQTL produced four significant G×G interactions (one Aβ42, two ptau, and one tau) with four rQTL where each second locus was from a unique location. On follow-up, rs1036819 and rs74025622 were associated with Alzheimer’s disease (AD) case/control status; rs15205 and rs79099429 were associated with rate of decline. Conclusions: The two most significant rQTL (rs8027714 and rs1036819) for ptau/Aβ42 are on different chromosomes and both are strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/Aβ42 relationship but may suggest that these two loci share a pathway. In addition to a ptau/Aβ42 rQTL and association with AD case/control status, rs1036819 is a strong rQTL for case/control status/Aβ42 and for tau/Aβ42. It resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/Aβ42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a β-secretase enzyme that initiates production of the β-amyloid peptide involved in AD and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important AD endophenotypes and some are due to interactions with other loci. Some affect the risk of AD and/or rate of progression. © 2018 The Author(s).

Author Keywords
Alzheimer’s;  AΒ42;  G×G;  p-tau (3 to 10);  rQTL;  Tau

Document Type: Article
Source: Scopus

“Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease” (2018) Neurology

Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease
(2018) Neurology, 91 (9), pp. e859-e866. 

Aschenbrenner, A.J.a , Gordon, B.A.a c d , Benzinger, T.L.S.a d , Morris, J.C.a b , Hassenstab, J.J.a b c

a Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St, Louis, MO, United States
b Department of Neurology, Washington University in St, Louis, MO, United States
c Department of Psychological and Brain Sciences, Washington University in St, Louis, MO, United States
d Department of Radiology, Washington University in St, Louis, MO, United States

Abstract
Objective To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline. Methods A total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18 F-AV-1451) tau PET scan, a florbetapir (18 F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed. Results Results from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning. Conclusions Together, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression. © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

“Learning-based Approaches for Controlling Neural Spiking” (2018) Proceedings of the American Control Conference

Learning-based Approaches for Controlling Neural Spiking
(2018) Proceedings of the American Control Conference, 2018-June, art. no. 8431158, pp. 2827-2832. 

Liu, S.a , Sock, N.M.c , Ching, S.a b

a Washington University in St. Louis, Department of Electrical and Systems Engineering, St. Louis, MO, United States
b Department of Biomedical Engineering, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
c California Institute of Technology, Pasadena, CA, United States

Abstract
We consider the problem of controlling populations of interconnected neurons using extrinsic stimulation. Such a problem, which is relevant to applications in both basic neuroscience as well as brain medicine, is challenging due to the nonlinearity of neuronal dynamics and the highly unpredictable structure of underlying neuronal networks. Compounding this difficulty is the fact that most neurostimulation technologies offer a single degree of freedom to actuate tens to hundreds of interconnected neurons. To meet these challenges, here we consider an adaptive, learning-based approach to controlling neural spike trains. Rather than explicitly modeling neural dynamics and designing optimal controls, we instead synthesize a so-called control network (CONET) that interacts with the spiking network by maximizing the Shannon mutual information between it and the realized spiking outputs. Thus, the CONET learns a representation of the spiking network that subsequently allows it to learn suitable control signals through a reinforcement-type mechanism. We demonstrate feasibility of the approach by controlling networks of stochastic spiking neurons, wherein desired patterns are induced for neuron-to-actuator ratios in excess of 10 to 1. © 2018 AACC.

Document Type: Conference Paper
Source: Scopus

“Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau” (2018) JAMA Neurology

Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau
(2018) JAMA Neurology, 75 (8), pp. 989-998. 

Hohman, T.J.a , Dumitrescu, L.a , Barnes, L.L.b af , Thambisetty, M.c , Beecham, G.d e aj , Kunkle, B.e aj , Gifford, K.A.a , Bush, W.S.f , Chibnik, L.B.g h , Mukherjee, S.i ak , De Jager, P.L.j k , Kukull, W.l ak , Crane, P.K.i , Resnick, S.M.c , Keene, C.D.m ak , Montine, T.J.n , Schellenberg, G.D.o , Haines, J.L.g , Zetterberg, H.p q s , Blennow, K.p q , Larson, E.B.i t , Johnson, S.C.u , Albert, M.v y , Bennett, D.A.b , Schneider, J.A.b , Jefferson, A.L.a , Blennowe, K.r cc , Abner, E.w , Adams, P.x , Albin, R.z , Apostolova, L.aa , Arnold, S.ab , Asthana, S.ac , Atwood, C.ac , Baldwin, C.ad , Barber, R.ae , Barral, S.ag , Beach, T.ah , Becker, J.ai , Beekly, D.ak , Bennett, D.af , Bigio, E.al , Bird, T.ak , Blacker, D.am , Boeve, B.an , Bowen, J.ao , Boxer, A.ap , Burke, J.aq , Burns, J.ar , Buxbaum, J.as , Cairns, N.at , Cantwell, L.ab , Cao, C.au , Carlson, C.av , Carlsson, C.ac , Carney, R.aj , Carrasquillo, M.an , Chui, H.aw , Crane, P.ak , Cribbs, D.ax , Crocco, E.aj , Cruchaga, C.ay , De Jager, P.az , DeCarli, C.ba , Dick, M.ax , Dickson, D.an , Doody, R.bb , Duara, R.bc , Ertekin-Taner, N.an , Evans, D.af , Faber, K.aa , Fairchild, T.ae , Fallon, K.bd , Fardo, D.w , Farlow, M.aa , Farrer, L.ad , Ferris, S.be , Foroud, T.aa , Frosch, M.bf , Galasko, D.bg , Gearing, M.bh , Geschwind, D.bi , Ghetti, B.aa , Gilbert, J.aj , Goate, A.as , Graff-Radford, N.an , Green, R.az , Growdon, J.bf , Haines, J.bj , Hakonarson, H.bk , Hamilton, R.bl , Hamilton-Nelson, K.aj , Hardy, J.bm , Harrell, L.bd , Honig, L.ag , Huebinger, R.x , Huentelman, M.bn , Hulette, C.aq , Hyman, B.bf , Jarvik, G.ak , Jin, L.-W.ba , Jun, G.ad , Kamboh, M.I.bl , Karydas, A.ap , Katz, M.bo , Kauwe, J.bp , Kaye, J.bq , Kim, R.ax , Kowall, N.ad , Kramer, J.ap , Kuzma, A.ab , LaFerla, F.ax , Lah, J.bh , Larson, E.ak , Leverenz, J.br , Levey, A.bh , Li, G.bs , Lieberman, A.z , Lipton, R.bo , Lopez, O.bt , Lunetta, K.ad , Lyketsos, C.y , Malamon, J.ab , Marson, D.bd , Martin, E.aj , Martiniuk, F.be , Mash, D.aj , Masliah, E.bg , Mayeux, R.ag , McCormick, W.ak , McCurry, S.ak , McDavid, A.av , McDonough, S.bu , McKee, A.ad , Mesulam, M.al , Miller, B.ap , Miller, C.aw , Miller, J.ba , Montine, T.ak , Morris, J.at , Myers, A.aj , Naj, A.ab , O’Bryant, S.ae , Olichney, J.ba , Parisi, J.an , Paulson, H.z , Pericak-Vance, M.aj , Peskind, E.bv , Petersen, R.an , Pierce, A.ax , Poon, W.ax , Potter, H.bw , Qu, L.ab , Quinn, J.bq , Raj, A.au , Raskind, M.bv , Reiman, E.bn , Reisberg, B.be , Reisch, J.x , Reitz, C.ag , Ringman, J.aw , Roberson, E.bd , Rogaeva, E.bx , Rosen, H.ap , Rosenberg, R.by , Royall, D.bz , Sager, M.ac , Sano, M.as , Saykin, A.aa , Schellenberg, G.ab , Schneider, J.af , Schneider, L.aw , Seeley, W.ap , Smith, A.au , Sonnen, J.ak , Spina, S.aa , St George-Hyslop, P.bx , Stern, R.ad , Swerdlow, R.ar , Tanzi, R.bf , Trojanowski, J.ab , Troncoso, J.y , Tsuang, D.bs , Valladares, O.ab , Van Deerlin, V.ab , Van Eldik, L.w , Vardarajan, B.ag , Vinters, H.bi , Vonsattel, J.P.ag , Wang, L.-S.ab , Weintraub, S.al , Welsh-Bohmer, K.aq , Wilhelmsen, K.ca , Williamson, J.ag , Wingo, T.bh , Woltjer, R.bq , Wright, C.aj , Wu, C.-K.cb , Younkin, S.an , Yu, C.-E.ak , Yu, L.af , Zhao, Y.ab

a Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, 1207 17th Ave S., Nashville, TN 37212, United States
b Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
c Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
d John T MacDonald Foundation, Department of Human Genetics, University of Miami, Miami, FL, United States
e Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, United States
f Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States
g Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
h Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
i Department of Medicine, University of Washington, Seattle, United States
j Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, United States
k Cell Circuits Program, Broad Institute, Cambridge, MA, United States
l Department of Epidemiology, School of Public Health, University of Washington, Seattle, United States
m Department of Pathology, University of Washington, Seattle, United States
n Department of Pathology, Stanford University, Stanford, CA, United States
o Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
p Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden
q Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden
r Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, United Kingdom
s UK Dementia Research Institute, London, United Kingdom
t Kaiser Permanente Washington Health Research Institute, Seattle, United States
u Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, United States
v Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
w University of Kentucky, United States
x University of Texas Southwestern Medical Center, United States
y Johns Hopkins University, United States
z University of Michigan, United States
aa Indiana University, United States
ab University of Pennsylvania Perelman School of Medicine, United States
ac University of Wisconsin, United States
ad Boston University, United States
ae University of North Texas Health Science Center, United States
af Rush University Medical Center, United States
ag Columbia University, United States
ah Banner Sun Health Research Institute, United States
ai University of Pittsburgh School of Medicine, United States
aj University of Miami, United States
ak University of Washington, United States
al Northwestern University Feinberg School of Medicine, United States
am Harvard School of Public Health, United States
an Mayo Clinic, United States
ao Swedish Medical Center, United States
ap University of California San Francisco, United States
aq Duke University, United States
ar University of Kansas Medical Center, United States
as Mount Sinai School of Medicine, United States
at Washington University, United States
au University of South Florida, United States
av Fred Hutchinson Cancer Research Center, United States
aw University of Southern California, United States
ax University of California Irvine, United States
ay Washington University School of Medicine, United States
az Brigham and Women’s Hospital, Harvard Medical School, United States
ba University of California Davis, United States
bb Baylor College of Medicine, United States
bc Mount Sinai Medical Center, United States
bd University of Alabama at Birmingham, United States
be New York University, United States
bf Massachusetts General Hospital, Harvard Medical School, United States
bg University of California San Diego, United States
bh Emory University, United States
bi University of California Los Angeles, Harvard Medical School, United States
bj Case Western Reserve University, United States
bk Children’s Hospital of Philadelphia, United States
bl University of Pittsburgh, United States
bm University College London, United Kingdom
bn Translational Genomics Research Institute, United States
bo Albert Einstein College of Medicine, United States
bp Brigham Young University, United States
bq Oregon Health and Science University, United States
br Cleveland Clinic, United States
bs VA Puget Sound Health Care System, GRECC, United States
bt University of Pittsburgh Alzheimer’s Disease Research Center, United States
bu Pfizer Worldwide Research and Development, United States
bv University of Washington School of Medicine, United States
bw University of Colorado School of Medicine, United States
bx University of Toronto, Canada
by University of Texas Southwestern, United States
bz South Texas Veterans Health Administration Geriatric Research Education and Clinical Center (GRECC), UT Health Science Center at San Antonio, United States
ca University of North Carolina Chapel Hill, United States
cb Texas Tech University Health Science Center, United States

Abstract
IMPORTANCE The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. OBJECTIVE To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. DESIGN, SETTING, AND PARTICIPANTS This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017. MAIN OUTCOMES AND MEASURES Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer’s Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles. RESULTS Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-e4 and sex on CSF total tau (β = 0.41; 95%CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95%CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95%CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95%CI, -0.18 to 0.31; P = .62).We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden. CONCLUSIONS AND RELEVANCE We provide robust evidence of a stronger association between APOE-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-e4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

“Steroid treatment of optic neuropathies” (2018) Asia-Pacific Journal of Ophthalmology

Steroid treatment of optic neuropathies
(2018) Asia-Pacific Journal of Ophthalmology, 7 (4), pp. 218-228. Cited 1 time.

Stunkel, L.a , Van Stavern, G.P.b c

a Department of Neurology, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States

Abstract
The etiologies of optic neuropathy include inflammation, ischemia, toxic and metabolic injury, genetic disease, and trauma. There is little controversy over the practice of using steroids in the treatment of optic neuritis—it is well established that intravenous steroid treatment can speed visual recovery but does not alter final visual function. However, there is controversy surrounding the acceptable routes of administration, dosage, and course of treatment. Additionally, the typical patient with optic neuritis is young and otherwise healthy, and thus is likely to tolerate steroids well. In ischemic and traumatic causes of optic neuropathies, the initial injury is not inflammatory, but damage may be compounded by secondary injury due to resultant inflammation and swelling in the confined space of the optic canal. Steroids have been considered as a means of minimizing inflammation and swelling, and thus minimizing the secondary injury that results. However, the use of steroids in traumatic and ischemic optic neuropathies is highly controversial—the evidence for the efficacy of treatment with steroids is insufficient to show that there is significant benefit. Additionally, patients with these conditions are more likely to have comorbidities that make them vulnerable to significant adverse events with the use of steroids. In this article, we attempt to analyze the current state of the literature regarding the use of steroids in the treatment of optic neuropathies, specifically optic neuritis, nonarteritic anterior ischemic optic neuropathy, and traumatic optic neuropathy. Copyright © 2018 by Asia Pacific Academy of Ophthalmology.

Author Keywords
Optic neuropathies;  Steroids

Document Type: Review
Source: Scopus

“Clinical predictors of extrapyramidal symptoms associated with aripiprazole augmentation for the treatment of late-life depression in a randomized controlled trial” (2018) Journal of Clinical Psychiatry

Clinical predictors of extrapyramidal symptoms associated with aripiprazole augmentation for the treatment of late-life depression in a randomized controlled trial
(2018) Journal of Clinical Psychiatry, 79 (4), art. no. 17m11764, . 

Hsu, J.H.a b , Mulsant, B.H.a b , Lenze, E.J.c , Sanches, M.a d , Karp, J.F.e f , Reynolds, C.F., IIIe , Blumberger, D.M.a b g

a Campbell Family Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
b Division of Geriatric Psychiatry, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
c Healthy Mind Laboratory, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
d Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
e Department of Psychiatry, Western Psychiatric Institute, Clinic of University of Pittsburgh Medical Center, Pittsburgh, PA, United States
f Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States
g Late-Life Mood Disorders Clinic, Centre for Addiction and Mental Health, 1001 Queen St W, Unit 4, Room 115, Toronto, ON M6J 1H4, United States

Abstract
Objective: Augmentation with aripiprazole is an effective pharmacotherapy for treatment-resistant late-life depression (LLD). However, aripiprazole can cause extrapyramidal symptoms (EPS) such as akathisia and parkinsonism; these symptoms are distressing and can contribute to treatment discontinuation. We investigated the clinical trajectories and predictors of akathisia and parkinsonism in older patients receiving aripiprazole augmentation for treatment-resistant LLD. Methods: Between 2009 and 2013, depressed older adults who did not remit with venlafaxine were randomized to aripiprazole or placebo in a 12-week trial. Participants were 60 years or older and met DSM-IV-TR criteria for major depressive episode with at least moderate symptoms. The presence of akathisia and parkinsonism was measured at each visit using the Barnes Akathisia Scale (BAS) and Simpson-Angus Scale (SAS), respectively. In an exploratory analysis, we examined a broad set of potential clinical predictors and correlates: age, sex, ethnicity, weight, medical comorbidity, baseline anxiety severity, depression severity, concomitant medications including rescue medications, and aripiprazole dosage. Results: Twenty-four (26.7%) of 90 participants randomized to aripiprazole and who had akathisia scores available developed akathisia compared to 11 (12.2%) of 90 randomized to placebo. Greater depression severity was the main predictor of treatment-emergent akathisia. Most participants who developed akathisia improved over time, especially with reductions in dosage. Fifteen (16.5%) of 91 participants taking aripiprazole and who had parkinsonism scores available developed parkinsonism, but no clinical predictors or correlates were identified. Conclusions: Akathisia is a common side effect of aripiprazole, but it is typically mild and responds to dose reduction. Patients with greater baseline depression may warrant closer monitoring for akathisia. More research is needed to understand the course and predictors of treatment-emergent EPS with antipsychotic augmentation for treatment-resistant LLD. © Copyright 2018 Physicians Postgraduate Press, Inc.

Document Type: Article
Source: Scopus

“Noise in the neonatal intensive care unit: A new approach to examining acoustic events” (2018) Noise and Health

Noise in the neonatal intensive care unit: A new approach to examining acoustic events
(2018) Noise and Health, 20 (95), pp. 121-130. 

Smith, S.W.a b , Ortmann, A.J.a , Clark, W.W.a

a Program in Audiology and Communication Sciences, Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Children’s Mercy Hearing and Speech, 3101 Broadway Boulevard, Kansas City, MO 64111, United States

Abstract
Introduction: Environmental noise is associated with negative developmental outcomes for infants treated in the neonatal intensive care unit (NICU). The existing noise level recommendations are outdated, with current studies showing that these standards are universally unattainable in the modern NICU environment. Study Aim: This study sought to identify the types, rate, and levels of acoustic events that occur in the NICU and their potential effects on infant physiologic state. Materials and Methods: Dosimeters were used to record the acoustic environment in open and private room settings of a large hospital NICU. Heart and respiratory rate data of three infants located near the dosimeters were obtained. Infant physiologic data measured at time points when there was a marked increase in sound levels were compared to data measured at time points when the acoustic levels were steady. Results: All recorded sound levels exceeded the recommended noise level of 45 decibels, A-weighted (dBA). The 4-h Leq of the open-pod environment was 58.1 dBA, while the private room was 54.7 dBA. The average level of acoustic events was 11-14 dB higher than the background noise. The occurrence of transient events was 600% greater in the open room when compared to the private room. While correlations between acoustic events and infant physiologic state could not be established due to the extreme variability of infant state, a few trends were visible. Increasing the number of data points to overcome the extreme physiologic variability of medically fragile neonates would not be feasible or cost-effective in this environment. Conclusion: NICU noise level recommendations need to be modified with an emphasis placed on reducing acoustic events that disrupt infant state. The goal of all future standards should be to optimize infant neurodevelopmental outcomes. © 2018 Noise & Health | Published by Wolters Kluwer – Medknow.

Author Keywords
acoustic environment;  hospital noise;  infant development;  neonatal intensive care unit;  physiologic monitoring

Document Type: Article
Source: Scopus

“Modern Laser Scanning Confocal Microscopy” (2018) Current Protocols in Cytometry

Modern Laser Scanning Confocal Microscopy
(2018) Current Protocols in Cytometry, 85 (1), art. no. e39, . 

Bayguinov, P.O.a , Oakley, D.M.a , Shih, C.-C.a , Geanon, D.J.a , Joens, M.S.a , Fitzpatrick, J.A.J.a b c

a Center for Cellular Imaging, Washington University in St. Louis, St. Louis, MO, United States
b Departments of Cell Biology & Physiology and Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Since its commercialization in the late 1980’s, confocal laser scanning microscopy (CLSM) has since become one of the most prevalent fluorescence microscopy techniques for three-dimensional structural studies of biological cells and tissues. The flexibility of the approach has enabled its application in a diverse array of studies, from the fast imaging of dynamic processes in living cells, to meticulous morphological analyses of tissues, and co-localization of protein expression patterns. In this chapter, we introduce the principles of confocal microscopy and discuss how the approach has become a mainstay in the biological sciences. We describe the components of a CLSM system and assess how modern implementations of the approach have further expanded the use of the technique. Finally, we briefly outline some practical considerations to take into account when acquiring data using a CLSM system. © 2018 by John Wiley & Sons, Inc. © 2018 John Wiley & Sons, Inc.

Author Keywords
confocal laser scanning microscopy (CLSM);  fluorescent imaging;  live-cell imaging;  optical sectioning;  spinning disk confocal;  swept-field confocal;  three-dimensional imaging

Document Type: Note
Source: Scopus

“Systematic review and meta-analysis of effectiveness of preoperative embolization in surgery for metastatic spine disease” (2018) Journal of neurointerventional surgery

Systematic review and meta-analysis of effectiveness of preoperative embolization in surgery for metastatic spine disease
(2018) Journal of neurointerventional surgery, 10 (6), pp. 596-601. 

Luksanapruksa, P.a , Buchowski, J.M.b , Tongsai, S.c , Singhatanadgige, W.d , Jennings, J.W.e

a Department of Orthopedic Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
b Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
c Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
d Department of Orthopedic Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
e Department of Radiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
BACKGROUND: Preoperative embolization (PE) may decrease intraoperative blood loss (IBL) in decompressive surgery of hypervascular spinal metastases. However, no consensus has been found in other metastases and no meta-analysis which reviewed the benefit of PE in spinal metastases has been conducted.

OBJECTIVE: To assess IBL in spinal metastases surgery in a randomized controlled trial (RCT) and cohort studies comparing PE and a control group of non-embolized patients.

METHODS: A systematic search of relevant publications in PubMed and EMBASE was undertaken. Inclusion criteria were RCTs and observational studies in patients with spinal metastases who underwent spine surgery and reported IBL. Meta-analysis was performed using standardized mean difference (SMD) and mean difference (MD) of IBL. Heterogeneity was assessed using the I2 statistic.

RESULTS: A total of 265 abstracts (126 from PubMed and 139 from Embase) were identified through database searching. The reviewers selected six studies for qualitative synthesis and meta-analysis. The pooled SMD of the included studies was 0.58 (95% CI -0.10 to 1.25, p=0.09). Sensitivity analysis revealed that, if the study by Rehak et al was omitted, the pooled SMD was significantly changed to 0.88 (95% CI 0.39 to 1.36, p<0.001) and PE reduced the IBL significantly. The pooled MD was 708.3 mL (95% CI -224.4 to 1640.9 mL, p=0.14). If the results of the Rehak et al study were omitted, the pooled MD was significantly changed to 1226.9 mL (95% CI 345.8 to 2108.1 mL, p=0.006).

CONCLUSIONS: PE can be effective in reducing IBL in spinal metastases surgery in both renal cell carcinoma and mixed primary tumor groups. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Author Keywords
epidural;  metastatic;  neoplasm;  spine

Document Type: Article
Source: Scopus

“Positron emission tomography (PET) for prediction of glioma histology: Protocol for an individual-level data meta-analysis of test performance” (2018) BMJ Open

Positron emission tomography (PET) for prediction of glioma histology: Protocol for an individual-level data meta-analysis of test performance
(2018) BMJ Open, 8 (2), art. no. e020187, . 

Trikalinos, N.A.a , Nihashi, T.b c , Evangelou, E.d e , Terasawa, T.f

a Department of Oncology, Washington University in St Louis School of Medicine, St Louis, MO, United States
b Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
c Department of Radiology, Komaki City Hospital, Jobushi, Japan
d Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
e Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
f Section of General Internal Medicine, Department of Emergency and General Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

Abstract
Introduction Gliomas, the most commonly diagnosed primary brain tumours, are associated with varied survivals based, in part, on their histological subtype. Therefore, accurate pretreatment tumour grading is essential for patient care and clinical trial design. Methods and analysis We will perform an individual-level data meta-analysis of published studies to evaluate the ability of different types of positron emission tomography (PET) to differentiate high from low-grade gliomas. We will search PubMed and Scopus from inception through 30 July 2017 with no language restriction and full-text evaluation of potentially relevant articles. We will choose studies that assess PET using 18-Fludeoxyglucose (18F-FDG), l-[Methyl-()11C]Methionine (11C-MET), 18F-Fluoro-Ethyl-Tyrosine (18F-FET) or (18)F-Fluorothymidine (18F-FLT)for grading, verified with histological confirmation. We will include both prospective and retrospective studies. Bias will be assessed by two reviewers with the Quality Assessment of Diagnostic Accuracy Studies-2 tool and as per method described by Deeks et al. Ethics and dissemination Ethics approval was not applicable, as this is a meta-analytic study. Results of the analysis will be submitted for publication in a peer-reviewed journal. PROSPERO registration number CRD42017078649. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Author Keywords
glioma;  meta-analysis;  pet

Document Type: Article
Source: Scopus

“Single scan quantitative gradient recalled echo MRI for evaluation of tissue damage in lesions and normal appearing gray and white matter in multiple sclerosis” (2018) Journal of Magnetic Resonance Imaging

Single scan quantitative gradient recalled echo MRI for evaluation of tissue damage in lesions and normal appearing gray and white matter in multiple sclerosis
(2018) Journal of Magnetic Resonance Imaging, . Article in Press. 

Xiang, B.a , Wen, J.b , Cross, A.H.c , Yablonskiy, D.A.b

a Department of Chemistry, Washington University, St. Louis, MO, United States
b Department of Radiology, Washington University, St. Louis, MO, United States
c Department of Neurology, Washington University, St. Louis, MO, United States

Abstract
Background: Multiple sclerosis (MS) is a chronic disease affecting the human central nervous system (CNS) and leading to neurologic disability. Although conventional MRI techniques can readily detect focal white matter (WM) lesions, it remains challenging to quantify tissue damage in normal-appearing gray matter (GM) and WM. Purpose: To demonstrate that a new MRI biomarker, R2t*, can provide quantitative analysis of tissue damage across the brain in MS patients in a single scan. Study Type: Prospective. Subjects: Forty-four MS patients and 19 healthy controls (HC). Field Strength/Sequence: 3T, quantitative gradient-recalled-echo (qGRE), Magnetization-prepared rapid gradient-echo, fluid-attenuated inversion recovery. Assessment: Severity of tissue damage was assessed by reduced R2t*. Tissue atrophy was assessed by cortical thickness and cervical spinal cord cross-sectional area (CSA). Multiple Sclerosis Functional Composite was used for clinical assessment. Results: R2t* in cortical GM was more sensitive to MS damage than cortical atrophy. Using more than two standard deviations (SD) reduction versus age-matched HC as the cutoff, 48% of MS patients showed lower R2t*, versus only 9% with lower cortical thickness. Significant correlations between severities of tissue injury were identified among 1) upper cervical cord and several cortical regions, including motor cortex (P < 0.001), and 2) adjacent regions of GM and subcortical WM (P < 0.001). R2t*-defined tissue cellular damage in cortical GM was greater relative to adjacent WM. Reductions in cortical R2t* correlated with cognitive impairment (P < 0.01). Motor-related clinical signs correlated most with cervical cord CSA (P < 0.001). Data Conclusion: Reductions in R2t* within cortical GM was more sensitive to tissue damage than atrophy, potentially allowing a reduced sample size in clinical trials. R2t* together with structural morphometry suggested topographic patterns of regions showing correlated tissue damage throughout the brain and the cervical spinal cord of MS patients. Level of Evidence: 2. Technical Efficacy: Stage 3. J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine

Author Keywords
cervical spinal cord cross-sectional area;  magnetic resonance imaging;  multiple sclerosis;  multiple sclerosis lesions;  R2t* relaxation

Document Type: Article in Press
Source: Scopus

“FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance” (2018) Molecular Genetics and Metabolism

FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance
(2018) Molecular Genetics and Metabolism, . Article in Press. 

Almannai, M.a , Wang, J.b , Dai, H.c , El-Hattab, A.W.d , Faqeih, E.A.a , Saleh, M.A.a , Al Asmari, A.a , Alwadei, A.H.e , Aljadhai, Y.I.f , AlHashem, A.g h , Tabarki, B.i , Lines, M.A.j , Grange, D.K.k , Benini, R.e , Alsaman, A.S.e , Mahmoud, A.e , Katsonis, P.c , Lichtarge, O.c , Wong, L.-J.C.c

a Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
b Medical Scientist Training Program and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, United States
c Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
d Division of Clinical Genetics and Metabolic Disorders, Pediatric Department, Tawam Hospital, Al-Ain, United Arab Emirates
e Department of Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
f Department of Neuroimaging and Intervention, Medical Imaging Administration, King Fahad Medical City, Riyadh, Saudi Arabia
g Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia
h Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
i Divisions of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
j Division of Metabolics and Newborn Screening, Children’s Hospital of Eastern Ontario, Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Canada
k Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here. © 2018 Elsevier Inc.

Author Keywords
Epileptic encephalopathy;  FARS2;  Mitochondria;  Mitochondrial aminoacyl-tRNA synthetase;  Spastic paraplegia

Document Type: Article in Press
Source: Scopus

“N-Methyl- d -aspartate Receptor Antibody Encephalitis: A Concise Review of the Disorder, Diagnosis, and Management” (2018) ACS Chemical Neuroscience

N-Methyl- d -aspartate Receptor Antibody Encephalitis: A Concise Review of the Disorder, Diagnosis, and Management
(2018) ACS Chemical Neuroscience, . Article in Press. 

Staley, E.M.a , Jamy, R.b , Phan, A.Q.c , Figge, D.A.d , Pham, H.P.e

a Department of Pathology and Immunology, Washington University, School of Medicine in St. Louis, St. Louis, MO 63110, United States
b Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35249, United States
c Doctor of Medicine Program, University of Wisconsin, School of Medicine and Public Health, Madison, WI 53726, United States
d Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, United States
e Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States

Abstract
Anti-NMDA (N-methyl-d-aspartate) receptor (anti-NMDAR) encephalitis is one of the most common paraneoplastic encephalitides. It occurs in both sexes, across all age ranges, and may occur in the presence or absence of an associated tumor. Its pathogenesis and clinical presentation relate to the presence of IgG1 or IgG3 antibodies targeting the NR1 subunit of the NMDA receptor, leading to a disinhibition of neuronal excitatory pathways. Initial clinical manifestations may be nonspecific, resembling a viral-like illness; however, with disease progression, symptoms can become quite severe, including prominent psychiatric features, cognitive problems, motor dysfunction, and autonomic instability. Anti-NMDAR encephalitis may even result in death in severe untreated cases. Diagnosis can be challenging, given that initial laboratory and radiographic results are typically nonspecific. The majority of patients respond to first or second-line treatments, although therapeutic options remain limited, usually consisting of tumor removal (if there is confirmation of an underlying malignancy) in conjunction with prompt initiation of immunosuppressive medications along with intravenous immunoglobulins and/or plasma exchange. Although the clinical presentation of anti-NMDAR encephalitis overlaps with several other more common neurological and psychiatric disorders, early diagnosis and treatment is essential for a positive prognosis. Here, we concisely review the pathogenesis, diagnosis, and clinical management of this disease. © 2018 American Chemical Society.

Author Keywords
Autoimmune;  encephalitis;  NMDA receptor;  paraneoplastic;  plasma exchange

Document Type: Article in Press
Source: Scopus

“Parent-Child Conflict during Elementary School as a Longitudinal Predictor of Sense of Purpose in Emerging Adulthood” (2018) Journal of Youth and Adolescence

Parent-Child Conflict during Elementary School as a Longitudinal Predictor of Sense of Purpose in Emerging Adulthood
(2018) Journal of Youth and Adolescence, . Article in Press. 

Hill, P.L.a , Schultz, L.H.a , Jackson, J.J.a , Andrews, J.A.b

a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Oregon Research Institute, Eugene, OR, United States

Abstract
Having a sense of purpose is viewed as a benchmark of adaptive development. Though adolescence and emerging adulthood are viewed as central periods for the development of a purpose, work still is needed to understand the childhood factors that influence this developmental process. The current study provides an initial investigation into whether parent-child conflict during elementary school predicts later sense of purpose, assessed during emerging adulthood (mean age: 21.01 years; range: 19.97–23.53). The sample included 1074 students (50% female), and their parents, who both reported on their levels of parent-child conflict during grades 1–5. Higher levels of parent-child conflict were associated with lower levels of purpose in emerging adulthood. Moreover, the study examined whether these effects remained when predicting the variance unique to purpose while accounting for other indicators of well-being in emerging adulthood. Bi-factor models demonstrated that the child’s perception of mother-child conflict has a unique prospective effect on purpose in emerging adulthood, above and beyond its negative association with general well-being. The findings are discussed with respect to how positive parent-child relationships may prove important for starting youth on the path to purpose. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Childhood;  Emerging adulthood;  Parent-child conflict;  Purpose in life;  Well-being

Document Type: Article in Press
Source: Scopus

“Hey buddy, why don’t we take it outside: An experience sampling study of prospective memory” (2018) Memory and Cognition

Hey buddy, why don’t we take it outside: An experience sampling study of prospective memory
(2018) Memory and Cognition, . Article in Press. 

Anderson, F.T., McDaniel, M.A.

Department of Psychological and Brain Sciences, Washington University, 1 Brookings Dr, Campus Box 1125, St. Louis, MO 63130, United States

Abstract
Relatively little research has focused on how prospective memory (PM) operates outside of the laboratory, partially due to the methodological problems presented by naturalistic memory research in general and by the unique challenges of PM in particular. Experience sampling methods (ESM) offer a fruitful avenue for this type of research, as recent work from Gardner and Ascoli (Psychology and Aging, 30, 209-219, 2015) has shown. They found that people thought about PM around 15% of the time, and that future thinking was more common than past thinking. In two studies, we replicated our own findings and those reported by Gardner and Ascoli. To summarize, people think about the future more often than the past (30% compared to 13%), and PM occupies our thoughts approximately 13–15% of the time, supporting claims made by some researchers that our episodic memory systems are forward-looking (Klein in Journal of Applied Research in Memory and Cognition, 2, 222-234, 2013). Of those PM thoughts, participants reported that 61% were internally cued, rather than externally triggered. Through the use of multi-level modeling, we additionally found that PM thoughts were more likely when the respondant was alone than with people, and earlier in the day. Finally, we found that participants higher in neuroticism were more likely to report thinking of PM, and that this was driven entirely by the anxiety facet. Most generally, we hope to have demonstrated the value of ESM to help researchers investigate and understand naturalistic PM. © 2018, Psychonomic Society, Inc.

Author Keywords
ESM;  Experience sampling;  Future thoughts;  Momentary thoughts;  Prospective memory

Document Type: Article in Press
Source: Scopus

“Effect of Nitrous Oxide as a Treatment for Subjective, Idiopathic, Nonpulsatile Bothersome Tinnitus: A Randomized Clinical Trial” (2018) JAMA Otolaryngology – Head and Neck Surgery

Effect of Nitrous Oxide as a Treatment for Subjective, Idiopathic, Nonpulsatile Bothersome Tinnitus: A Randomized Clinical Trial
(2018) JAMA Otolaryngology – Head and Neck Surgery, . Article in Press. 

Hong, H.Y.a , Karadaghy, O.a , Kallogjeri, D.a , Brown, F.T.b , Yee, B.b , Piccirillo, J.F.a , Nagele, P.b

a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, 660 S Euclid Ave, St Louis, MO 63110, United States
b Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: The tinnitus research literature suggests that N-methyl-d-Aspartate (NMDA) receptor antagonists may be useful in reducing tinnitus. Nitrous oxide, a member of the NMDA receptor antagonist class, is a widely used general anesthetic and sedative with a proven safety record. Objective: To investigate whether nitrous oxide can reduce bothersome tinnitus. Design, Setting, and Participants: Randomized, placebo-controlled crossover trial conducted between October 15, 2016, and June 22, 2017. Participants attended 2 interventional sessions separated by at least 14 days and were randomized to receive either placebo first or nitrous oxide first. Participants were followed up through completion of the second arm of the study. The setting was a clinical research unit at an academic medical center. Adults aged 18 to 65 years with subjective, idiopathic, nonpulsatile bothersome tinnitus of 6 months’ duration or longer were recruited from 2 clinical research databases. Seventy-one individuals were screened, of whom 40 were enrolled. Of those enrolled, 37 participants completed all components of the study. Interventions: The placebo session consisted of 50% nitrogen and 50% oxygen inhaled for 40 minutes, and the treatment session consisted of 50% nitrous oxide and 50% oxygen inhaled for 40 minutes. Main Outcomes and Measures: Tinnitus was assessed before and after intervention, with the change in the Tinnitus Functional Index (TFI) as the primary outcome measure. Secondary outcome measures included the Patients’ Global Impression of Change score and the change in the Global Bothersome Scale score. Results: Among 40 participants in this intent-To-Treat randomized clinical trial with 20 participants randomly assigned to each group, the mean (SD) age of participants was 52.9 (11.1) years, with equal numbers of male and female participants. The TFI after intervention was a mean (SD) of 1.8 (8.8) points lower than before intervention in the placebo arm and a mean (SD) of 2.5 (11.0) points lower than before intervention in the nitrous oxide arm. The within-participant mean difference in the change in the TFI of the placebo arm compared with the nitrous oxide arm was-1.1 points (95% CI,-5.6 to 3.4 points). The difference between the placebo and nitrous oxide arms was neither clinically meaningful nor statistically significant. Conclusions and Relevance: Nitrous oxide was no more effective than placebo for the treatment of subjective, idiopathic tinnitus. © 2018 American Medical Association. All rights reserved.

Document Type: Article in Press
Source: Scopus

“Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome” (2018) Molecular Psychiatry

Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome
(2018) Molecular Psychiatry, . Article in Press. 

Semick, S.A.a , Collado-Torres, L.a b , Markunas, C.A.c , Shin, J.H.a , Deep-Soboslay, A.a , Tao, R.a , Huestis, M.A.d , Bierut, L.J.e , Maher, B.S.f , Johnson, E.O.g , Hyde, T.M.a h i , Weinberger, D.R.a h i j k , Hancock, D.B.c , Kleinman, J.E.a h , Jaffe, A.E.a b f k l

a Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, United States
b Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21205, United States
c Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park 3040 East Cornwallis Road, NC 27709, United States
d The Lambert Center for the Study of Medicinal Cannabis and Hemp, Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States
g Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park 3040 East Cornwallis Road, NC 27709, United States
h Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
i Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
j Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
k McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
l Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States

Abstract
Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N = 33; 16 smoking-exposed) as well as adult (N = 207; 57 active smokers) human postmortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)—these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders. © 2018, Springer Nature Limited.

Document Type: Article in Press
Source: Scopus

“The Role of Obesity in the Association between Posttraumatic Stress Disorder and Incident Diabetes” (2018) JAMA Psychiatry

The Role of Obesity in the Association between Posttraumatic Stress Disorder and Incident Diabetes
(2018) JAMA Psychiatry, . Article in Press. 

Scherrer, J.F.a b , Salas, J.a b , Lustman, P.J.c , Van Den Berk-Clark, C.a , Schnurr, P.P.d e , Tuerk, P.f g , Cohen, B.E.h i , Friedman, M.J.d , Norman, S.B.d j , Schneider, F.D.k , Chard, K.M.l m

a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 N Grand Blvd, St. Louis, MO 63104, United States
b Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
d National Center for PTSD, White River Junction, Vermont, United States
e Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
f Ralph H. Johnson VA Medical Center, Charleston, SC, United States
g Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States
h Department of Medicine, University of California San Francisco School of Medicine, San Francisco, United States
i San Francisco VA Medical Center, San Francisco, CA, United States
j Department of Psychiatry, University of California, San Diego, United States
k Department of Family and Community Medicine, University of Texas Southwestern, Dallas, United States
l Trauma Recovery Center Cincinnati VA Medical Center, Cincinnati, OH, United States
m Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States

Abstract
Importance: Posttraumatic stress disorder (PTSD) is associated with an increased risk of type 2 diabetes mellitus (T2DM). Existing literature has adjusted for obesity in combination with other confounders, which does not allow estimating the contribution of obesity alone on the association of PTSD with incident T2DM. Objective: The current study was designed to determine if obesity accounted for the association between PTSD and incident T2DM. Design, Setting, and Participants: This cohort study used data from Veterans Health Administration medical records collected from patients with PTSD and without PTSD from 2008 to 2015. Patients were eligible for study inclusion if they were free of prevalent PTSD and T2DM for 12 months prior to index date. To estimate whether the association of PTSD and incident T2DM remained independent of obesity, Cox proportional hazard models were computed before and after adding obesity to the model and then further expanded by adding psychiatric disorders, psychotropic medications, physical conditions, smoking status, and demographics. Additional Cox models were computed to compare the risk of incident T2DM in patients with PTSD with and without obesity. Data analysis was completed from February 2018 to May 2018. Exposures: Two International Classification of Diseases, Ninth Revision (ICD-9) codes for PTSD in the same 12 months and obesity, defined by a body mass index of 30 or more or an ICD-9 code for obesity. Main Outcomes and Measures: Incident T2DM, as defined by ICD-9 codes. Results: Among 2204 patients without PTSD, the mean (SD) age was 47.7 (14.3) years; 1860 (84.4%) were men, 1426 (64.7%) were white, and 956 (43.4%) were married. Among 3450 patients with PTSD, the mean (SD) age was 42.8 (14.2) years; 2983 (86.5%) were men, 2238 (64.9%) were white, and 1525 (44.2%) were married. The age-adjusted association between PTSD and incident T2DM was significant (hazard ratio [HR], 1.33 [95% CI, 1.08-1.64]; P =.01), and after adding obesity to the model, this association was reduced and no longer significant (HR, 1.16 [95% CI, 0.94-1.43]; P =.18). Results of the full model, which included additional covariate adjustment, revealed no association between PTSD and incident T2DM (HR, 0.84 [95% CI, 0.64-1.10]; P =.19). Among patients with PTSD with obesity, the age-adjusted incidence of T2DM was 21.0 per 1000 person-years vs 5.8 per 1000 person-years in patients without obesity. In patients without PTSD, it was 21.2 per 1000 person-years for patients with obesity vs 6.4 per 1000 person-years in those without obesity. Conclusions and Relevance: In this study of patients who use the Veterans Health Administration for health care, obesity moderated the association between PTSD and incident T2DM. The incidence of T2DM in patients with PTSD who are not obese is similar to the national incidence rate in the United States. These results suggest PTSD is not likely to have a causal association with incident T2DM. Future research is needed to determine if PTSD remission can lead to weight loss and reduced T2DM incidence. © 2018 American Medical Association. All rights reserved.

Document Type: Article in Press
Source: Scopus

“We may be Homo sapiens, but anaesthetists are merely apes when evaluating risk” (2018) British Journal of Anaesthesia

We may be Homo sapiens, but anaesthetists are merely apes when evaluating risk
(2018) British Journal of Anaesthesia, . Article in Press. 

Aranake-Chrisinger, A.a , Whitlock, E.L.b , Avidan, M.S.a

a Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
b Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States

Document Type: Article in Press
Source: Scopus

“Colour vision variation in leaf-nosed bats (Phyllostomidae): Links to cave roosting and dietary specialization” (2018) Molecular Ecology

Colour vision variation in leaf-nosed bats (Phyllostomidae): Links to cave roosting and dietary specialization
(2018) Molecular Ecology, . Article in Press. 

Kries, K.a , Barros, M.A.S.b , Duytschaever, G.c , Orkin, J.D.c , Janiak, M.C.d , Pessoa, D.M.A.b , Melin, A.D.c e

a Department of Anthropology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Physiology, Federal University of Rio Grande do Norte, Natal, Brazil
c Department of Anthropology and Archaeology, University of Calgary, Calgary, AB, Canada
d Department of Anthropology, Rutgers University, New Brunswick, NJ, United States
e Department of Medical Genetics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Abstract
Bats are a diverse radiation of mammals of enduring interest for understanding the evolution of sensory specialization. Colour vision variation among species has previously been linked to roosting preferences and echolocation form in the suborder Yinpterochiroptera, yet questions remain about the roles of diet and habitat in shaping bat visual ecology. We sequenced OPN1SW and OPN1LW opsin genes for 20 species of leaf-nosed bats (family Phyllostomidae; suborder Yangochiroptera) with diverse roosting and dietary ecologies, along with one vespertilionid species (Myotis lavali). OPN1LW genes appear intact for all species, and predicted spectral tuning of long-wavelength opsins varied among lineages. OPN1SW genes appear intact and under purifying selection for Myotis lavali and most phyllostomid bats, with two exceptions: (a) We found evidence of ancient OPN1SW pseudogenization in the vampire bat lineage, and loss-of-function mutations in all three species of extant vampire bats; (b) we additionally found a recent, independently derived OPN1SW pseudogene in Lonchophylla mordax, a cave-roosting species. These mutations in leaf-nosed bats are independent of the OPN1SW pseudogenization events previously reported in Yinpterochiropterans. Therefore, the evolution of monochromacy (complete colour blindness) has occurred in both suborders of bats and under various evolutionary drivers; we find independent support for the hypothesis that obligate cave roosting drives colour vision loss. We additionally suggest that haematophagous dietary specialization and corresponding selection on nonvisual senses led to loss of colour vision through evolutionary sensory trade-off. Our results underscore the evolutionary plasticity of opsins among nocturnal mammals. © 2018 John Wiley & Sons Ltd

Author Keywords
Chiroptera;  nocturnal visual ecology;  OPN1LW;  OPN1SW pseudogenization;  opsin genes;  vampire bat

Document Type: Article in Press
Source: Scopus

“Meta-analytic techniques reveal that corvid causal reasoning in the Aesop’s Fable paradigm is driven by trial-and-error learning” (2018) Animal Cognition

Meta-analytic techniques reveal that corvid causal reasoning in the Aesop’s Fable paradigm is driven by trial-and-error learning
(2018) Animal Cognition, . Article in Press. 

Hennefield, L.a , Hwang, H.G.a , Weston, S.J.b , Povinelli, D.J.c

a Washington University, St Louis, MO 63130, United States
b Northwestern University, Chicago, IL, United States
c Department of Biology, University of Louisiana, Lafayette, LA 70504, United States

Abstract
The classic Aesop’s fable, Crow and the Pitcher, has inspired a major line of research in comparative cognition. Over the past several years, five articles (over 32 experiments) have examined the ability of corvids (e.g., rooks, crows, and jays) to complete lab-based analogs of this fable, by requiring them to drop stones and other objects into tubes of water to retrieve a floating worm (Bird and Emery in Curr Biol 19:1–5, 2009b; Cheke et al. in Anim Cogn 14:441–455, 2011; Jelbert et al. in PLoS One 3:e92895, 2014; Logan et al. in PLoS One 7:e103049, 2014; Taylor et al. in Gray R D 12:e26887, 2011). These researchers have stressed the unique potential of this paradigm for understanding causal reasoning in corvids. Ghirlanda and Lind (Anim Behav 123:239–247, 2017) re-evaluated trial-level data from these studies and concluded that initial preferences for functional objects, combined with trial-and-error learning, may account for subjects’ performance on key variants of the paradigm. In the present paper, we use meta-analytic techniques to provide more precise information about the rate and mode of learning that occurs within and across tasks. Within tasks, subjects learned from successful (but not unsuccessful) actions, indicating that higher-order reasoning about phenomena such as mass, volume, and displacement is unlikely to be involved. Furthermore, subjects did not transfer information learned in one task to subsequent tasks, suggesting that corvids do not engage with these tasks as variants of the same problem (i.e., how to generate water displacement to retrieve a floating worm). Our methodological analysis and empirical findings raise the question: Can Aesop’s fable studies distinguish between trial-and-error learning and/or higher-order causal reasoning? We conclude they cannot. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Aesop’s fable;  Causal reasoning;  Causal understanding;  Comparative cognition;  Corvid;  New Caledonian crows;  Object bias;  Perceptual-motor feedback

Document Type: Article in Press
Source: Scopus

“Establishing prevalence in rare neuromuscular diseases: A lesson from congenital myopathies” (2017) Neurology

Establishing prevalence in rare neuromuscular diseases: A lesson from congenital myopathies
(2017) Neurology: Genetics, 3 (2), art. no. e146, . 

Bamaga, A.K., Weihl, C.C.

Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States

Document Type: Editorial
Source: Scopus