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WUSTL Neuroscience Publications Archive - November 2013

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November 15, 2013

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November 29, 2013

Documents

Jafurulla, M.a , Rao, B.D.a , Sreedevi, S.a , Ruysschaert, J.-M.b , Covey, D.F.c , Chattopadhyay, A.a 
Stereospecific requirement of cholesterol in the function of the serotonin1A receptor
(2014) Biochimica et Biophysica Acta - Biomembranes, 1838 (1 PARTB), pp. 158-163. 

a Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, India
b Structure and Function of Biological Membranes, Université Libre de Bruxelles, Boulevard du Triomphe, CP 206/2, B-1050 Brussels, Belgium
c Department of Developmental Biology, Washington University in St. Louis Medical School, St. Louis, MO 63110, United States

Abstract
The serotonin1A receptor is an important member of the G protein-coupled receptor (GPCR) family. It is involved in the generation and modulation of a variety of cognitive and behavioral functions and serves as a drug target. Previous work from our laboratory has established the sensitivity of the function of the serotonin1A receptor to membrane cholesterol. Solubilization of the hippocampal serotonin1A receptor utilizing the zwitterionic detergent CHAPS is accompanied by loss of cholesterol and results in reduction in specific ligand binding. Replenishment of cholesterol to solubilized membranes restores specific ligand binding to the receptor. We utilized this strategy of sterol replenishment of solubilized membranes to explore the stereospecific stringency of cholesterol for receptor function. We used two stereoisomers of cholesterol, ent-cholesterol (enantiomer of cholesterol) and epi-cholesterol (a diastereomer of cholesterol), for this purpose. Importantly, we show here that while ent-cholesterol could replace cholesterol in supporting receptor function, epi-cholesterol could not. These results imply that the requirement of membrane cholesterol for the serotonin1A receptor function is diastereospecific, yet not enantiospecific. Our results extend and help define specificity of the interaction of membrane cholesterol with the serotonin1A receptor, and represent the first report utilizing ent-cholesterol to examine stereospecificity of GPCR-cholesterol interaction. © 2013 Elsevier B.V.

Author Keywords
Cholesterol;  ent-Cholesterol;  epi-Cholesterol;  Fluorescence anisotropy;  Ligand binding;  Serotonin1A receptor

Document Type: Article
Source: Scopus

Stephens, S.H.a , Hartz, S.M.b , Hoft, N.R.c , Saccone, N.L.b , Corley, R.C.c , Hewitt, J.K.c , Hopfer, C.J.c , Breslau, N.d , Coon, H.e , Chen, X.f , Ducci, F.g h , Dueker, N.a , Franceschini, N.i , Frank, J.j , Han, Y.k , Hansel, N.N.l , Jiang, C.m , Korhonen, T.n , Lind, P.A.o , Liu, J.p , Lyytikäinen, L.-P.q , Michel, M.r , Shaffer, J.R.s , Short, S.E.t , Sun, J.u , Teumer, A.v , Thompson, J.R.w , Vogelzangs, N.x , Vink, J.M.y , Wenzlaff, A.z , Wheeler, W.aa , Yang, B.-Z.m , Aggen, S.H.f , Balmforth, A.J.ab , Baumeister, S.E.v , Beaty, T.H.l , Benjamin, D.J.ac , Bergen, A.W.r , Broms, U.n , Cesarini, D.ad , Chatterjee, N.ae , Chen, J.f , Cheng, Y.-C.a , Cichon, S.af bh , Couper, D.h , Cucca, F.ag , Dick, D.f , Foroud, T.ah , Furberg, H.ai , Giegling, I.aj , Gillespie, N.A.f , Gu, F.ae , Hall, A.S.ab , Hällfors, J.n , Han, S.m , Hartmann, A.M.aj , Heikkilä, K.n , Hickie, I.B.ak , Hottenga, J.J.y , Jousilahti, P.al , Kaakinen, M.am , Kähönen, M.an , Koellinger, P.D.ao , Kittner, S.ap , Konte, B.aj , Landi, M.-T.aq , Laatikainen, T.al , Leppert, M.e , Levy, S.M.ar , Mathias, R.A.l , Mcneil, D.W.as , Medland, S.E.o , Montgomery, G.W.o , Murray, T.l , Nauck, M.v , North, K.E.i , Paré, P.D.at , Pergadia, M.b , Ruczinski, I.l , Salomaa, V.al , Viikari, J.au , Willemsen, G.y , Barnes, K.C.l , Boerwinkle, E.av , Boomsma, D.I.y , Caporaso, N.aq , Edenberg, H.J.ah , Francks, C.aw , Gelernter, J.m , Grabe, H.J.v , Hops, H.ax , Jarvelin, M.-R.ay bi bj bk , Johannesson, M.az , Kendler, K.S.f , Lehtimäki, T.q , Magnusson, P.K.E.ba , Marazita, M.L.s , Marchini, J.p , Mitchell, B.D.a , Nöthen, M.M.bb , Penninx, B.W.x , Raitakari, O.bc , Rietschel, M.j , Rujescu, D.aj , Samani, N.J.bd , Schwartz, A.G.z , Shete, S.k , Spitz, M.k , Swan, G.E.r , Völzke, H.v , Veijola, J.am , Wei, Q.k , Amos, C.k , Cannon, D.S.e , Grucza, R.b , Hatsukami, D.be , Heath, A.b , Johnson, E.O.bf , Kaprio, J.n , Madden, P.b , Martin, N.G.o , Stevens, V.L.u , Weiss, R.B.e , Kraft, P.bg , Bierut, L.J.b , Ehringer, M.A.c
Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking
(2013) Genetic Epidemiology, 37 (8), pp. 846-859. 

a Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States
d Department of Epidemiology, Michigan State University, East Lansing, MI, United States
e Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
f Department of Psychiatry, Virginia Commonwealth University, Richmond, VIC, United States
g Institute of Psychiatry, King's College London and Department of Mental Health, St George's University, London, United States
h Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy
i Department of Epidemiology, University of North Carolina, Chapel Hill, NC, United States
j Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Clinical Faculty Mannheim, Heidelberg University, Mannheim, Germany
k Department of Epidemiology, MD Anderson, Houston, TX, United States
l Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
m Departments of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
n Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
o Department of Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia
p Department of Statistics, University of Oxford, Oxford, United Kingdom
q Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
r Center for Health Sciences, SRI International, Menlo Park, CA, United States
s Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
t Department of Sociology, Brown University, Providence, Rhode Island, United States
u Department of Epidemiology Research, American Cancer Society, Atlanta, GE, United States
v University Medicine Greifswald, University of Greifswald, Greifswald, Germany
w Department of Health Sciences, University of Leicester, Leicester, United Kingdom
x Department of Psychiatry, VU University Medical Center, Amsterdam, Netherlands
y Department of Biological Psychology, VU University, Amsterdam, Netherlands
z Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
aa Division of Cancer Epidemiology and Genetics, National Institute of Health, Bethesda, MD, United States
ab LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
ac Department of Economics, Cornell University, Ithaca, NY, United States
ad Department of Economics, New York University, New York, NY, United States
ae Division of Cancer Epidemiology and Genetics, National Institutes of Health, Bethesda, MD, United States
af Institute of Neuroscience and Medicine (INM-1), Structural and Funct. Organ. of the Brain Genomic Imaging; Dept. of Genomics, Life and Brain Center, Research Center Juelich, Juelich, Germany
ag Istituto di Ricerca Genetica e Biomedica, CNR, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy
ah Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
ai Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
aj Department of Psychiatry, University of Munich (LMU), Munich, Germany
ak Brain and Mind Research Institute, University of Sydney, Sydney, Australia
al Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
am Institute of Health Sciences and Biocenter Oulu, University of Oulu, Finland
an Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
ao Department of Applied Economics, Erasmus Universiteit Rotterdam, Rotterdam, Netherlands
ap Department of Neurology, Baltimore Veterans Affairs Medical Center, University of Maryland School of Medicine, Baltimore, MD, United States
aq Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
ar Department of Preventive and Community Dentistry and Department of Epidemiology, University of Iowa, Iowa City, IA, United States
as Department of Psychology and Dental Practice and Rural Health, West Virginia University, Morgantown, WV, United States
at Department of Medicine, University of British Columbia, Vancouver, Canada
au Department of Medicine, Turku University Hospital, Turku, Finland
av Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, United States
aw Department of the MPI Psycholinguistics, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
ax Oregon Research Institute, Eugene, OR, United States
ay Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health School of Public Health, Imperial College London, United Kingdom
az Department of Economics, Stockholm School of Economics, Stockholm, Sweden
ba Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
bb Department of Genomics, Life and Brain Center, Life and Brain Center, Institute of Human Genetics, University of Bonn, Bonn, Germany
bc Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
bd Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
be Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
bf Department of Behavioral Health Epidemiology, RTI International, Research Triangle Park, NC, United States
bg Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
bh Life and Brain Center and Institute of Human Genetics, University of Bonn, Bonn, Germany
bi Institute of Health Sciences and Biocenter Oulu, University of Oulu, Finland
bj Unit of Primary Care, Oulu University Hospital, Oulu, Finland
bk Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland

Abstract
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype. © 2013 WILEY PERIODICALS, INC.

Author Keywords
CHRNA3;  CHRNA5;  CHRNB4;  Meta-analysis;  Nicotine;  Smoke

Document Type: Article
Source: Scopus

Fagan, A.M.a , Vos, S.J.B.b 
Preclinical Alzheimer's disease criteria
(2013) The Lancet Neurology, 12 (12), p. 1134. 

a Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
b Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, 6200 MD Maastricht, Netherlands

Document Type: Letter
Source: Scopus

Zarem, C.a , Kidokoro, H.b , Neil, J.b c d , Wallendorf, M.e , Inder, T.b c d , Pineda, R.a b 
Psychometrics of the neonatal oral motor assessment scale
(2013) Developmental Medicine and Child Neurology, 55 (12), pp. 1115-1120. 

a Washington University School of Medicine, St Louis, MO, United States
b Department of Pediatrics, 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 Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Aim: To establish the psychometrics of the Neonatal Oral Motor Assessment Scale (NOMAS). Method: In this prospective cohort study of 75 preterm infants (39 females, 36 males) born at or before 30 weeks gestation (mean gestational age 26.56wks, SD 1.90, range 23-30wks; mean birthweight 967.33g, SD 288.54, range 480-2240), oral feeding was videotaped before discharge from the neonatal intensive care unit (NICU). The NOMAS was used to classify feeding as normal, disorganized, or dysfunctional. Neurobehavior was assessed at term equivalent, and infants underwent magnetic resonance imaging. Children returned for developmental testing at 2 years corrected age. Associations between NOMAS scores and (1) neurobehavior; (2) cerebral injury and metrics; and (3) developmental outcome were investigated using χ2-analyses, t-tests, and linear regression. For reliability, six certified NOMAS evaluators rated five randomly selected NOMAS recordings and re-scored them 2 weeks later in a second randomized order. Reliability was calculated with Cohen's kappa statistics. Results: Dysfunctional NOMAS scores were associated with lower Dubowitz scores [t=-2.14; mean difference -2.32 (95% confidence interval [CI] -0.157 to -4.49); p=0.036], higher stress on the NICU Network Neurobehavioral Scale (t=2.61; mean difference 0.073 [95% CI 0.017-0.129]; p=0.0110), and decreased transcerebellar diameter (t=-2.22; mean difference -2.04 [CI=-3.89 to -0.203]; p=0.03). No significant associations were found between NOMAS scores and 2-year outcome. Interpretation: Some concurrent validity was established with associations between NOMAS scores and measures of infant behavior and cerebral structure. The NOMAS did not show predictive validity in this study of preterm infants at high risk of developmental delay. Reliability was variable and suboptimal. © 2013 Mac Keith Press.

Document Type: Article
Source: Scopus

Jesuraj, N.J.a , Santosa, K.B.b , Macewan, M.R.a , Moore, A.M.b , Kasukurthi, R.b , Ray, W.Z.c , Flagg, E.R.b , Hunter, D.A.b , Borschel, G.H.b , Johnson, P.J.b , Mackinnon, S.E.b , Sakiyama-Elbert, S.E.a 
Schwann cells seeded in acellular nerve grafts improve functional recovery
(2013) Muscle and Nerve, . Article in Press. Cited 1 time.

a Department of Biomedical Engineering Washington University Campus Box 1097, One Brookings Drive St. Louis, Missouri 63130 USA
b Division of Plastic and Reconstructive Surgery Department of Surgery Washington University School of Medicine St. Louis, Missouri USA
c Department of Neurological Surgery Washington University School of Medicine St. Louis, Missouri USA

Abstract
Introduction: This study evaluated whether Schwann cells (SCs) from different nerve sources transplanted into cold-preserved acellular nerve grafts (CP-ANGs) would improve functional regeneration compared with nerve isografts. Methods: SCs isolated and expanded from motor and sensory branches of rat femoral and sciatic nerves were seeded into 14mm CP-ANGs. Growth factor expression, axonal regeneration, and functional recovery were evaluated in a 14-mm rat sciatic injury model and compared with isografts. Results: At 14 days, motor or sensory-derived SCs increased expression of growth factors in CP-ANGs versus isografts. After 42 days, histomorphometric analysis found CP-ANGs with SCs and isografts had similar numbers of regenerating nerve fibers. At 84 days, muscle force generation was similar for CP-ANGs with SCs and isografts. SC source did not affect nerve fiber counts or muscle force generation. Conclusions: SCs transplanted into CP-ANGs increase functional regeneration to isograft levels; however SC nerve source did not have an effect. © 2013 Wiley Periodicals, Inc.

Author Keywords
Cell transplantation;  Growth factor;  Nerve regeneration;  Peripheral nerve injury;  Reinnervation

Document Type: Article in Press
Source: Scopus

Winkler, A.M., Maslov, K., Wang, L.V.
Noise-equivalent sensitivity of photoacoustics
(2013) Journal of Biomedical Optics, 18 (9), art. no. 097003, . 

Washington University in St. Louis, Department of Biomedical Engineering, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
The fundamental limitations of photoacoustic microscopy for detecting optically absorbing molecules are investigated both theoretically and experimentally. We experimentally demonstrate noise-equivalent detection sensitivities of 160,000 methylene blue molecules (270 zeptomol or 2.7 × 10-19 mol) and 86,000 oxygenated hemoglobin molecules (140 zeptomol) using narrowband continuous-wave photoacoustics. The ultimate sensitivity of photoacoustics is fundamentally limited by thermal noise, which can present in the acoustic detection system as well as in the medium itself. Under the optimized conditions described herein and using commercially available detectors, photoacoustic microscopy can detect as few as 100s of oxygenated hemoglobin molecules. Realizable improvements to the detector may enable single molecule detection of select molecules. © 2013 Society of Photo-Optical Instrumentation Engineers (SPIE).

Author Keywords
acoustic black body radiation;  microscopy;  Photoacoustic;  single molecule;  thermal noise

Document Type: Article
Source: Scopus

Euteneuer, J.a , Carvalho, C.b , Kulkarni, S.c d , Vineyard, M.d , Mark Grady, R.e , Lupski, J.b , Shinawi, M.d 
Molecular and phenotypic characterization of atypical Williams-Beuren syndrome
(2013) Clinical Genetics, . Article in Press. 

a Department of Pediatrics Washington University School of Medicine St. Louis, MO USA
b Department of Molecular and Human Genetics Baylor College of Medicine Houston, TX USA
c Department of Pathology and Immunology
d Division of Genetics and Genomic Medicine, Department of Pediatrics
e Division of Cardiology Washington University School of Medicine St. Louis, MO USA

Abstract
Williams-Beuren syndrome (WBS) is a multisystemic genomic disorder typically caused by a recurrent ~1.5-1.8Mb deletion on 7q11.23. Atypical deletions can provide important insight into the genotype-phenotype correlations. Here, we report the phenotypic and molecular characterization of a girl with a de novo 81.8kb deletion in the WBS critical region, which involves the ELN and LIMK1 genes only. The patient presented at 2months of age with extensive vascular abnormalities, mild facial dysmorphism and delays in her fine motor skills. We discuss potential molecular mechanisms and the role of ELN and LIMK1 in the different phenotypic features. We compare the findings in our patient with previously reported overlapping deletions. The phenotypic variability among these patients suggests that other factors are important in the phenotype and possibly include: position effects related to copy number variation size, variations in the non-deleted alleles, genetic modifiers elsewhere in the genome, or reduced penetrance for specific phenotypes. © 2013 John Wiley & Sons A/S.

Author Keywords
7q11.23;  Deletion;  Elastin;  LIMK1;  Microarray;  Williams-Beuren syndrome

Document Type: Article in Press
Source: Scopus

Mills, S.M., Mallmann, J., Santacruz, A.M., Fuqua, A., Carril, M., Aisen, P.S., Althage, M.C., Belyew, S., Benzinger, T.L., Brooks, W.S., Buckles, V.D., Cairns, N.J., Clifford, D., Danek, A., Fagan, A.M., Farlow, M., Fox, N., Ghetti, B., Goate, A.M., Heinrichs, D., Hornbeck, R., Jack, C., Jucker, M., Klunk, W.E., Marcus, D.S., Martins, R.N., Masters, C.M., Mayeux, R., McDade, E., Morris, J.C., Oliver, A., Ringman, J.M., Rossor, M.N., Salloway, S., Schofield, P.R., Snider, J., Snyder, P., Sperling, R.A., Stewart, C., Thomas, R.G., Xiong, C., Bateman, R.J.
Erratum to "Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial" [Rev. Neurol. 169 (10) (2013) 737-743] (DOI:10.1016/j.neurol.2013.07.017)
(2013) Revue Neurologique, . Article in Press. 

DIAN-TU, Washington University in St. Louis, 660, S. Euclid Ave., Campus Box 8111, MO 63108 St. Louis, USA

Document Type: Article in Press
Source: Scopus

Pacton, S.a , Borchardt, G.a , Treiman, R.b , Lété, B.c , Fayol, M.d 
Learning to spell from reading: General knowledge about spelling patterns influences memory for specific words
(2013) Quarterly Journal of Experimental Psychology, . Article in Press. 

a Department of Psychology, Université Paris Descartes, Paris, France
b Department of Psychology, Washington University, St. Louis, MO, USA
c Department of Psychology, Université Lumière Lyon 2, Lyon, France
d Department of Psychology, Université Blaise Pascal, Clermont-Ferrand, France

Abstract
Adults often learn to spell words during the course of reading for meaning, without intending to do so. We used an incidental learning task in order to study this process. Spellings that contained double n, r and t which are common doublets in French, were learned more readily by French university students than spellings that contained less common but still legal doublets. When recalling or recognizing the latter, the students sometimes made transposition errors, doubling a consonant that often doubles in French rather than the consonant that was originally doubled (e.g., tiddunar recalled as tidunnar). The results, found in three experiments using different nonwords and different types of instructions, show that people use general knowledge about the graphotactic patterns of their writing system together with word-specific knowledge to reconstruct spellings that they learn from reading. These processes contribute to failures and successes in memory for spellings, as in other domains. © 2013 © 2013 The Experimental Psychology Society.

Author Keywords
Double letters;  Graphotactic regularities;  Implicit learning;  Spelling

Document Type: Article in Press
Source: Scopus

Benitez, A.a , Hassenstab, J.b , Bangen, K.J.c 
Neuroimaging Training Among Neuropsychologists: A Survey of the State of Current Training and Recommendations for Trainees
(2013) Clinical Neuropsychologist, . Article in Press. 

a Center for Biomedical Imaging and Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, USA
b Departments of Neurology and Psychology, Washington University in St. Louis, MO, USA
c Department of Psychiatry, University of California, San Diego, CA, USA

Abstract
Neuroimaging has gained widespread use in neuropsychological research and practice. However, there are neither established guidelines on how neuropsychologists might become competent researchers or consumers of neuroimaging data, nor any published studies describing the state of neuroimaging training among neuropsychologists. We report the results of two online surveys, one of 13 expert neuropsychologist-neuroimagers whose responses informed the formulation of a second, larger survey to neuropsychologists-at-large that were a random selection of a third of the members of the International Neuropsychological Society and American Academy of Clinical Neuropsychology. A total of 237 doctoral-level neuropsychologists, or 15.3% of potential participants, provided complete responses. Most respondents (69.2%) received training in neuroimaging, mostly at the post-doctoral level, largely through independent study, clinical conferences, instruction by clinical supervisors, and individualized mentoring, on topics such as neuroimaging modalities in neurology, neuroanatomy, and the appropriate information to glean from neuroradiology reports. Of the remaining respondents who did not receive training in neuroimaging, 64.4% indicated that such training would be very or extremely beneficial to one's career as a neuropsychologist. Both neuropsychologist-neuroimagers and neuropsychologists-at-large provided specific recommendations for training. Findings from this initial effort will guide trainees who seek to develop competence in neuroimaging, and inform future formulations of neuropsychological training. © 2013 © 2013 Taylor & Francis.

Author Keywords
MRI;  Neuroimaging;  Neuropsychology.;  Survey;  Training

Document Type: Article in Press
Source: Scopus

Brausch, A.M.a , Decker, K.M.b 
Self-Esteem and Social Support as Moderators of Depression, Body Image, and Disordered Eating for Suicidal Ideation in Adolescents
(2013) Journal of Abnormal Child Psychology, pp. 1-11. Article in Press. 

a Department of Psychological Sciences, Western Kentucky University, 1906 College Heights Blvd., Bowling Green, 42101, United States
b Department of Psychology, Washington University, 1 Brookings Drive, St. Louis, 63130, United States

Abstract
The current study investigated risk factors for suicidal ideation in a community sample of 392 adolescents (males 51.9 %; females 48.1 %), while also evaluating self-esteem, perceived parent support, and perceived peer support as protective factors and potential moderators between suicidal ideation and the 3 risk factors. Disordered eating, depression, parent support, and peer support were found to be significant predictors of current suicidal ideation, but body satisfaction was not. The relationship between depression and suicidal ideation was significantly moderated by both self-esteem and parent support, while the relationship between disordered eating and suicidal ideation was significantly moderated by peer support. Results underscore the importance of examining protective factors for suicide risk, as they have the potential to reduce suicidal ideation in adolescents. © 2013 Springer Science+Business Media New York.

Author Keywords
Adolescents;  Depression;  Disordered eating;  Self-esteem;  Social support;  Suicidal ideation

Document Type: Article in Press
Source: Scopus

Owoso, A.a , Ndetei, D.M.b c , Mbwayo, A.W.b , Mutiso, V.N.b , Khasakhala, L.I.b , Mamah, D.a 
Validation of a modified version of the PRIME screen for psychosis-risk symptoms in a non-clinical Kenyan youth sample
(2013) Comprehensive Psychiatry, . Article in Press. 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
b Africa Mental Health Foundation, Nairobi, Kenya
c Department of Psychiatry, University of Nairobi, Kenya

Abstract
Background: The PRIME screen is a self-administered questionnaire designed to quickly assess individuals at risk for developing a psychotic disorder. It is shorter in both length and administration time compared to the Structured Interview for Psychosis-Risk Syndromes (SIPS)-a standard instrument for psychosis prodromal risk assessment. Validation of the PRIME against the SIPS has not been reported in large non-clinical populations. Methods: A culturally modified version of the PRIME screen (mPRIME) was administered to Kenyan youth between the ages of 14 and 29. 182 completed both the SIPS and mPRIME. Validation measures (sensitivity, specificity, positive predictive value, negative predictive value) were calculated and the study sample was then broken down into true positives, false positives, and false negatives for comparison on different quantitative measures. Results: Using previously suggested thresholds for a positive screen, the mPRIME had a sensitivity of 40% and a specificity of 64.8% for our entire sample. Positive predictive value (PPV) and negative predictive value (NPV) were 12.3% and 89.7%, respectively. Breaking the sample down by questionnaire outcome showed that true-positive individuals scored higher on average rate and intensity of endorsement of mPRIME items compared to false-positive and false-negatives, while false-negatives on average registered disagreement on all mPRIME questionnaire items. Conclusions: The mPRIME does not appear to be an effective screener of at-risk individuals for psychosis in our non-clinical sample. Further validation efforts in other general populations are warranted. © 2013 Elsevier Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

Miller, R.L., Wang, M.H., Gray, P.A., Salkoff, L.B., Loewy, A.D.
ENaC-expressing neurons in the sensory circumventricular organs become c-Fos activated following systemic sodium changes
(2013) American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 305 (10), pp. R1141-R1152. 

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The sensory circumventricular organs (CVOs) are specialized collections of neurons and glia that lie in the midline of the third and fourth ventricles of the brain, lack a blood-brain barrier, and function as chemosensors, sampling both the cerebrospinal fluid and plasma. These structures, which include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), are sensitive to changes in sodium concentration but the cellular mechanisms involved remain unknown. Epithelial sodium channel (ENaC)-expressing neurons of the CVOs may be involved in this process. Here we demonstrate with immunohistochemical and in situ hybridization methods that ENaC-expressing neurons are densely concentrated in the sensory CVOs. These neurons become c-Fos activated, a marker for neuronal activity, after various manipulations of peripheral levels of sodium including systemic injections with hypertonic saline, dietary sodium deprivation, and sodium repletion after prolonged sodium deprivation. The increases seen c-Fos activity in the CVOs were correlated with parallel increases in plasma sodium levels. Since ENaCs play a central role in sodium reabsorption in kidney and other epithelia, we present a hypothesis here suggesting that these channels may also serve a related function in the CVOs. ENaCs could be a significant factor in modulating CVO neuronal activity by controlling the magnitude of sodium permeability in neurons. Hence, some of the same circulating hormones controlling ENaC expression in kidney, such as angiotensin II and atrial natriuretic peptide, may coordinate ENaC expression in sensory CVO neurons and could potentially orchestrate sodium appetite, osmoregulation, and vasomotor sympathetic drive. © 2013 the American Physiological Society.

Author Keywords
Area postrema;  Enac;  Epithelial sodium channels;  Organum vasculosum of the lamina terminalis;  OVLT;  Subfornical organ

Document Type: Article
Source: Scopus

Kubanek, J.a b , Wang, C.a , Snyder, L.H.a b 
Neuronal responses to target onset in oculomotor and somatomotor parietal circuits differ markedly in a choice task
(2013) Journal of Neurophysiology, 110 (10), pp. 2247-2256. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
We often look at and sometimes reach for visible targets. Looking at a target is fast and relatively easy. By comparison, reaching for an object is slower and is associated with a larger cost. We hypothesized that, as a result of these differences, abrupt visual onsets may drive the circuits involved in saccade planning more directly and with less intermediate regulation than the circuits involved in reach planning. To test this hypothesis, we recorded discharge activity of neurons in the parietal oculomotor system (area LIP) and in the parietal somatomotor system (area PRR) while monkeys performed a visually guided movement task and a choice task. We found that in the visually guided movement task LIP neurons show a prominent transient response to target onset. PRR neurons also show a transient response, although this response is reduced in amplitude, is delayed, and has a slower rise time compared with LIP. A more striking difference is observed in the choice task. The transient response of PRR neurons is almost completely abolished and replaced with a slow buildup of activity, while the LIP response is merely delayed and reduced in amplitude. Our findings suggest that the oculomotor system is more closely and obligatorily coupled to the visual system, whereas the somatomotor system operates in a more discriminating manner. © 2013 the American Physiological Society.

Author Keywords
Decision;  LIP;  Parietal reach region;  Reward;  Transient

Document Type: Article
Source: Scopus

Rotman, Z., Klyachko, V.A.
Role of synaptic dynamics and heterogeneity in neuronal learning of temporal code
(2013) Journal of Neurophysiology, 110 (10), pp. 2275-2286. 

Department of Biomedical Engineering, Department of Cell Biology and Physiology, Washington University, St. Louis, MO, United States

Abstract
Temporal codes are believed to play important roles in neuronal representation of information. Neuronal ability to classify and learn temporal spiking patterns is thus essential for successful extraction and processing of information. Understanding neuronal learning of temporal code has been complicated, however, by the intrinsic stochasticity of synaptic transmission. Using a computational model of a learning neuron, the tempotron, we studied the effects of synaptic unreliability and short-term dynamics on the neuron's ability to learn spike timing rules. Our results suggest that such a model neuron can learn to classify spike timing patterns even with unreliable synapses, albeit with a significantly reduced success rate. We explored strategies to improve correct spike timing classification and found that firing clustered spike bursts significantly improves learning performance. Furthermore, rapid activity-dependent modulation of synaptic unreliability, implemented with realistic models of dynamic synapses, further improved classification of different burst properties and spike timing modalities. Neuronal models with only facilitating or only depressing inputs exhibited preference for specific types of spike timing rules, but a mixture of facilitating and depressing synapses permitted much improved learning of multiple rules. We tested applicability of these findings to real neurons by considering neuronal learning models with the naturally distributed input release probabilities found in excitatory hippocampal synapses. Our results suggest that spike bursts comprise several encoding modalities that can be learned effectively with stochastic dynamic synapses, and that distributed release probabilities significantly improve learning performance. Synaptic unreliability and dynamics may thus play important roles in the neuron's ability to learn spike timing rules during decoding. © 2013 the American Physiological Society.

Author Keywords
Neural learning;  Short-term plasticity;  Synapse;  Synaptic dynamics;  Temporal code

Document Type: Article
Source: Scopus

Smith, M.A.a b , Roediger III, H.L.a , Karpicke, J.D.b 
Covert retrieval practice benefits retention as much as overt retrieval practice
(2013) Journal of Experimental Psychology: Learning Memory and Cognition, 39 (6), pp. 1712-1725. 

a Psychology Department, Washington University, St. Louis, United States
b Department of Psychological Sciences, Purdue University, United States

Abstract
Many experiments provide evidence that practicing retrieval benefits retention relative to conditions of no retrieval practice. Nearly all prior research has employed retrieval practice requiring overt responses, but a few experiments have shown that covert retrieval also produces retention advantages relative to control conditions. However, direct comparisons between overt and covert retrieval are scarce: Does covert retrieval-thinking of but not producing responses-on a first test produce the same benefit as overt retrieval on a criterial test given later? We report 4 experiments that address this issue by comparing retention on a second test following overt or covert retrieval on a first test. In Experiment 1 we used a procedure designed to ensure that subjects would retrieve on covert as well as overt test trials and found equivalent testing effects in the 2 cases. In Experiment 2 we replicated these effects using a procedure that more closely mirrored natural retrieval processes. In Experiment 3 we showed that overt and covert retrieval produced equivalent testing effects after a 2-day delay. Finally, in Experiment 4 we showed that covert retrieval benefits retention more than restudying. We conclude that covert retrieval practice is as effective as overt retrieval practice, a conclusion that contravenes hypotheses in the literature proposing that overt responding is better. This outcome has an important educational implication: Students can learn as much from covert self-testing as they would from overt responding. © 2013 American Psychological Association.

Author Keywords
Covert retrieval;  Memory;  Retrieval practice;  Testing effect

Document Type: Article
Source: Scopus

McClintick, J.N.a , Xuei, X.a , Tischfield, J.A.b , Goate, A.c , Foroud, T.d , Wetherill, L.d e , Ehringer, M.A.f g , Edenberg, H.J.a d 
Stress-response pathways are altered in the hippocampus of chronic alcoholics
(2013) Alcohol, 47 (7), pp. 505-515. 

a Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
b Department of Genetics, Rutgers University, Piscataway, NJ 08854, United States
c Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
d Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
e Department of Psychology, IUPUI School of Science, Indianapolis, IN 46202, United States
f Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, United States
g Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, United States

Abstract
The chronic high-level alcohol consumption seen in alcoholism leads to dramatic effects on the hippocampus, including decreased white matter, loss of oligodendrocytes and other glial cells, and inhibition of neurogenesis. Examining gene expression in post mortem hippocampal tissue from 20 alcoholics and 19 controls allowed us to detect differentially expressed genes that may play a role in the risk for alcoholism or whose expression is modified by chronic consumption of alcohol. We identified 639 named genes whose expression significantly differed between alcoholics and controls at a False Discovery Rate (FDR)≤0.20; 52% of these genes differed by at least 1.2-fold. Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 (FKBP5), UDP glycosyltransferase 8 (UGT8), urea transporter (SLC14A1), zinc transporter (SLC39A10), Interleukin 1 receptor type 1 (IL1R1), thioredoxin interacting protein (TXNIP), and many metallothioneins. Pathways related to inflammation, hypoxia, and stress showed activation, and pathways that play roles in neurogenesis and myelination showed decreases. The cortisol pathway dysregulation and increased inflammation identified here are seen in other stress-related conditions such as depression and post-traumatic stress disorder and most likely play a role in addiction. Many of the detrimental effects on the hippocampus appear to be mediated through NF-κB signaling. Twenty-four of the differentially regulated genes were previously identified by genome-wide association studies of alcohol use disorders; this raises the potential interest of genes not normally associated with alcoholism, such as suppression of tumorigenicity 18 (ST18), BCL2-associated athanogene 3 (BAG3), and von Willebrand factor (VWF). © 2013 Elsevier Inc.

Author Keywords
Alcoholism;  Cortisol;  Gene expression;  GWAS;  Hippocampus;  Inflammation;  NF-κB;  Stress

Document Type: Article
Source: Scopus

Du, F.a , Yang, J.a b , Yin, Y.a b , Zhang, K.a , Abrams, R.A.c 
On the automaticity of contingent capture: Disruption caused by the attentional blink
(2013) Psychonomic Bulletin and Review, 20 (5), pp. 944-950. 

a Key Laboratory of Behavorial Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China
b University of the Chinese Academy of Sciences, Beijing, 100049, China
c Washington University, St. Louis, MO, 63130, United States

Abstract
Converging evidence has shown that onset capture can be completely eliminated by the demands of a concurrent task and during the attentional blink. In the present study, we investigated contingent capture during the attentional blink. We found that contingent capture was attenuated, or even completely eliminated, during the "blink" time of the attentional blink. These results indicate that contingent capture requires limited attentional resources. © 2013 Psychonomic Society, Inc.

Author Keywords
Attentional blink;  Contingent capture;  Involuntary orienting;  Onset capture

Document Type: Article
Source: Scopus

Bolzenius, J.D.a , Laidlaw, D.H.b , Cabeen, R.P.b , Conturo, T.E.c , McMichael, A.R.c , Lane, E.M.d , Heaps, J.M.a , Salminen, L.E.a , Baker, L.M.a , Gunstad, J.e , Paul, R.H.a 
Impact of body mass index on neuronal fiber bundle lengths among healthy older adults
(2013) Brain Imaging and Behavior, 7 (3), pp. 300-306. 

a University of Missouri-Saint Louis, One University Boulevard, Stadler Hall 443, Saint Louis, MO, 63121, United States
b Computer Science Department, Brown University, Providence, RI, 02912, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, 63110, United States
d Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, United States
e Department of Psychology, Kent State University, Kent, OH, 44242, United States

Abstract
Increased body mass index (BMI) has been linked to various detrimental health outcomes, including cognitive dysfunction. Recent work investigating associations between obesity and the brain has revealed decreased white matter microstructural integrity in individuals with elevated BMI, independent of age or comorbid health conditions. However, the relationship between high BMI and white matter fiber bundle length (FBL), which represents a novel metric of microstructural brain integrity, remains unknown. The present study utilized quantitative tractography based on diffusion tensor imaging (DTI) to investigate the relationship between BMI and FBL in 72 otherwise healthy older adults (24 males, 48 females). All participants were between 51 and 85 years of age (M = 63.26, SD = 8.76). Results revealed that elevated BMI was associated with shorter FBL in the temporal lobe, independent of age (p <.01). In addition, increased age was associated with shorter frontal, temporal, and whole brain FBL (all p values <.01). These findings indicate that, while increased age is an important factor associated with reduced FBL, high BMI is uniquely associated with reduced FBL in the temporal lobe. These data offer evidence for additive adverse effects of high BMI on the brain, especially in areas already vulnerable to aging processes and age-related neurodegenerative diseases. Further research is necessary to determine the physiological mechanisms associated with the shortening of FBL in individuals with high BMI. © 2013 Springer Science+Business Media New York.

Author Keywords
Aging;  BMI;  DTI;  Fiber bundle length;  Tractography;  White matter

Document Type: Article
Source: Scopus

Salminen, L.E.a , Schofield, P.R.b c , Lane, E.M.d , Heaps, J.M.a , Pierce, K.D.b , Cabeen, R.e , Laidlaw, D.H.e , Akbudak, E.f , Conturo, T.E.f , Correia, S.g , Paul, R.H.a 
Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: A quantitative tractography DTI study
(2013) Brain Imaging and Behavior, 7 (3), pp. 274-281. 

a Department of Psychology, University of Missouri-Saint Louis, 1 University Boulevard, Stadler Hall 442 B, Saint Louis, MO, 63121, United States
b Neuroscience Research Australia, Sydney, NSW, 2031, Australia
c School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
d Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, United States
e Computer Science Department, Brown University, Providence, RI, 02912, United States
f Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO, 63110, United States
g Alpert Medical School, Department of Psychiatry and Human Behavior, Brown University, Box G-A, Providence, RI, 02912, United States

Abstract
The epsilon 4 (e4) isoform of apolipoprotein E (ApoE) is a known genetic risk factor for suboptimal brain health. Morphometry studies of brains with Alzheimer's disease have reported significant alterations in temporal lobe brain structure of e4 carriers, yet it remains unclear if the presence of an e4 allele is associated with alterations in the microstructure of white matter fiber bundles in healthy populations. The present study used quantitative tractography based on diffusion tensor imaging (qtDTI) to examine the influence of the e4 allele on temporal lobe fiber bundle lengths (FBLs) in 64 healthy older adults with at least one e4 allele (carriers, N = 23) versus no e4 allele (non-carriers, N = 41). Subtests from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were also analyzed to examine memory performance between groups. Analyses revealed shorter FBLs in the left uncinate fasciculus (UF) (p =.038) of e4 carriers compared to non-carriers. By contrast, neither FBLs specific to the temporal lobe nor memory performances differed significantly between groups. Increased age correlated significantly with shorter FBL in the temporal lobe and UF, and with decreased performance on tests of memory. This is the first study to utilize qtDTI to examine relationships between FBL and ApoE genotype. Results suggest that FBL in the UF is influenced by the presence of an ApoE e4 allele (ApoE4) in healthy older adults. Temporal lobe FBLs, however, are more vulnerable to aging than the presence of an e4 allele. © 2013 Springer Science+Business Media New York.

Author Keywords
Aging;  ApoE;  ApoE4;  DTI;  Fiber bundle lengths;  Tractography;  White matter

Document Type: Article
Source: Scopus

Thomas, A.K.a , Lee, M.a , Balota, D.A.b 
Metacognitive monitoring and dementia: How intrinsic and extrinsic cues influence judgments of learning in people with early-stage alzheimer's disease
(2013) Neuropsychology, 27 (4), pp. 452-463. 

a Department of Psychology, Tufts University, Medford, MA, United States
b Department of Psychology, Washington University, St. Louis MO, United States

Abstract
Objective: The present research compared metamemorial monitoring processes among younger adults, nondemented older adults, and older adults diagnosed with early stage Dementia of the Alzheimer's Type (DAT). Method: In three experiments we examined the influence of intrinsic and extrinsic cues on Judgment of Learning (JOL) accuracy. Changes in association strength between cue-target word pairs served as the intrinsic manipulation in Experiments 1 and 2. Changes in encoding orientation served as the extrinsic manipulation in Experiment 3. Results: Across all experiments we found that young adults, nondemented older adults, and individuals in the early stages of DAT effectively used intrinsic and extrinsic factors to guide JOL predictions. Conclusions: We conclude that while certain aspects of metacognition may be impaired in both the normal and demented older populations, these groups remain able to use theory-based processing, or general knowledge about how memory works, to make metamemory monitoring predictions. © 2013 American Psychological Association.

Author Keywords
Aging;  Alzheimer's disease;  Memory;  Metacognition

Document Type: Article
Source: Scopus

November 22, 2013

Documents

Bierut, L.J.a , Johnson, E.O.b , Saccone, N.L.c
A glimpse into the future - Personalized medicine for smoking cessation
(2014) Neuropharmacology, 76 (PART B), pp. 592-599. Cited 1 time.

a Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Behavioral Health Epidemiology Program, RTI International, Research Triangle Park, NC, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The devastating consequences of tobacco smoking for individuals and societies motivate studies to identify and understand the biological pathways that drive smoking behaviors, so that more effective preventions and treatments can be developed. Cigarette smokers respond to nicotine in different ways, with a small number of smokers remaining lifelong low-level smokers who never exhibit any symptoms of dependence, and a larger group becoming nicotine dependent. Whether or not a smoker transitions to nicotine dependence has clear genetic contributions, and variants in the genes encoding the α5-α3-β4 nicotinic receptor subunits most strongly contribute to differences in the risk for developing nicotine dependence among smokers. More recent work reveals a differential response to pharmacologic treatment for smoking cessation based on these same genetic variants in the α5-α3-β4 nicotinic receptor gene cluster. We anticipate a continuing acceleration of the translation of genetic discoveries into more successful treatment for smoking cessation. Given that over 400,000 people in the United States and over 5 million people world-wide die each year from smoking related illnesses, an improved understanding of the mechanisms underlying smoking behavior and smoking cessation must be a high public health priority so we can best intervene at both the public health level and the individual level. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. © 2013 Elsevier Ltd. All rights reserved.

Author Keywords
Genetics;  Nicotine dependence;  Nicotine metabolizing genes;  Nicotinic receptor genes;  Smoking cessation

Document Type: Review
Source: Scopus

Glass, J.E.a , Mowbray, O.P.b , Link, B.G.c , Kristjansson, S.D.d , Bucholz, K.K.d
Alcohol stigma and persistence of alcohol and other psychiatric disorders: A modified labeling theory approach
(2013) Drug and Alcohol Dependence, 133 (2), pp. 685-692. 

a School of Social Work, University of Wisconsin-Madison, 1350 University Avenue, Madison, WI 53706, United States
b School of Social Work, University of Georgia, 310 E. Campus Drive, Athens, GA 30602, United States
c Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, United States
d Department of Psychiatry and Midwest Alcoholism Research Center, Washington University in St. Louis School of Medicine, 660 Euclid, St. Louis, MO 63110, United States

Abstract
Background: We sought to apply modified labeling theory in a cross-sectional study of alcohol use disorder (AUD) to investigate the mechanisms through which perceived alcohol stigma (PAS) may lead to the persistence of AUD and risk of psychiatric disorder. Methods: We conducted structural equation modeling (SEM) including moderated mediation analyses of two waves (W1 and W2) of data from the National Epidemiologic Survey on Alcohol and Related Conditions. We analyzed validated measures of PAS, perceived social support, social network involvement, and psychiatric disorders among (n= 3608) adults with two or more DSM-5 AUD symptoms in the first two of the three years between the W1 and W2 survey. Cross-sectional analyses were conducted owing to the assessment of PAS only at W2. Results: Per mediation analyses, lower levels of perceived social support explained the association of PAS with past-year AUD and past-year internalizing psychiatric disorder at W2. The size of the mediated relationship was significantly larger for those classified as labeled (i.e., alcoholic) per their prior alcohol treatment or perceived need (n= 938) as compared to unlabeled (n= 2634), confirming a hypothesis of moderated mediation. Unexpectedly, mediation was also present for unlabeled individuals. Conclusions: Lower levels of social support may be an important intermediate outcome of alcohol stigma. Longitudinal data are needed to establish the temporal precedence of PAS and its hypothesized intermediate and distal outcomes. Research is needed to evaluate direct measures of labeling that could replace proxy measures (e.g., prior treatment status) commonly employed in studies of the stigma of psychiatric disorders. © 2013 Elsevier Ireland Ltd.

Author Keywords
Alcohol;  Alcoholism stigma;  Modified labeling theory;  Psychiatric disorders;  Social network;  Social support

Document Type: Article
Source: Scopus

Disney, K.L.
Dependent personality disorder: A critical review
(2013) Clinical Psychology Review, 33 (8), pp. 1184-1196. 

Washington University in Saint Louis, Department of Psychology, 1 Brookings Drive, Campus Box 1100, Saint Louis, MO 63130, United States

Abstract
Dependent personality disorder (DPD) has evolved from an abstract idea rooted in a historic and psychoanalytic context to a codified diagnosis in the DSM-IV-TR. This comprehensive review paper chronicles the evolution of DPD through each version of the DSM. Major topics relevant to the disorder are also investigated, including gender and cultural considerations, stability and manifestations of DPD across different developmental stages, comorbidity issues, and others. The purpose of this review is to provide a broad yet comprehensive examination of the complex angles of maladaptive dependency and to identify essential next steps in furthering our knowledge of this disorder. The paper concludes with a discussion of shortcomings in the body of research relevant to DPD, along with specific suggestions for improvement in this field of study.© 2013 Elsevier Ltd.

Author Keywords
Dependency;  Dependent personality disorder;  Personality disorders

Document Type: Review
Source: Scopus

Verweij, K.J.H.a , Huizink, A.C.a , Agrawal, A.b , Martin, N.G.c , Lynskey, M.T.d
Is the relationship between early-onset cannabis use and educational attainment causal or due to common liability?
(2013) Drug and Alcohol Dependence, 133 (2), pp. 580-586. 

a VU University, Department of Developmental Psychology, EMGO Institute for Health and Care Research, 1081 BT Amsterdam, Netherlands
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia
d Addictions Department, Institute of Psychiatry, King's College London, SE5 8BB, United Kingdom

Abstract
Background: Several studies have shown that early cannabis use is correlated with poor educational performance including high school drop-out. The predominant explanation for this relationship is that cannabis use causes disengagement from education. Another explanation is that the association between early cannabis use and educational attainment is not causal, but the result of overlapping risk factors that increase the likelihood of both early cannabis use and disengagement from education. These confounding factors could be of genetic and/or environmental origin. Methods: Here we use data from a large community-based sample of adult twins (N= 3337) who completed a comprehensive semi-structured telephone interview. We first apply the classical twin-design to determine whether genetic and/or environmental influences underlie the relationship between early-onset cannabis use (prior to age 18) and early school leaving. Next, with a co-twin control design we investigate whether the relationship between the two variables is more likely due to direct causality or overlapping risk factors. Results: We find a significant phenotypic correlation between early-onset cannabis use and early school leaving (r= 0.26), which could be explained by familial influences (of genetic and/or shared environmental origin). The pattern of odds ratios found in the co-twin control design is not consistent with direct causation, but rather suggests that the association is due to shared environmental factors influencing both variables. Conclusion: Our findings suggest that the relationship between early-onset cannabis use and school leaving is due to shared environmental risk factors influencing both the risk of early-onset cannabis use and early school leaving. © 2013 Elsevier Ireland Ltd.

Author Keywords
Cannabis;  Education;  Environment;  Genetics;  School drop-out;  Twin research

Document Type: Article
Source: Scopus

Stephens, S.H.a , Hartz, S.M.b , Hoft, N.R.c , Saccone, N.L.b , Corley, R.C.c , Hewitt, J.K.c , Hopfer, C.J.c , Breslau, N.d , Coon, H.e , Chen, X.f , Ducci, F.g h , Dueker, N.a , Franceschini, N.i , Frank, J.j , Han, Y.k , Hansel, N.N.l , Jiang, C.m , Korhonen, T.n , Lind, P.A.o , Liu, J.p , Lyytikäinen, L.-P.q , Michel, M.r , Shaffer, J.R.s , Short, S.E.t , Sun, J.u , Teumer, A.v , Thompson, J.R.w , Vogelzangs, N.x , Vink, J.M.y , Wenzlaff, A.z , Wheeler, W.aa , Yang, B.-Z.m , Aggen, S.H.f , Balmforth, A.J.ab , Baumeister, S.E.v , Beaty, T.H.l , Benjamin, D.J.ac , Bergen, A.W.r , Broms, U.n , Cesarini, D.ad , Chatterjee, N.ae , Chen, J.f , Cheng, Y.-C.a , Cichon, S.af ag , Couper, D.h , Cucca, F.ah , Dick, D.f , Foroud, T.ai , Furberg, H.aj , Giegling, I.ak , Gillespie, N.A.f , Gu, F.ae , Hall, A.S.ab , Hällfors, J.n , Han, S.m , Hartmann, A.M.ak , Heikkilä, K.n , Hickie, I.B.al , Hottenga, J.J.y , Jousilahti, P.am , Kaakinen, M.an , Kähönen, M.ao , Koellinger, P.D.ap , Kittner, S.aq , Konte, B.ak , Landi, M.-T.ar , Laatikainen, T.am , Leppert, M.e , Levy, S.M.as , Mathias, R.A.l , Mcneil, D.W.at , Medland, S.E.o , Montgomery, G.W.o , Murray, T.l , Nauck, M.v , North, K.E.i , Paré, P.D.au , Pergadia, M.b , Ruczinski, I.l , Salomaa, V.am , Viikari, J.av , Willemsen, G.y , Barnes, K.C.l , Boerwinkle, E.aw , Boomsma, D.I.y , Caporaso, N.ar , Edenberg, H.J.ai , Francks, C.ax , Gelernter, J.m , Grabe, H.J.v , Hops, H.ay , Jarvelin, M.-R.az ba bb bc , Johannesson, M.bd , Kendler, K.S.f , Lehtimäki, T.q , Magnusson, P.K.be , Marazita, M.L.s , Marchini, J.p , Mitchell, B.D.a , Nöthen, M.M.bf , Penninx, B.W.x , Raitakari, O.bg , Rietschel, M.j , Rujescu, D.aj , Samani, N.J.bh , Schwartz, A.G.z , Shete, S.k , Spitz, M.k , Swan, G.E.r , Völzke, H.v , Veijola, J.am , Wei, Q.k , Amos, C.k , Cannon, D.S.e , Grucza, R.b , Hatsukami, D.bi , Heath, A.b , Johnson, E.O.bj , Kaprio, J.n , Madden, P.b , Martin, N.G.o , Stevens, V.L.u , Weiss, R.B.e , Kraft, P.bk , Bierut, L.J.b , Ehringer, M.A.c
Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking
(2013) Genetic Epidemiology, . Article in Press. 

a Department of Epidemiology and Public Health University of Maryland Baltimore, Maryland United States of America
b Department of Psychiatry Washington University School of Medicine St. Louis, Missouri United States of America
c Institute for Behavioral Genetics University of Colorado Boulder, Colorado United States of America
d Department of Epidemiology Michigan State University East Lansing, Michigan United States of America
e Department of Psychiatry University of Utah School of Medicine Salt Lake City, Utah United States of America
f Department of Psychiatry Virginia Commonwealth University Richmond, Virginia United States of America
g Institute of Psychiatry, King's College London and Department of Mental Health St George's University London United Kingdom
h Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology University of Pisa Pisa Italy
i Department of Epidemiology University of North Carolina Chapel Hill, North Carolina United States of America
j Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Clinical Faculty Mannheim/Heidelberg University Mannheim Germany
k Department of Epidemiology MD Anderson Houston, Texas United States of America
l Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore, Maryland United States of America
m Departments of Psychiatry Yale University School of Medicine New Haven, Connecticut United States of America
n Department of Public Health Hjelt Institute, University of Helsinki Helsinki Finland
o Department of Epidemiology Queensland Institute of Medical Research Brisbane, Queensland Australia
p Department of Statistics University of Oxford Oxford United Kingdom
q Department of Clinical Chemistry, Fimlab Laboratories Tampere University Hospital and University of Tampere School of Medicine Tampere Finland
r Center for Health Sciences SRI International Menlo Park, California United States of America
s Department of Human Genetics University of Pittsburgh Pittsburgh, Pennsylvania United States of America
t Department of Sociology Brown University Providence, Rhode Island United States of America
u Department of Epidemiology Research American Cancer Society Atlanta, Georgia United States of America
v University Medicine Greifswald University of Greifswald Greifswald Germany
w Department of Health Sciences University of Leicester Leicester United Kingdom
x Department of Psychiatry VU University Medical Center Amsterdam The Netherlands
y Department of Biological Psychology VU University Amsterdam, Amsterdam The Netherlands
z Karmanos Cancer Institute Wayne State University Detroit, Michigan United States of America
aa Division of Cancer Epidemiology and Genetics National Institute of Health Bethesda, Maryland United States of America
ab LIGHT Research Institute, Faculty of Medicine and Health University of Leeds Leeds United Kingdom
ac Department of Economics Cornell University Ithaca, New York United States of America
ad Department of Economics New York University New York, New York United States of America
ae Division of Cancer Epidemiology and Genetics National Institutes of Health Bethesda, Maryland United States of America
af Institute of Neuroscience and Medicine (INM-1); Structural and Functional Organization of the Brain Genomic Imaging; Department of Genomics, Life and Brain Center; Research Center Juelich, Juelich, Germany
ag Life and Brain Center and Institute of Human Genetics University of Bonn Bonn Germany
ah Istituto di Ricerca Genetica e Biomedica CNR, Cittadella Universitaria di Monserrato Monserrato, Cagliari Italy
ai Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, Indiana United States of America
aj Department of Epidemiology and Biostatistics Memorial Sloan-Kettering Cancer Center New York, New York United States of America
ak Department of Psychiatry University of Munich (LMU) Munich Germany
al Brain and Mind Research Institute University of Sydney Sydney Australia
am Department of Chronic Disease Prevention National Institute for Health and Welfare Helsinki Finland
an Institute of Health Sciences and Biocenter Oulu University of Oulu Finland
ao Department of Clinical Physiology Tampere University Hospital and University of Tampere School of Medicine Tampere Finland
ap Department of Applied Economics Erasmus Universiteit Rotterdam Rotterdam Netherlands
aq Department of Neurology, Baltimore Veterans Affairs Medical Center University of Maryland School of Medicine Baltimore, Maryland United States of America
ar Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda, Maryland United States of America
as Department of Preventive and Community Dentistry and Department of Epidemiology University of Iowa Iowa City, Iowa United States of America
at Department of Psychology and Dental Practice and Rural Health West Virginia University Morgantown, West Virginia United States of America
au Department of Medicine University of British Columbia Vancouver Canada
av Department of Medicine Turku University Hospital Turku Finland
aw Human Genetics Center The University of Texas Health Science Center at Houston Houston, Texas United States of America
ax Department of the MPI Psycholinguistics Max Planck Institute for Psycholinguistics Nijmegen The Netherlands
ay Oregon Research Institute Eugene, Oregon United States of America
az Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health School of Public Health, Imperial College London, United Kingdom
ba Institute of Health Sciences and Biocenter Oulu, University of Oulu, Finland
bb Unit of Primary Care, Oulu University Hospital, Oulu, Finland
bc Department of Children and Young People and Families National Institute for Health and Welfare Oulu Finland
bd Department of Economics Stockholm School of Economics Stockholm Sweden
be Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
bf Department of Genomics, Life and Brain Center Life and Brain Center, Institute of Human Genetics, University of Bonn Bonn Germany
bg Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital; Research Centre of Applied and Preventive Cardiovascular Medicine University of Turku Turku Finland
bh Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Department of Cardiovascular Sciences University of Leicester Leicester United Kingdom
bi Department of Psychiatry University of Minnesota Minneapolis, Minnesota United States of America
bj Department of Behavioral Health Epidemiology RTI International Research Triangle Park, North Carolina United States of America
bk Department of Epidemiology Harvard School of Public Health Boston, Massachusetts United States of America

Abstract
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype. © 2013 WILEY PERIODICALS, INC.

Author Keywords
CHRNA3;  CHRNA5;  CHRNB4;  Meta-analysis;  Nicotine;  Smoke

Document Type: Article in Press
Source: Scopus

Chen, L.-S., Bierut, L.J.
Genomics and personalized medicine: CHRNA5-CHRNA3-CHRNB4 and smoking cessation treatment
(2013) Journal of Food and Drug Analysis, . Article in Press. 

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Cigarette smoking is highly addictive, and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We review the significance of variants in the nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) in the prediction of smoking quantity, smoking cessation, and response to cessation medication in multiple studies of smoking cessation. Three common haplotypes (low-risk, intermediate-risk, and high-risk) in the CHRNA5-CHRNA3-CHRNB4 region are defined by rs16969968 and rs680244. The genetic variants in the CHRNA5-CHRNA3-CHRNB4 region that predict nicotine dependence also predicted a later age of smoking cessation in a community-based sample. In a smoking cessation trial, these variants predicted abstinence at the end of treatment in individuals receiving placebo medication, but not among individuals receiving active medication. Pharmacological treatments moderate the genetic risk in affecting cessation success. These pharmacogenetic interactions have been reproduced by a recent meta-analysis of smoking cessation trials. The number needed to treat was four for smokers with the high-risk haplotype, seven for smokers with the intermediate-risk haplotype, and > 1000 for smokers with the low-risk haplotype. The wide variation in number needed to treat between smokers with different haplotypes supports the notion that personalized smoking cessation intervention based upon genotype could meaningfully increase the efficiency of such treatment. In summary, variants in the CHRNA5-CHRNA3-CHRNB4 region identify individuals at increased risk of cessation failure, and this increased risk can be ameliorated by cessation pharmacotherapy. © 2013.

Author Keywords
Personalized medicine;  Pharmacogenetics;  Smoking cessation

Document Type: Article in Press
Source: Scopus

Valakh, V.a , Walker, L.J.a , Skeath, J.B.b , DiAntonio, A.a
Loss of the spectraplakin short stop activates the DLK injury response pathway in drosophila
(2013) Journal of Neuroscience, 33 (45), pp. 17863-17873. 

a Department of Developmental Biology, Hope Center for Neurological Disorders, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The MAPKKK dual leucine zipper-containing kinase (DLK, Wallenda in Drosophila) is an evolutionarily conserved component of the axonal injury response pathway. After nerve injury,DLKpromotes degeneration of distal axons and regeneration of proximal axons. This dual role in coordinating degeneration and regeneration suggests that DLK may be a sensor of axon injury, and so understanding how DLK is activated is important. Two mechanisms are known to activate DLK. First, increasing the levels of DLK via overexpression or loss of thePHRubiquitin ligases that target DLK activate DLK signaling. Second, in Caenorhabditis elegans, a calcium-dependent mechanism, can activate DLK. Here we describe a new mechanism that activates DLK in Drosophila: Loss of the spectraplakin short stop (shot). In a genetic screen for mutants with defective neuromuscular junction development, we identify a hypomorphic allele of shot that displays synaptic terminal overgrowth and a precocious regenerative response to nerve injury. We demonstrate that both phenotypes are the result of overactivation of the DLK signaling pathway. Wefurther show that, unlike mutations in the PHR ligase Highwire, loss of function of shot activates DLK without a concomitant increase in the levels of DLK. As a spectraplakin, Shot binds to both actin and microtubules and promotes cytoskeletal stability. The DLK pathway is also activated by downregulation of the TCP1 chaperonin complex, whose normal function is to promote cytoskeletal stability. These findings support the model that DLK is activated by cytoskeletal instability, which is a shared feature of both spectraplakin mutants and injured axons. © 2013 the authors.

Document Type: Article
Source: Scopus

Lehtinen, M.K.a , Bjornsson, C.S.b , Dymecki, S.M.c , Gilbertson, R.J.d , Holtzman, D.M.e , Monuki, E.S.f
The choroid plexus and cerebrospinal fluid: Emerging roles in development, disease, and therapy
(2013) Journal of Neuroscience, 33 (45), pp. 17553-17559. 

a Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States
b Neural Stem Cell Institute, Rensselaer, NY 12144, United States
c Department of Genetics, Harvard Medical School, Boston, MA 02115, United States
d St. Jude Children's Research Hospital, Memphis, TN 03105, United States
e Department of Neurology, Washington University, St. Louis, MI 63110, United States
f Department of Pathology and Laboratory Medicine, University of California, Irvine School of Medicine, Irvine, CA 92697, United States

Abstract
Although universally recognized as the source of cerebrospinal fluid (CSF), the choroid plexus (ChP) has been one of the most understudied tissues in neuroscience. The reasons for this are multiple and varied, including historical perceptions about passive and permissive roles for the ChP, experimental issues, and lack of clinical salience. However, recent work on theChPand instructive signals in the CSF have sparked new hypotheses about how the ChP and CSF provide unexpected means for regulating nervous system structure and function in health and disease, as well as new ChP-based therapeutic approaches using pluripotent stem cell technology. This minisymposium combines new and established investigators to capture some of the newfound excitement surrounding the ChP-CSF system. © 2013 the authors.

Document Type: Article
Source: Scopus

Zhan, X.a , Larson, D.E.b , Wang, C.a c , Koboldt, D.C.b , Sergeev, Y.V.d , Fulton, R.S.b , Fulton, L.L.b , Fronick, C.C.b , Branham, K.E.e , Bragg-Gresham, J.a , Jun, G.a , Hu, Y.a , Kang, H.M.a , Liu, D.a , Othman, M.e , Brooks, M.f , Ratnapriya, R.f , Boleda, A.f , Grassmann, F.g , Von Strachwitz, C.h , Olson, L.M.i j , Buitendijk, G.H.S.k l , Hofman, A.l m , Van Duijn, C.M.l , Cipriani, V.n o , Moore, A.T.n o , Shahid, H.p q , Jiang, Y.r , Conley, Y.P.s , Morgan, D.J.t , Kim, I.K.u , Johnson, M.P.v , Cantsilieris, S.w , Richardson, A.J.w , Guymer, R.H.w , Luo, H.x y , Ouyang, H.x y , Licht, C.z , Pluthero, F.G.aa , Zhang, M.M.x y , Zhang, K.x y , Baird, P.N.w , Blangero, J.v , Klein, M.L.ab , Farrer, L.A.ac ad ae af ag , DeAngelis, M.M.t , Weeks, D.E.r ah , Gorin, M.B.ai , Yates, J.R.W.n o p , Klaver, C.C.W.k l , Pericak-Vance, M.A.aj , Haines, J.L.i j , Weber, B.H.F.g , Wilson, R.K.b , Heckenlively, J.R.e , Chew, E.Y.ak , Stambolian, D.al , Mardis, E.R.b , Swaroop, A.f , Abecasis, G.R.a
Identification of a rare coding variant in complement 3 associated with age-related macular degeneration
(2013) Nature Genetics, 45 (11), pp. 1375-1381. 

a Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, United States
b Genome Institute, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Biostatistics, Harvard School of Public Health, Boston, MA, United States
d Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD, United States
e Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI, United States
f Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, US National Institutes of Health, Bethesda, MD, United States
g Institute of Human Genetics, University of Regensburg, Regensburg, Germany
h Southwest Eye Center, Stuttgart, Germany
i Center for Human Genetics Research, Vanderbilt University Medical School, Nashville, TN, United States
j Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN, United States
k Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
l Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
m Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, The Hague, Netherlands
n UCL Institute of Ophthalmology, University College London, London, United Kingdom
o Moorfields Eye Hospital, London, United Kingdom
p Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
q Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
r Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
s Department of Health Promotion and Development, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
t Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT, United States
u Retina Service and Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, United States
v Texas Biomedical Research Institute, San Antonio, TX, United States
w Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia
x Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, San Diego, CA, United States
y Institute for Genomic Medicine, University of California, San Diego, San Diego, CA, United States
z Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
aa Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
ab Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland, OR, United States
ac Section on Biomedical Genetics, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, United States
ad Department of Epidemiology, Boston University, School of Public Health, Boston, MA, United States
ae Department of Biostatistics, Boston University, School of Public Health, Boston, MA, United States
af Department of Neurology, Boston University, School of Medicine, Boston, MA, United States
ag Department of Ophthalmology, Boston University, School of Medicine, Boston, MA, United States
ah Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
ai Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
aj John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, United States
ak Division of Epidemiology and Clinical Applications, National Eye Institute, US National Institutes of Health, Bethesda, MD, United States
al Department of Ophthalmology and Human Genetics, University of Pennsylvania Medical School, Philadelphia, PA, United States

Abstract
Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (f case) = 0.51%; control frequency (f control) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (f case = 1.06%; f control = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology. © 2013 Nature America, Inc. All rights reserved.

Document Type: Letter
Source: Scopus

Wintermark, M.a , Sanelli, P.C.b , Albers, G.W.c , Bello, J.A.d , Derdeyn, C.P.e f , Hetts, S.W.g , Johnson, M.H.h , Kidwell, C.S.i , Lev, M.H.j , Liebeskind, D.S.k , Rowley, H.A.l , Schaefer, P.W.j , Sunshine, J.L.m , Zaharchuk, G.n , Meltzer, C.C.o
Imaging recommendations for acute stroke and transient ischemic attack patients: A joint statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery
(2013) JACR Journal of the American College of Radiology, 10 (11), pp. 828-832. 

a Division of Neuroradiology, University of Virginia, Department of Radiology, 1215 Lee Street, Charlottesville, VA 22903, United States
b Department of Radiology, Weill Cornell Medical College, NewYork Presbyterian Hospital, New York, NY, United States
c Stanford Stroke Center, Stanford University, Stanford, CA, United States
d Division of Neuroradiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States
e Mallinckrodt Institute of Radiology, St Louis MO, United States
f Stroke and Cerebrovascular Center, Washington University School of Medicine, St Louis MO, United States
g San Francisco General Hospital, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA, United States
h Division of Neuroradiology, Yale University School of Medicine, New Haven, CT, United States
i Georgetown University Stroke Center, Georgetown University Medical Center, Washington, DC, United States
j Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
k University of California, Los Angeles, Department of Neurology, Stroke Center, Los Angeles, CA, United States
l Division of Neuroradiology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States
m Division of Neuroradiology, Case Western Reserve University and University Hospitals, Cleveland, OH, United States
n Division of Neuroradiology, Stanford University, Stanford, CA, United States
o Department of Radiology, Emory University School of Medicine, Atlanta, GA, United States

Abstract
In the article entitled "Imaging Recommendations for Acute Stroke and Transient Ischemic Attack Patients: A Joint Statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery", we are proposing a simple, pragmatic approach that will allow the reader to develop an optimal imaging algorithm for stroke patients at their institution. © 2013 American College of Radiology.

Author Keywords
catheter angiography;  computed tomography;  magnetic resonance imaging;  Stroke;  thrombolysis

Document Type: Article
Source: Scopus

Seddon, J.M.a b c , Yu, Y.a , Miller, E.C.d , Reynolds, R.a , Tan, P.L.e f g , Gowrisankar, S.h , Goldstein, J.I.i j , Triebwasser, M.d , Anderson, H.E.k , Zerbib, J.l , Kavanagh, D.k , Souied, E.l , Katsanis, N.e f g , Daly, M.J.i j , Atkinson, J.P.d , Raychaudhuri, S.h i m n o
Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration
(2013) Nature Genetics, 45 (11), pp. 1366-1373. 

a Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, United States
b Department of Ophthalmology, Tufts University, School of Medicine, Boston, MA, United States
c Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States
d Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Center for Human Disease Modeling, Duke University, Durham, NC, United States
f Department of Cell Biology, Duke University, Durham, NC, United States
g Department of Pediatrics, Duke University, Durham, NC, United States
h Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, United States
i Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
j Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
k Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle-upon-Tyne, United Kingdom
l Department of Ophthalmology, Hôpital Intercommunal de Créteil, Université Paris Est Créteil, Créteil, France
m Division of Genetics, Brigham and Women's Hospital, Boston, MA, United States
n Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, United States
o Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom

Abstract
To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10 -8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10 -5, OR = 2.8; joint P = 5.2 × 10 -9, OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10 -5, OR = 2.2; joint P = 6.5 × 10 -7, OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder. © 2013 Nature America, Inc. All rights reserved.

Document Type: Letter
Source: Scopus

Ray, W.a , Dailey, A.T.b
Response
(2013) Journal of Neurosurgery: Spine, 19 (5), p. 647. 

a School of Medicine, Washington University, St. Louis, MO, United States
b Clinical Neurosciences Center, University of Utah, Salt Lake City, UT, United States

Document Type: Letter
Source: Scopus

Jasinska, A.J.a , Schmitt, C.A.b , Service, S.K.c , Cantor, R.M.d , Dewar, K.e , Jentsch, J.D.f , Kaplan, J.R.g , Turner, T.R.h i , Warren, W.C.j , Weinstock, G.M.j , Woods, R.P.k , Freimer, N.B.l
Systems biology of the vervet monkey
(2013) ILAR Journal, 54 (2), art. no. ilt049, pp. 122-143. Cited 1 time.

a Center for Neurobehavioral, Genetics at UCLA, Los Angeles, CA, United States
b Department of Anthropology, University of Southern California, Los Angeles, CA, United States
c Center for Neurobehavioral, Genetics at UCLA, Los Angeles, CA, United States
d Department of Human Genetics at the David Geffen, School of Medicine at UCLA, Los Angeles, CA, United States
e McGill University, Montreal, Canada
f Department of Psychology at UCLA, Los Angeles, CA, United States
g Translational Science, and Anthropology, Wake Forest School of Medicine, Winston-Salem, NC, United States
h Department of Anthropology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
i Department of Genetics, University of the Free State, Bloemfontein, South Africa
j Genome Institute, Washington University, St. Louis, MO, United States
k Departments of Neurology, Psychiatry and Biobehavioral Sciences at the David Geffen, School of Medicine at UCLA, Los Angeles, CA, United States
l Department of Psychiatry, Biobehavioral Sciences at UCLA, Los Angeles, CA, United States

Abstract
Nonhuman primates (NHP) provide crucial biomedical model systems intermediate between rodents and humans. The vervet monkey (also called the African green monkey) is a widely used NHP model that has unique value for genetic and genomic investigations of traits relevant to human diseases. This article describes the phylogeny and population history of the vervet monkey and summarizes the use of both captive and wild vervet monkeys in biomedical research. It also discusses the effort of an international collaboration to develop the vervet monkey as the most comprehensively phenotypically and genomically characterized NHP, a process that will enable the scientific community to employ this model for systems biology investigations. © The Author 2013. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved.

Author Keywords
African green monkey;  Genetics;  Genomics;  Phenomics;  Simian immunodeficiency virus [siv];  Systems biology;  Transcriptomics;  Vervet

Document Type: Article
Source: Scopus

Kolling, W.M.a , McPherson, T.B.a , McJunkin, J.L.b
The use of extemporaneously compounded 1% tetracaine to improve adherence with clotrimazole 1% topical solution in the treatment of ear infection: A case report
(2013) American Journal of Otolaryngology - Head and Neck Medicine and Surgery, 34 (6), pp. 757-758. 

a Department of Pharmaceutical Sciences, Southern Illinois University, Edwardsville School of Pharmacy, Edwardsville, IL, United States
b Department of Otolaryngology-Head and Neck Surgery, Washington University, St. Louis, MO, United States

Abstract
For most medically amenable conditions, adherence to drug therapy is a necessary condition for a successful outcome. Drug side effects, especially pain, can interfere with the desired outcome. We report a case of non-adherence due to severe pain associated with the topical use of clotrimazole 1% solution in the ear. Instillation of tetracaine 1% solution prior to the administration of the clotrimazole blocked the pain sensation allowing the patient to successfully complete the antifungal therapy. © 2013 Elsevier Inc. All rights reserved.

Document Type: Article
Source: Scopus

VanEssen, D.C.
Cartography and connectomes
(2013) Neuron, 80 (3), pp. 775-790. 

Anatomy and Neurobiology Department, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
The past 25 years have seen great progress in parcellating the cerebral cortex into a mosaic of many distinct areas in mice, monkeys, and humans. Quantitative studies of interareal connectivity have revealed unexpectedly many pathways and a wide range of connection strengths in mouse and macaque cortex. In humans, advances in analyzing "structural" and "functional" connectivity using powerful but indirect noninvasive neuroimaging methods are yielding intriguing insights about brain circuits, their variability across individuals, and their relationship to behavior. The last decades have witnessed a revolution in mapping the brain. David Van Essen reviews the history of brain cartography and discusses how recent innovations in neuroimaging of the human connectome are leading to new insights into brain circuits and the relationships between neural structure, function, and behavior. © 2013 Elsevier Inc.

Document Type: Review
Source: Scopus

Shi, Y.a , Tu, Y.b , Mecham, R.P.b , Bassnett, S.a b b
Ocular phenotype of Fbn2-null mice
(2013) Investigative Ophthalmology and Visual Science, 54 (12), pp. 7163-7173. 

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose. Fibrillin-2 (Fbn2) is the dominant fibrillin isoform expressed during development of the mouse eye. To test its role in morphogenesis, we examined the ocular phenotype of Fbn2-/- mice. Methods. Ocular morphology was assessed by confocal microscopy using antibodies against microfibril components. Results. Fbn2-/- mice had a high incidence of anterior segment dysgenesis. The iris was the most commonly affected tissue. Complete iridal coloboma was present in 37% of eyes. Dyscoria, corectopia and pseudopolycoria were also common (43% combined incidence). In wild-type (WT) mice, fibrillin-2-rich microfibrils are prominent in the pupillary membrane (PM) during development. In Fbn2-null mice, the absence of Fbn2 was partially compensated for by increased expression of fibrillin-1, although the resulting PM microfibrils were disorganized, compared with WTs. In colobomatous adult Fbn2-/- eyes, the PM failed to regress normally, especially beneath the notched region of the iris. Segments of the ciliary body were hypoplastic, and zonular fibers, although relatively plentiful, were unevenly distributed around the lens equator. In regions where the zonular fibers were particularly disturbed, the synchronous differentiation of the underlying lens fiber cells was affected. Conclusions. Fbn2 has an indispensable role in ocular morphogenesis in mice. The high incidence of iris coloboma in Fbn2-null animals implies a previously unsuspected role in optic fissure closure. The observation that fiber cell differentiation was disturbed in Fbn2-/- mice raises the possibility that the attachment of zonular fibers to the lens surface may help specify the equatorial margin of the lens epithelium. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

Author Keywords
Ciliary epithelium;  Ciliary zonule;  Coloboma;  Fibrillin;  Lens;  Optic fissure;  Pupillary membrane;  Tunica vasculosa lentis

Document Type: Article
Source: Scopus

Oeding, K., Valente, M.
The effectiveness of the directional microphone in the oticon medical ponto pro in participants with unilateral sensorineural hearing loss
(2013) Journal of the American Academy of Audiology, 24 (8), pp. 701-713. 

Division of Adult Audiology, Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis School of Medicine, 4566 Scott Ave., St. Louis, MO 63110, United States

Abstract
Background: Current bone anchored hearing solutions (BAHSs) have incorporated automatic adaptive multichannel directional microphones (DMs). Previous fixed single-channel hypercardioid DMs in BAHSs have provided benefit in a diffuse listening environment, but little data are available on the performance of adaptive multichannel DMs in BAHSs for persons with unilateral sensorineural hearing loss (USNHL). Purpose: The primary goal was to determine if statistically significant differences existed in the mean Reception Threshold for Sentences (RTS in dB) in diffuse uncorrelated restaurant noise between unaided, an omnidirectional microphone (OM), split DM (SDM), and full DM (FDM) in the Oticon Medical Ponto Pro. A second goal was to assess subjective benefit using the Abbreviated Profile of Hearing Aid Benefit (APHAB) comparing the Ponto Pro to the participant's current BAHS, and the Ponto Pro and participant's own BAHS to unaided. The third goal was to compare RTS data of the Ponto Pro to data from an identical study examining Cochlear Americas' Divino. Research Design: A randomized repeated measures, single blind design was used to measure an RTS for each participant for unaided, OM, SDM, and FDM. Study Sample: Fifteen BAHS users with USNHL were recruited from Washington University in St. Louis and the surrounding area. Data Collection and Analysis: The Ponto Pro was fit by measuring in-situ bone conduction thresholds and was worn for 4 wk. An RTS was obtained utilizing Hearing in Noise Test (HINT) sentences in uncorrelated restaurant noise from an eight loudspeaker array, and subjective benefit was determined utilizing the APHAB. Analysis of variance (ANOVA) was used to analyze the results of the Ponto Pro HINT and APHAB data, and comparisons between the Ponto Pro and previous Divino data. Results: No statistically significant differences existed in mean RTS between unaided, the Ponto Pro's OM, SDM, or FDM (p = 5 0.10). The Ponto Pro provided statistically significant benefit for the Background Noise (BN) (p < 0.01) and Reverberation (RV) (p < 0.05) subscales compared to the participant's own BAHS. The Ponto Pro (Ease of Communication [EC] [p < 0.01], BN [p < 0.001], and RV [p < 0.01] subscales) and participant's own BAHS (BN [p < 0.01] and RV [p < 0.01] subscales) overall provided statistically significant benefit compared to unaided. Clinically significant benefit of 5% was present for the Ponto Pro compared to the participant's own BAHS and 10% for the Ponto Pro and the participant's own BAHS compared to unaided. The Ponto Pro's OM (p = 5 0.05), SDM (p = 5 0.05), and FDM (p < 0.01) were statistically significantly better than the Divino's OM. No significant differences existed between the Ponto Pro's OM, SDM, and FDM compared to the Divino's DM. Conclusions: No statistically significant differences existed between unaided, OM, SDM, or FDM. Participants preferred the Ponto Pro compared to the participant's own BAHS and the Ponto Pro and participant's own BAHS compared to unaided. The RTS of the Ponto Pro's adaptive multichannel DM was similar to the Divino's fixed hypercardioid DM, but the Ponto Pro's OM was statistically significantly better than the Divino's OM.

Author Keywords
Bone anchored hearing aid;  Directional microphone;  Ponto Pro;  Single sided deafness;  Unilateral sensorineural hearing loss

 Document Type: Conference Paper
Source: Scopus

 

November 15, 2013

Documents

Suzuki, H.a , Belden, A.C.a , Spitznagel, E.b , Dietrich, R.a , Luby, J.L.a
Blunted stress cortisol reactivity and failure to acclimate to familiar stress in depressed and sub-syndromal children
(2013) Psychiatry Research, 210 (2), pp. 575-583. 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Depressed adults have shown blunted or elevated cortisol reactivity in response to various forms of psychosocial stress. However, there have been few studies of cortisol reactivity in children who had early onset depression or a history of depression during the preschool-school period. The present study utilized a laboratory stress paradigm and collected salivary cortisol from preschoolers at baseline (ages 3-5 years) and 24-month follow-up (ages 5-7 years). Repeated-measures multivariate analyses of variance (MANOVAs) were used to compare cortisol reactivity to mild stress between children with Major Depressive Disorder (MDD), elevated symptoms of depression (sub-syndromal MDD), and healthy controls. For healthy children, a quadratic cortisol reactivity curve was found at baseline ( n=73), which appeared flatter under similar stressful situations at follow-up ( n=14), which may reflect acclimation to the paradigm. In contrast, children with MDD ( n=46) and sub-syndromal MDD ( n=76) showed a peak cortisol response to the novelty of lab arrival and then reduced and blunted responses to stressors at baseline. These cortisol responses persisted at follow-up in children with a history of MDD ( n=41) or sub-syndromal MDD ( n=73). These results suggest that the hypothalamic-pituitary-adrenal (HPA) axis shows a blunted response to stress and failed to acclimate to familiar stressful situations in depressed and sub-syndromal depressed children. © 2013 Elsevier Ireland Ltd.

Author Keywords
Child;  High-risk;  Hypothalamic-pituitary-adrenal axis;  Major depressive disorder;  Preschool;  Salivary cortisol

Document Type: Article
Source: Scopus

Brier, M.R.a , Thomas, J.B.b , Fagan, A.M.b c e , Hassenstab, J.b e f , Holtzman, D.M.b c e , Benzinger, T.L.d e , Morris, J.C.b e , Ances, B.M.b c e g
Functional connectivity and graph theory in preclinical Alzheimer's disease
(2013) Neurobiology of Aging, . Article in Press. 

a Program in Neuroscience, Division of Biological and Biomedical Science, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
b Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
c Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA
d Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
e Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA
f Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA
g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA

Abstract
Alzheimer's disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Alzheimer's disease;  Biomarker;  Functional connectivity;  Graph theory;  Resting-state

Document Type: Article in Press
Source: Scopus

Delerue, F.a b c , White, M.d , Ittner, L.M.a b c e
Inducible, tightly regulated and non-leaky neuronal gene expression in mice
(2013) Transgenic Research, pp. 1-9. Article in Press. 

a Transgenic Animal Unit, School of Medical Science, University of New South Wales, Sydney, 2052, Australia
b Dementia Research Unit, School of Medical Science, University of New South Wales, Sydney, 2052, Australia
c Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Sydney, 2050, Australia
d Department of Pathology, Washington University School of Medicine, St Louis, United States
e Neuroscience Research Australia, Sydney, 2031, Australia

Abstract
The Tetracycline (Tet)-controlled inducible system is the most widely used reversible system for transgene expression in mice with over 500 lines created to date. Although this system has been optimized over the years, it still has limitations such as residual transgene expression when turned off, referred to as leakiness. Here, we present a series of new Tet-OFF transgenic mice based on the second generation tetracycline-responsive transactivator system. The tTA-Advanced (tTA2S) is expressed under control of the neuron-specific Thy1.2 promoter (Thy-OFF), to regulate expression in the mouse brain. In addition, we generated a lacZ reporter line, utilizing the Ptight Tet-responsive promoter (Ptight-lacZ), to test our system. Two Thy-OFF transgenic lines displaying two distinct patterns of expression were selected. Oral doxycycline treatment of Thy-OFF/Ptight-lacZ mice demonstrated tight transgene regulation with no leak expression. These new Thy-OFF mice are valuable for studies in a broad range of neurodegenerative diseases such as Alzheimer's disease and related forms of dementia, where control of transgene expression is critical to understanding mechanisms underlying the disease. Furthermore, Ptight-lacZ reporter mice may be widely applicable. © 2013 Springer Science+Business Media Dordrecht.

Author Keywords
Doxycycline;  LacZ reporter;  Leakage;  TET system;  Thy1.2 promoter;  Transgenic mice

Document Type: Article in Press
Source: Scopus

Ferentinos, P.a , Rivera, M.a b , Ising, M.c , Spain, S.L.d , Cohen-Woods, S.e , Butler, A.W.a f , Craddock, N.g , Owen, M.J.g , Korszun, A.h , Jones, L.i , Jones, I.g , Gill, M.j , Rice, J.P.k , Maier, W.l , Mors, O.m , Rietschel, M.n , Lucae, S.c , Binder, E.B.c , Preisig, M.o , Tozzi, F.p , Muglia, P.q , Breen, G.a r , Craig, I.W.a , Farmer, A.E.a , Müller-Myhsok, B.c , McGuffin, P.a , Lewis, C.M.a d
Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution
(2013) Journal of Affective Disorders, . Article in Press. 

a MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom
b Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, University of Granada, Spain
c Max Planck Institute of Psychiatry, Munich, Germany
d Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom
e Department of Psychiatry, University of Adelaide, Adelaide, Australia
f Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, China
g MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
h Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
i Department of Psychiatry, Neuropharmacology and Neurobiology Section, University of Birmingham, Birmingham, United Kingdom
j Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland
k Department of Psychiatry, Washington University, St. Louis, Missouri, United States
l Department of Psychiatry, University of Bonn, Bonn, Germany
m Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
n Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
o University Hospital Center and University of Lausanne, Lausanne, Switzerland
p Aptuit Center for Drug Discovery and Development, Verona, Italy
q Department of Psychiatry, University of Toronto, Toronto, Canada
r NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, United Kingdom

Abstract
Background: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. Methods: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. Results: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10-7), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10-6 after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. Limitations: Episode count was self-reported and, therefore, subject to recall bias. Conclusions: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts. © 2013 Elsevier B.V. All rights reserved.

Author Keywords
Bipolar spectrum;  Episode count;  Family history;  Genome-wide association study;  Major depression;  Polygenic

Document Type: Article in Press
Source: Scopus

Thomas, M.G.a b , Pascual, M.L.a b c , Maschi, D.a d , Luchelli, L.a b , Boccaccio, G.L.a b c
Synaptic control of local translation: the plot thickens with new characters
(2013) Cellular and Molecular Life Sciences, pp. 1-21. Article in Press. 

a Instituto Leloir, Av. Patricias Argentinas 435, Buenos Aires, C1405BWE, Argentina
b IIBBA-CONICET, Buenos Aires, C1405BWE, Argentina
c Facultad de Ciencias Exactas y Naturales, University of Buenos Aires, Buenos Aires, Argentina
d Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, United States

Abstract
The production of proteins from mRNAs localized at the synapse ultimately controls the strength of synaptic transmission, thereby affecting behavior and cognitive functions. The regulated transcription, processing, and transport of mRNAs provide dynamic control of the dendritic transcriptome, which includes thousands of messengers encoding multiple cellular functions. Translation is locally modulated by synaptic activity through a complex network of RNA-binding proteins (RBPs) and various types of non-coding RNAs (ncRNAs) including BC-RNAs, microRNAs, piwi-interacting RNAs, and small interference RNAs. The RBPs FMRP and CPEB play a well-established role in synaptic translation, and additional regulatory factors are emerging. The mRNA repressors Smaug, Nanos, and Pumilio define a novel pathway for local translational control that affects dendritic branching and spines in both flies and mammals. Recent findings support a role for processing bodies and related synaptic mRNA-silencing foci (SyAS-foci) in the modulation of synaptic plasticity and memory formation. The SyAS-foci respond to different stimuli with changes in their integrity thus enabling regulated mRNA release followed by translation. CPEB, Pumilio, TDP-43, and FUS/TLS form multimers through low-complexity regions related to prion domains or polyQ expansions. The oligomerization of these repressor RBPs is mechanistically linked to the aggregation of abnormal proteins commonly associated with neurodegeneration. Here, we summarize the current knowledge on how specificity in mRNA translation is achieved through the concerted action of multiple pathways that involve regulatory ncRNAs and RBPs, the modification of translation factors, and mRNA-silencing foci dynamics. © 2013 Springer Basel.

Author Keywords
Abnormal protein aggregation;  ARC/Arg3.1;  EJC;  mTOR;  NMDAR;  Stress granules

Document Type: Article in Press
Source: Scopus

Netland, P.A.a , Sarkisian Jr., S.R.b , Moster, M.R.c , Ahmed, I.I.K.d , Condon, G.e , Salim, S.f , Sherwood, M.B.g , Siegfried, C.J.h
Randomized, Prospective, Comparative Trial of EX-PRESS Glaucoma Filtration Device versus Trabeculectomy (XVT Study)
(2013) American Journal of Ophthalmology, . Article in Press. 

a University of Virginia School of Medicine, Charlottesville, Virginia
b Dean McGee Eye Institute, University of Oklahoma, Oklahoma City, Oklahoma
c Wills Eye Hospital, Philadelphia, Pennsylvania
d University of Toronto, Toronto, Ontario
e Allegheny General Hospital, Pittsburgh, Pennsylvania
f Hamilton Eye Institute, University of Tennessee, Memphis, Tennesee
g University of Florida, Gainesville, Florida
h Washington University, St. Louis, Missouri

Abstract
Purpose: To compare the clinical outcomes of the EX-PRESS glaucoma filtration device placed under a partial-thickness scleral flap with trabeculectomy. Design: Randomized, prospective, multicenter trial. Methods: A total of 120 eyes in 120 subjects were analyzed, including 59 eyes treated with EX-PRESS and 61 eyes treated with trabeculectomy. Both the EX-PRESS and the trabeculectomy groups were treated intraoperatively with mitomycin C and followed postoperatively for 2 years. Surgical success was defined as 5 mm Hg ≤ intraocular pressure ≤ 18 mm Hg, with or without medications, without further glaucoma surgery. Results: Mean intraocular pressure was significantly reduced compared with baseline in both groups (P < 0.001). Average intraocular pressure and number of medications were similar in both groups during follow-up, with mean intraocular pressure at 2 years after surgery of 14.7 ± 4.6 mm Hg and 14.6 ± 7.1 mm Hg in the EX-PRESS and trabeculectomy groups, respectively (P = 0.927). At 2 years after surgery, the success rate was 83% and 79% in the EX-PRESS and trabeculectomy groups, respectively (P = 0.563). Although visual acuity (logMAR) was significantly decreased on day 1 in both groups, the vision was not significantly different compared with baseline at 1 month after EX-PRESS implant (P = 0.285) and 3 months after trabeculectomy (P = 0.255). The variance of early postoperative intraocular pressure values was similar between groups on the first postoperative day but higher after trabeculectomy compared with EX-PRESS implant on day 7 (P = 0.003). The total number of postoperative complications was higher after trabeculectomy than after EX-PRESS implantation (P = 0.013). Conclusions: Mean intraocular pressures, medication use, and surgical success were similar at 2 years after treatment with the EX-PRESS device and trabeculectomy. Vision recovery between groups was also similar throughout the study, although return to baseline vision was more rapid in the EX-PRESS group. Intraocular pressure variation was lower during the early postoperative period, and postoperative complications were less common after EX-PRESS implantation compared with trabeculectomy. © 2013 Elsevier Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

Peterson, D.S.a , Pickett, K.A.a b , Duncan, R.P.a , Perlmutter, J.S.a b c d e , Earhart, G.M.a b c
Brain activity during complex imagined gait tasks in Parkinson disease
(2013) Clinical Neurophysiology, . Article in Press. 

a Program in Physical Therapy, Washington University in St. Louis, 660 S. Euclid, St. Louis, MO 63110, United States
b Department of Neurology, Washington University in St. Louis, 660 S. Euclid, St. Louis, MO 63110, United States
c Department of Neurobiology, Washington University in St. Louis, 660 S. Euclid, St. Louis, MO 63110, United States
d Department of Radiology, Washington University in St. Louis, 660 S. Euclid, St. Louis, MO 63110, United States
e Program in Occupational Therapy, Washington University in St. Louis, 660 S. Euclid, St. Louis, MO 63110, United States

Abstract
Objective: Motor imagery during functional magnetic resonance imaging (fMRI) allows assessment of brain activity during tasks, like walking, that cannot be completed in an MRI scanner. We used gait imagery to assess the neural pathophysiology of locomotion in Parkinson disease (PD). Methods: Brain activity was measured in five locomotor regions (supplementary motor area (SMA), globus pallidus (GP), putamen, mesencephalic locomotor region, cerebellar locomotor region) during simple (forward) and complex (backward, turning) gait imagery. Brain activity was correlated to overground walking velocity. Results: Across tasks, PD exhibited reduced activity in the globus pallidus compared to controls. People with PD, but not controls, exhibited more activity in the SMA during imagined turning compared to forward or backward walking. In PD, walking speed was correlated to brain activity in several regions. Conclusions: Altered SMA activity in PD during imagined turning may represent compensatory neural adaptations during complex gait. The lowered activity and positive correlation to locomotor function in GP suggests reduced activity in this region may relate to locomotor dysfunction. Significance: This study elucidates changes in neural activity during gait in PD, underscoring the importance of testing simple and complex tasks. Results support a positive relationship between activity in locomotor regions and walking ability. © 2013 International Federation of Clinical Neurophysiology.

Author Keywords
fMRI;  Gait;  Imagery;  Parkinson disease

Document Type: Article in Press
Source: Scopus

Miller, R.L., Loewy, A.D.
ENaC γ-expressing astrocytes in the circumventricular organs, white matter, and ventral medullary surface: Sites for Na+ regulation by glial cells
(2013) Journal of Chemical Neuroanatomy, . Article in Press. 

Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA

Abstract
Using a double immunofluorescence procedure, we report the discovery of a novel group of fibrous astrocytes that co-express epithelial sodium channel (ENaC) γ-subunit protein along with glial acidic fibrillary protein (GFAP). These cells are concentrated along the borders of the sensory circumventricular organs (CVOs), embedded in the white matter (e.g., optic nerve/chiasm, anterior commissure, corpus callosum, pyramidal tract) and are components of the pia mater. In the CVOs, a compact collection of ENaC γ-immunoreactive glial fibers form the lamina terminalis immediately rostral to the organum vasculosum of the lamina terminalis (OVLT). Astrocyte processes can be traced into the median preoptic nucleus - a region implicated in regulation of sodium homeostasis. In the subfornical organ (SFO), ENaC γ-GFAP astrocytes lie in its lateral border, but not in the ventromedial core. In the area postrema (AP), a dense ENaC γ-GFAP glial fibers form the interface between the AP and nucleus tractus solitarius; this area is termed the subpostremal region. Antibodies against the ENaC α- or β-subunit proteins do not immunostain these regions. In contrast, the antibodies against the ENaC γ-subunit protein react weakly with neuronal cell bodies in the CVOs. Besides affecting glial-neural functions in the CVOs, the astrocytes found in the white matter may affect saltatory nerve conduction, serving as a sodium buffer. The ENaC γ-expressing astrocytes of the ventral medulla send processes into the raphe pallidus which intermingle with the serotoninergic (5-HT) neurons found in this region as well as with the other nearby 5-HT neurons distributed along ventral medullary surface. © 2013 Elsevier B.V. All rights reserved.

Author Keywords
Circumventricular organ;  ENaC;  Epithelial sodium channel;  Glial acidic fibrillary protein;  Saltatory nerve conduction;  Ventral medullary surface

Document Type: Article in Press
Source: Scopus

Tao, P.-L.a , Chen, L.-S.b , Chen, C.-K.c , Liu, Y.-L.a
Genetics and pharmacogenetics of substance use disorders
(2013) Journal of Food and Drug Analysis, . Article in Press. 

a Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, ROC
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
c Department of Psychiatry, Chang Gung Memorial Hospital, Taipei, Taiwan, ROC

Abstract
The "Genetics and pharmacogenetics of substance use disorder" session was chaired by Dr Pao-Luh Tao and had three speakers. The speakers and topics were as follows. Dr Li-Shiun Chen discussed "Genomics and personalized medicine for smoking cessation treatments". Dr Chih-Ken Chen presented a talk on the "Genetics of methamphetamine abuse and methamphetamine psychosis". Dr Yu-Li Liu described a "Pharmacogenomics study in a Taiwan methadone maintenance cohort". © 2013.

Author Keywords
Genetics;  Methadone;  Methamphetamine;  Pharmacogenetics;  Smoking cessation;  Substance use disorders

Document Type: Article in Press
Source: Scopus

Racette, B.A.a b
Manganism in the 21st century: The Hanninen lecture
(2013) NeuroToxicology, . Article in Press. 

a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, MO 63110, USA
b University of the Witwatersrand, School of Public Health, Faculty of Health Sciences, Johannesburg, South Africa

Abstract
Since the original description of the health effects of inhaled occupational manganese (Mn) by Couper in 1837, an extensive literature details the clinical syndrome and pathophysiology of what was thought to be a rare condition. In the last decade, conventional wisdom regarding the clinicopathological effects of Mn has been challenged. Past exposures to Mn were an order of magnitude higher than modern exposures in developed countries; therefore, the clinical syndrome seen in the time of Couper is no longer typical of modern Mn exposed workers. Parkinsonism (rigidity, bradykinesia, rest tremor, and postural instability) is present in 15% of Mn-exposed workers in welding industries, and these parkinsonian signs are associated with reduced health status and quality of life. These parkinsonian signs also overlap considerably with the clinical findings seen in early stages of Parkinson's disease (PD); although, molecular imaging suggests that Mn-exposed workers have dopaminergic dysfunction in a pattern unique from PD. Furthermore, geographic information system studies demonstrate that regions of the US with high industrial Mn emissions have an increased incidence of PD and increased PD associated mortality. This review will contrast historical, descriptive human studies in Mn-exposed subjects with more recent data and will suggest a research agenda for the 21st century. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Dopamine;  Manganese;  Neurotoxicity;  Parkinson disease;  Parkinsonism;  PET

Document Type: Article in Press
Source: Scopus

Vergés, A.a , Kushner, M.G.b , Jackson, K.M.c , Bucholz, K.K.d , Trull, T.J.a , Lane, S.P.a , Sher, K.J.a
Personality disorders and the persistence of anxiety disorders: Evidence of a time-of-measurement effect in NESARC
(2013) Journal of Anxiety Disorders, . Article in Press. 

a University of Missouri-Columbia and the Midwest Alcoholism Research Center, Columbia, MO, USA
b University of Minnesota, Minneapolis, MN, USA
c Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA
d Washington University School of Medicine and the Midwest Alcoholism Research Center, St. Louis, MO, USA

Abstract
Recent studies using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) have found that some personality disorders (PDs) increase the persistence of several Axis I disorders. However, these effects are potentially confounded with the data collection wave in which PDs were assessed. Our aim was to extend published analyses to the case of anxiety disorders and to determine the robustness of the associations to analyses examining time-of-measurement effects. Persistence of anxiety disorders was defined either as follow-up diagnosis among participants diagnosed at baseline ("prediction") or baseline diagnosis among participants diagnosed at follow-up ("post-diction"). Results revealed a robust pattern of higher odds ratios for post-diction among PDs assessed at baseline, and lower odds ratios for post-diction among PDs assessed at follow-up, suggesting a time of measurement artifact. Although only 4% of associations were robust to both predictive and post-dictive analyses, these were consistent with previous research. © 2013 Elsevier Ltd. All rights reserved.

Author Keywords
Anxiety disorders;  NESARC;  Personality disorders

Document Type: Article in Press
Source: Scopus

Vretzakis, G.a , Bareka, M.a , Aretha, D.b , Karanikolas, M.c
Regional anesthesia for laparoscopic surgery: a narrative review
(2013) Journal of Anesthesia, pp. 1-18. Article in Press. 

a Department of Anesthesiology, University Hospital of Larissa, Larissa, Greece
b Department of Anaesthesiology, Pyrgos General Hospital, 76 Stratigou Konstantinopoulou St, Aroi, Patras, 26331, Greece
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States

Abstract
Laparoscopic surgery has advanced remarkably in recent years, resulting in reduced morbidity and shorter hospital stay compared with open surgery. Despite challenges from the expanding array of laparoscopic procedures performed with the use of pneumoperitoneum on increasingly sick patients, anesthesia has remained largely unchanged. At present, most laparoscopic operations are usually performed under general anesthesia, except for patients deemed "too sick" for general anesthesia. Recently, however, several large, retrospective studies questioned the widely held belief that general anesthesia is the best anesthetic method for laparoscopic surgery and suggested that regional anesthesia could also be a reasonable choice in certain settings. This narrative review is an attempt to critically summarize current evidence on regional anesthesia for laparoscopic surgery. Because most available data come from large, retrospective studies, large, rigorous, prospective clinical trials comparing regional vs. general anesthesia are needed to evaluate the true value of regional anesthesia in laparoscopic surgery. © 2013 Japanese Society of Anesthesiologists.

Author Keywords
Anesthesia;  Epidural;  Laparoscopic surgery;  Local;  Neuraxial;  Regional;  Spinal

Document Type: Article in Press
Source: Scopus

Li, C., Zhang, C., Gao, L., Garcia-Uribe, A., Wang, L.V.
Photoacoustic recovery after photothermal bleaching in living cells
(2013) Journal of Biomedical Optics, 18 (10), art. no. 106004, . 

Washington University in St. Louis, Department of Biomedical Engineering, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
We present an innovative method, photoacoustic recovery after photothermal bleaching (PRAP), for studying particle dynamics at micron scale via photoacoustic imaging. As an intuitive way to visualize and quantify dynamic processes, PRAP is demonstrated first in a simple phantom study and then in a more complex measurement involving live cells. Compared with the conventional fluorescence-based approach, PRAP provides high signal-to-noise ratio (SNR) imaging with minimal bleaching-induced artifacts during the recovery stage, ideal for monitoring the diffusive and kinetic processes inside a cell. © 2013 Society of Photo-Optical Instrumentation Engineers.

Author Keywords
photoacoustic microscopy nanoparticle photoacoustic recovery after photothermal bleaching diffusion kinetics

Document Type: Article
Source: Scopus

Yang, W.a , Carrasquillo, Y.b , Hooks, B.M.c , Nerbonne, J.M.b , Burkhalter, A.a
Distinct balance of excitation and inhibition in an interareal feedforward and feedback circuit of mouse visual cortex
(2013) Journal of Neuroscience, 33 (44), pp. 17373-17384. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, United States

Abstract
Mouse visual cortex is subdivided into multiple distinct, hierarchically organized areas that are interconnected through feedforward (FF) and feedback (FB) pathways. The principal synaptic targets of FF and FB axons that reciprocally interconnect primary visual cortex (V1) with the higher lateromedial extrastriate area (LM) are pyramidal cells (Pyr) and parvalbumin (PV)-expressing GABAergic interneurons. Recordings in slices of mouse visual cortex have shown that layer 2/3 Pyr cells receive excitatory monosynaptic FF and FB inputs, which are opposed by disynaptic inhibition. Most notably, inhibition is stronger in the FF than FB pathway, suggesting pathway-specific organization of feedforward inhibition (FFI). To explore the hypothesis that this difference is due to diverse pathway-specific strengths of the inputs to PV neurons we have performed subcellular Channelrhodopsin-2-assisted circuit mapping in slices of mouse visual cortex. Whole-cell patch-clamp recordings were obtained from retrobead-labeled FFV1→LM-and FBLM→V1-projecting Pyr cells, as well as from tdTomato-expressing PV neurons. The results show that the FFV1→LM pathway provides on average 3.7-fold stronger depolarizing input to layer 2/3 inhibitory PV neurons than to neighboring excitatory Pyr cells. In the FBLM→V1 pathway, depolarizing inputs to layer 2/3 PV neurons and Pyr cells were balanced. Balanced inputs were also found in the FFV1→LM pathway to layer 5 PV neurons and Pyr cells, whereas FBLM→V1 inputs to layer 5 were biased toward Pyr cells. The findings indicate that FFI in FFV1→LM and FBLM→V1 circuits are organized in a pathway- and lamina-specific fashion. © 2013 the authors.

Document Type: Article
Source: Scopus

He, B.a , Coleman, T.b , Genin, G.M.c , Glover, G.d , Hu, X.e , Johnson, N.f , Liu, T.g , Makeig, S.h , Sajda, P.i , Ye, K.j
Grand challenges in mapping the human brain: NSF workshop report
(2013) IEEE Transactions on Biomedical Engineering, 60 (11), art. no. 6615987, pp. 2983-2992. 

a Department of Biomedical Engineering, Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN 55455, United States
b Department of Bioengineering, University of California, San Diego, CA 92093, United States
c Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO 63130, United States
d Department of Radiology, Stanford University, Stanford, CA 94305, United States
e Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA 30332, United States
f Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, United States
g Computer Science Department, University of Georgia, Athens, GA 30602, United States
h Institute for Neural Computation, University of California, San Diego, CA 92093, United States
i Department of Biomedical Engineering, Columbia University, New York, NY 10027, United States
j Department of Bioengineering, State University of New York, Binghamton, NY 13902, United States

Abstract
This report summarizes the outcomes of the NSF Workshop on Mapping and Engineering the Brain, held at Arlington, VA, during August 13-14, 2013. Three grand challenges were identified, including high spatiotemporal resolution neuroimaging, perturbation-based neuroimaging, and neuroimaging in naturalistic environments. It was highlighted that each grand challenge requires groundbreaking discoveries, enabling technologies, appropriate knowledge transfer, and multi-and transdisciplinary education and training for success. © 2013 IEEE.

Author Keywords
biomedical imaging;  Brain mapping;  modeling;  neural engineering;  neuroimaging;  neuromodulation

Document Type: Review
Source: Scopus

Paul, S.M.a b , Doherty, J.J.a , Robichaud, A.J.a , Belfort, G.M.a , Chow, B.Y.a , Hammond, R.S.a , Crawford, D.C.c , Linsenbardt, A.J.c , Shu, H.-J.c , Izumi, Y.c , Mennerick, S.J.c , Zorumski, C.F.c
The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-Methyl-D-Aspartate receptors
(2013) Journal of Neuroscience, 33 (44), pp. 17290-17300. 

a Sage Therapeutics, Cambridge, MA 02142, United States
b Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Departments of Psychiatry and Pharmacology, Weill Cornell Medical College, New York, NY 10065, United States
c Department of Psychiatry, Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MI 63110, United States

Abstract
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABAARs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 μM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development. © 2013 the authors.

Document Type: Article
Source: Scopus

Saha, D.a , Leong, K.a , Li, C.a , Peterson, S.b , Siegel, G.b , Raman, B.b
A spatiotemporal coding mechanism for background-invariant odor recognition
(2013) Nature Neuroscience, . Article in Press. 

a 1] Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
b Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA

Abstract
Sensory stimuli evoke neural activity that evolves over time. What features of these spatiotemporal responses allow the robust encoding of stimulus identity in a multistimulus environment? Here we examined this issue in the locust (Schistocerca americana) olfactory system. We found that sensory responses evoked by an odorant (foreground) varied when presented atop or after an ongoing stimulus (background). These inconsistent sensory inputs triggered dynamic reorganization of ensemble activity in the downstream antennal lobe. As a result, partial pattern matches between neural representations encoding the same foreground stimulus across conditions were achieved. The degree and segments of response overlaps varied; however, any overlap observed was sufficient to drive background-independent responses in the downstream neural population. Notably, recognition performance of locusts in behavioral assays correlated well with our physiological findings. Hence, our results reveal how background-independent recognition of odors can be achieved using spatiotemporal patterns of neural activity.

Document Type: Article in Press
Source: Scopus

Peche, S.S.a , Alshekhlee, A.b , Kelly, J.c , Lenox, J.c , Mar, S.c
A long-term follow-Up study using IPMSSG criteria in children with CNS demyelination
(2013) Pediatric Neurology, 49 (5), pp. 329-334. 

a Department of Pediatrics, Division of Child and Adolescent Neurology, Southern Illinois University, 301 N 8th Street, Springfield, IL 62794, United States
b Saint Louis University, Saint Louis, MO, United States
c Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Objective To evaluate the practical application of International Pediatrics Multiple Sclerosis study group definitions in children with inflammatory demyelination of the central nervous system and to identify predictors of multiple sclerosis. Methods Baseline data on 123 children with a first episode of acute central nervous system demyelination were collected. The initial diagnosis according to the International Pediatrics Multiple Sclerosis study group was recorded and compared with final diagnosis. Results Forty-seven (38.2%) children met International Pediatrics Multiple Sclerosis study group criteria for acute disseminated encephalomyelitis and 67 (54.4%) had clinically isolated syndrome at the initial presentation. Four (3.2%) had the diagnosis of neuromyelitis optica and five (4%) did not meet any specific diagnosis per the study group criteria. Clinical follow-up was available on 118 of 123 children (95.9%), with a median of 61.5 months (quartile range 23, 110 months). Conversion from clinically isolated syndrome to multiple sclerosis occurred in 26 of 67 children (38.8%); acute disseminated encephalomyelitis to multiple sclerosis occurred in 4 of 47 children (8.5%). Adjusted multivariate logistic regression analysis for an outcome of future development of multiple sclerosis showed the following predictors: female gender (odds ratio 12.44; 95% confidence interval 1.03-149.3); initial diagnosis of monofocal brain stem or hemispheric dysfunction (odds ratio 24.57; 95% confidence interval 3.06-196.78); and Callen magnetic resonance imaging criteria if met (odds ratio 122.45; 95% confidence interval 16.57-904.57). Conclusion International Pediatrics Multiple Sclerosis study group criteria affirm that children with initial clinically isolated syndrome are more likely to develop future multiple sclerosis compared with those with an acute disseminated encephalomyelitis initial diagnosis. In addition, female gender, brain stem or hemispheric involvement, and Callen magnetic resonance imaging criteria predict the diagnosis of multiple sclerosis. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Callen MRI criteria;  demyelination;  IPMSSG (International pediatric multiple sclerosis study group);  MS (multiple sclerosis)

Document Type: Article
Source: Scopus

Sartor, C.E.a , Nelson, E.C.b , Lynskey, M.T.c , Madden, P.A.F.b , Heath, A.C.b , Bucholz, K.K.b
Are there differences between young African-American and European-American women in the relative influences of genetics versus environment on age at first drink and problem alcohol use?
(2013) Alcoholism: Clinical and Experimental Research, 37 (11), pp. 1939-1946. 

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Institute of Psychiatry, King's College, London, United Kingdom

Abstract
Background: Differences in age at initiation of alcohol use and rates of problem drinking between African Americans and European Americans are well documented, but the association between early and problem use-and distinctions by ethnic group in this association-have yet to be examined in a genetically informative framework. Methods: Data were derived from a longitudinal study of female twins in Missouri. The sample was composed of 3,532 twins (13.6% African-American [AA], 86.4% European-American [EA]), who participated in the fourth wave of data collection and reported consumption of at least 1 alcoholic drink over the lifetime. Mean age at Wave 4 was 21.7 (range = 18 to 29) years. Twin modeling was conducted to estimate the relative contributions of additive genetic (A), shared environmental (C), and unique environmental (E) factors to variation in age at first drink and problem alcohol use and the cross-phenotype overlap in these influences. Results: Early initiation of alcohol use predicted problem use in EA but not AA women. Separate AA and EA twin models produced substantially different estimates (but not statistically different models) of the relative contributions of A and C to problem alcohol use but similar genetic correlations between the phenotypes. Whereas 33% of the variance in the EA model of problem use was attributed to C, no evidence for C was found in the AA model. Heritability estimates for problem alcohol use were 41% in the AA model, 21% in the EA model. Evidence for A and C were found in both AA and EA models of age at first drink, but the A estimate was higher in the EA than AA model (44% vs. 26%). Conclusions: Findings are suggestive of distinctions between AA versus EA women in the relative contribution of genetic and environmental influences on the development of problem drinking. © 2013 by the Research Society on Alcoholism.

Author Keywords
African Americans;  Alcohol;  Twins;  Women

Document Type: Article
Source: Scopus

Farasatpour, M.a , Janardhan, R.a , Williams, C.D.a , Margenthaler, J.A.b , Virgo, K.S.c , Johnson, F.E.a d
Breast cancer in patients with schizophrenia
(2013) American Journal of Surgery, 206 (5), pp. 798-804. 

a Department of Surgery, Saint Louis University Medical Center, 3635 Vista Avenue, St. Louis, MO 63110-0250, United States
b Department of Surgery, Washington University, St. Louis, MO, United States
c American Cancer Society, Atlanta, GA, United States
d Department of Surgery, John Cochran Veterans Affairs Medical Center, St. Louis, MO, United States

Abstract
Background: Schizophrenia has a powerful impact on the outcomes of treatment for physical disorders. This study sought to estimate how the presence of schizophrenia disrupts the course of diagnosis and initial treatment of breast cancer. Methods: We searched the Patient Treatment File, a comprehensive computer-based system for inpatient data in the Department of Veterans Affairs (DVA) medical system, to identify patients with codes for schizophrenia or schizoaffective disorder who later developed breast cancer. These data were augmented with chart-based clinical data. Results: There were 56 evaluable patients from 34 DVA facilities; 37 (66%) were female. Delay in diagnosis was common. The mean size of the primary tumor was 4 cm in those for whom these data were recorded. Delay in diagnosis was common and many never received the indicated surgery. Distant metastases were present on diagnosis in 12 (21%) and developed after diagnosis in 14 (25%) others, including 7 who inappropriately delayed or refused indicated surgery and 4 who inappropriately delayed or refused indicated neoadjuvant chemotherapy. Twelve verbally abused or physically attacked caregivers. Conclusions: Patients with schizophrenia who later develop breast cancer often deny they have cancer. They often have high-stage disease at diagnosis and often delay or refuse therapy. Breast-conserving multimodality therapy is often not feasible. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Breast cancer;  Outcomes;  Schizophrenia;  Surgery

Document Type: Article
Source: Scopus

Harms, M.B.a , Baloh, R.H.b
Clinical Neurogenetics: Amyotrophic Lateral Sclerosis
(2013) Neurologic Clinics, 31 (4), pp. 929-950. 

a Neuromuscular Division, Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
b Department of Neurology, Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, United States

Abstract
Our understanding of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is expanding rapidly as its genetic causes are uncovered. The pace of new gene discovery over the last 5years has accelerated, providing new insights into the pathogenesis of disease and highlighting biological pathways as targets for therapeutic development. This article reviews our current understanding of the heritability of ALS and provides an overview of each of the major ALS genes, highlighting their phenotypic characteristics and frequencies as a guide for clinicians evaluating patients with ALS. © 2013 Elsevier Inc.

Author Keywords
ALS;  Amyotrophic lateral sclerosis;  Genetics;  Phenotypes

Document Type: Review
Source: Scopus

Coorg, R., Weisenberg, J.L.Z., Wong, M.
Clinical Neurogenetics: Recent Advances in the Genetics of Epilepsy
(2013) Neurologic Clinics, 31 (4), pp. 891-913. 

Department of Neurology, Washington University School of Medicine, Box8111, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
Epilepsy represents a diverse group of disorders with primary and secondary genetic etiologies, as well as non-genetic causes. As more causative genes are identified, genetic testing is becoming increasingly important in the evaluation and management of epilepsy. This article outlines the clinical approach to epilepsy patients, with emphasis on genetic testing. Specific targeted tests are available for numerous individual genetic causes of epilepsy. Broader screening tests, such as chromosome microarray analysis and whole exome sequencing, have also been developed. As a standardized protocol for genetic testing has not been established, individualized diagnostic approaches to epilepsy patients should be used. © 2013 Elsevier Inc.

Author Keywords
Epilepsy;  Genetics;  Seizure

Document Type: Review
Source: Scopus

Sommerville, R.B.a , Zaidman, C.M.a , Pestronk, A.b
Coenzyme Q10 deficiency in children: Frequent type 2C muscle fibers with normal morphology
(2013) Muscle and Nerve, 48 (5), pp. 722-726. 

a Washington University School of Medicine, Department of Neurology, 660 S. Euclid Avenue, Box 8111, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Neurological disorders with low tissue coenzyme Q10 (CoQ10) levels are important to identify, as they may be treatable. Methods: We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ10 deficiency in muscle to 31 with normal CoQ10 values. Results: Muscle from CoQ10-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P<0.0001). A type 2C fiber frequency of≥5% had 89% sensitivity and 84% specificity for CoQ10 deficiency in this cohort. No biopsy showed active myopathy. There were no differences between groups in frequencies of mitochondrial myopathologic, clinical, or laboratory features. Multiple abnormalities in muscle oxidative enzyme activities were more frequent in CoQ10-deficient patients than in controls. Conclusions: When a childhood mitochondrial disorder is suspected, an increased frequency of type 2C fibers in morphologically normal muscle suggests CoQ10 deficiency. © 2013 Wiley Periodicals, Inc.

Author Keywords
Coenzyme Q10 deficiency;  Developmental delay;  Mitochondrial disorders;  Muscle pathology;  Pediatric neurology;  Type 2C fibers

Document Type: Article
Source: Scopus

Laurens, J.a , Meng, H.b , Angelaki, D.E.b
Computation of linear acceleration through an internal model in the macaque cerebellum
(2013) Nature Neuroscience, 16 (11), pp. 1701-1708. 

a Department of Otolaryngology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States

Abstract
A combination of theory and behavioral findings support a role for internal models in the resolution of sensory ambiguities and sensorimotor processing. Although the cerebellum has been proposed as a candidate for implementation of internal models, concrete evidence from neural responses is lacking. Using unnatural motion stimuli, which induce incorrect self-motion perception and eye movements, we explored the neural correlates of an internal model that has been proposed to compensate for Einstein's equivalence principle and generate neural estimates of linear acceleration and gravity. We found that caudal cerebellar vermis Purkinje cells and cerebellar nuclei neurons selective for actual linear acceleration also encoded erroneous linear acceleration, as would be expected from the internal model hypothesis, even when no actual linear acceleration occurred. These findings provide strong evidence that the cerebellum might be involved in the implementation of internal models that mimic physical principles to interpret sensory signals, as previously hypothesized. © 2013 Nature America, Inc. All rights reserved.

Document Type: Article
Source: Scopus

Ortinau, C.a , Alexopoulos, D.a , Dierker, D.b , Van Essen, D.b , Beca, J.c , Inder, T.a d e
Cortical folding is altered before surgery in infants with congenital heart disease
(2013) Journal of Pediatrics, 163 (5), pp. 1507-1510. 

a Department of Pediatrics, St. Louis Children's Hospital, Washington University in St. Louis, 660 South Euclid Ave, St. Louis, MO 63110, United States
b Departments of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
c Pediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand
d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
e Mallinkrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Infants with congenital heart disease have altered brain development. We characterized cortical folding, a critical part of brain development, in congenital heart disease infants and demonstrated an overall decrease in cortical surface area and cortical folding with regional alterations in the right lateral sulcus and left orbitofrontal region, cingulate region, and central sulcus. These abnormalities were present prior to surgery. © 2013 Mosby Inc. All rights reserved.

Document Type: Article
Source: Scopus

Kanekura, K.a , Ishigaki, S.b , Merksamer, P.I.c , Papa, F.R.c d e f , Urano, F.a
Establishment of a system for monitoring endoplasmic reticulum redox state in mammalian cells
(2013) Laboratory Investigation, 93 (11), pp. 1254-1258. 

a Division of Endocrinology, Metabolism, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
c Department of Medicine, University of California San Francisco, San Francisco, CA, United States
d Diabetes Center, University of California San Francisco, San Francisco, CA, United States
e Lung Biology Center, University of California San Francisco, San Francisco, CA, United States
f California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, CA, United States

Abstract
The endoplasmic reticulum (ER) performs a critical role in the oxidative folding of nascent proteins, such that perturbations to ER homeostasis may lead to protein misfolding and subsequent pathological processes. Among the mechanisms for maintaining ER homeostasis is a redox regulation, which is a critical determinant of the fate of ER-stressed cells. Here, we report the establishment of a system for monitoring the ER redox state in mammalian cells. The new ER redox-sensing system was developed based on the previously described monitoring system in yeast. Our system could successfully monitor the dynamic ER redox state in mammalian cells. Using this system, we find that manipulation of ER oxidases changes the ER redox state. The mammalian ER redox-sensing system could be used to study the mechanisms of ER redox regulation and provide a foundation for an approach to develop novel therapeutic modalities for human diseases related to dysregulated ER homeostasis including diabetes, neurodegeneration, and Wolfram syndrome. © 2013 USCAP, Inc.

Author Keywords
beta cell;  diabetes;  ER stress;  neurodegeneration;  neuron;  redox regulation;  Wolfram syndrome

Document Type: Article
Source: Scopus

Lieu, J.E.C., Ratnaraj, F., Ead, B.
Evaluating a prediction model for infant hearing loss
(2013) Laryngoscope, 123 (11), pp. 2873-2879. 

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

Abstract
Objectives/Hypothesis The objective of this study was to determine whether a prognostic model using risk factors for hearing loss could predict the chance that infants who failed a newborn hearing screen would subsequently be found to have hearing loss diagnosed by auditory brainstem response testing. Study Design Individual retrospective case-control study. Methods We studied 229 infants with hearing loss compared with 458 infants with normal hearing. All infants had undergone natural sleep or sedated auditory brainstem response, predominantly for not passing a newborn hearing screen. Risk factors, birth history, and other information were extracted via medical record review. Multiple logistic regression analyses identified independent predictors of hearing loss. Results Four risk factors were independently predictive of hearing loss diagnosed by sleep or sedated auditory brainstem response: prematurity, 5-minute APGAR score ≤ 6, intracranial complication, and craniofacial abnormality. A prognostic model developed from these risk factors was associated with a 15% rate of hearing loss in stage I, 52% rate of hearing loss in stage II, and 96% rate of hearing loss in stage III. Conclusions The presence of any one of four independently predictive risk factors in infants who did not pass newborn hearing screen was associated with a 50% rate of hearing loss; having three or more was associated with a 90% rate of hearing loss. Knowing that an infant is at high risk of hearing loss can motivate parents to follow up with diagnostic auditory brainstem response testing so that early identification can lead to early intervention. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
auditory brainstem response;  Hearing loss;  infant;  newborn hearing screening;  prediction;  risk factors

Document Type: Article
Source: Scopus

Kong, L.a , Chen, K.a , Tang, Y.a b , Wu, F.a , Driesen, N.c , Womer, F.d , Fan, G.b , Ren, L.b , Jiang, W.a , Cao, Y.e , Blumberg, H.P.c , Xu, K.b , Wang, F.b c
Functional connectivity between the amygdala and prefrontal cortex in medication-naive individuals with major depressive disorder
(2013) Journal of Psychiatry and Neuroscience, 38 (6), pp. 417-422. 

a Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang, China
b Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang, China
c Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Mental Health Center of Shenyang, Shenyang, Liaoning, China

Abstract
Background: Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic resonance imaging (fMRI) to investigate amygdala-PFC functional connectivity during emotional face processing in medication-naive individ - uals with MDD. Methods: Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups. Results: Our study included 28 individuals with MDD and 30 controls. Decreased amygdala-left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition (p < 0.05, corrected). No significant differences were found in amygdala connectivity to any cerebral regions between the MDD and control groups for the happy or neutral conditions. Limitations: All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population. Conclusion: Medicationnaive individuals with MDD showed decreased amygdala-left rPFC functional connectivity in response to negative emotional stimuli, suggesting that abnormalities in amygdala-left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD. © 2013 Canadian Medical Association.

Document Type: Article
Source: Scopus

Clifford, D.B.a , Ances, B.M.b
HIV-associated neurocognitive disorder
(2013) The Lancet Infectious Diseases, 13 (11), pp. 6-86. 

a Department of Neurology and Medicine, Washington University in St Louis, St Louis, MO, United States
b Departments of Neurology, Bioengineering, and Radiology, Washington University in St Louis, St Louis, MO, United States

Abstract
Neurological involvement in HIV is often associated with cognitive impairment. Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. In this Review, we describe the manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy, outline diagnosis and treatment recommendations, and explore the research questions that remain. Although comorbid disorders, such as hepatitis C infection or epilepsy, might cause some impairment, their prevalence is insufficient to explain the frequency with which it is encountered. HIV disease markers, such as viral load and CD4 cell counts, are not strongly associated with ongoing impairment on treatment, whereas cardiovascular disease markers and inflammatory markers are. New cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research efforts to optimise HIV therapy within the CNS, and potentially to intervene in downstream mechanisms of neurotoxicity, remain important avenues for future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication. © 2013 Elsevier Ltd.

Document Type: Review
Source: Scopus

Luby, J.L.
Limited evidence that a brief education programme for parents of high-risk preschool children may reduce risk of internalising disorders in adolescence in girls but not boys
(2013) Evidence-Based Mental Health, 16 (4), p. 105. 

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

Document Type: Note
Source: Scopus

Licis, A.K.a , Vallorani, A.a , Gao, F.b , Chen, C.a , Lenox, J.a , Yamada, K.A.a , Duntley, S.P.a , Gutmann, D.H.a
Prevalence of sleep disturbances in children with neurofibromatosis type 1
(2013) Journal of Child Neurology, 28 (11), pp. 1400-1405. 

a Department of Neurology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St Louis, MO 63110, United States
b Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Children with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function, and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorder neurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2 to 17 years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantly more likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but not problems with abnormal sleep breathing, or excessive somnolence. Although the overall sleep scores were higher in children with neurofibromatosis type 1, this was not related to a coexisting attention deficit disorder, cognitive impairment, or stimulant medication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep disturbances, and support the use of appropriate interventions for this at-risk population. © The Author(s) 2013.

Author Keywords
brain tumor;  neurocutaneous disorders;  NF1;  sleep disturbances

Document Type: Article
Source: Scopus

Orsmond, G.I.a , Shattuck, P.T.b , Cooper, B.P.b , Sterzing, P.R.c , Anderson, K.A.d
Social participation among young adults with an autism spectrum disorder
(2013) Journal of Autism and Developmental Disorders, 43 (11), pp. 2710-2719. 

a Department of Occupational Therapy, Boston University, Boston, MA 02215, United States
b Brown School of Social Work, Washington University, St. Louis, MO, United States
c School of Social Welfare, University of California, Berkeley, CA, United States
d Waisman Center, University of Wisconsin Madison, Madison, WI, United States

Abstract
Investigating social participation of young adults with an autism spectrum disorder (ASD) is important given the increasing number of youth aging into young adulthood. Social participation is an indicator of life quality and overall functioning. Using data from the National Longitudinal Transition Study 2, we examined rates of participation in social activities among young adults who received special education services for autism (ASD group), compared to young adults who received special education for intellectual disability, emotional/behavioral disability, or a learning disability. Young adults with an ASD were significantly more likely to never see friends, never get called by friends, never be invited to activities, and be socially isolated. Among those with an ASD, lower conversation ability, lower functional skills, and living with a parent were predictors of less social participation. © 2013 Springer Science+Business Media New York.

Author Keywords
Autism spectrum disorder;  Social participation;  Young adulthood

Document Type: Article
Source: Scopus

Geraci, L.a , McDaniel, M.A.b , Miller, T.M.c , Hughes, M.L.a
The bizarreness effect: Evidence for the critical influence of retrieval processes
(2013) Memory and Cognition, 41 (8), pp. 1228-1237. 

a Department of Psychology, Texas AandM University, College Station, TX, 77843, United States
b Department of Psychology, Washington University, St. Louis, MO, United States
c Department of Psychology, South Dakota State University, Brookings, SD, United States

Abstract
People show better memory for bizarre sentences relative to common sentences, a finding referred to as the bizarrness effect. Interestingly, this effect is typically only obtained using a mixed-list design, in which participants study common and bizarre sentences in the same list. This bizarreness effect in mixed-list designs has been explained as the result of both enhanced encoding processes and efficient retrieval processes. The present experiment was designed to isolate the unique contributions of the retrieval context to the bizarreness effect. Participants studied common sentences in one room under one set of instructions, and bizarre sentences in another room under another set of instructions. At test, participants recalled the common and bizarre sentences either together or separately. The results showed that the bizarreness effect was only obtained when participants recalled the common and bizarre items together; no bizarreness advantage emerged when participants were required to recall the common and bizarre items separately. These results suggest that differential encoding processes are not necessary for explaining the bizarreness effect in memory. Rather, retrieval of the mixed-list context appears to be critical for obtaining the effect. © 2013 Psychonomic Society, Inc.

Author Keywords
Bizarreness;  Distinctiveness;  Encoding;  Memory;  Retrieval

Document Type: Article
Source: Scopus

Sharma, A.K.a , Pavlova, S.T.a , Kim, J.b , Kim, J.b , Mirica, L.M.a
The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity
(2013) Metallomics, 5 (11), pp. 1529-1536. 

a Department of Chemistry, Washington University, One Brookings Drive, St. Louis MO 63130-4899, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis MO 63108, United States

Abstract
The coordination chemistry of Cu and Zn metal ions with the amyloid β (Aβ) peptides has attracted a lot of attention in recent years due to its implications in Alzheimer's disease. A number of reports indicate that Cu and Zn have profound effects on Aβ aggregation. However, the impact of these metal ions on Aβ oligomerization and fibrillization is still not well understood, especially for the more rapidly aggregating and more neurotoxic Aβ42 peptide. Here we report the effect of Cu2+ and Zn2+ on Aβ42 oligomerization and aggregation using a series of methods such as Thioflavin T (ThT) fluorescence, native gel and Western blotting, transmission electron microscopy (TEM), and cellular toxicity studies. Our studies suggest that both Cu2+ and Zn2+ ions inhibit Aβ42 fibrillization. While presence of Cu2+ stabilizes Aβ42 oligomers, Zn2+ leads to formation of amorphous, non-fibrillar aggregates. The effects of temperature, buffer, and metal ion concentration and stoichiometry were also studied. Interestingly, while Cu2+ increases the Aβ42-induced cell toxicity, Zn2+ causes a significant decrease in Aβ42 neurotoxicity. While previous reports have indicated that Cu2+ can disrupt β-sheets and lead to non-fibrillar Aβ aggregates, the neurotoxic consequences were not investigated in detail. The data presented herein including cellular toxicity studies strongly suggest that Cu2+ increases the neurotoxicity of Aβ42 due to stabilization of soluble Aβ42 oligomers. © 2013 The Royal Society of Chemistry.

Document Type: Conference Paper
Source: Scopus

Lepage, K.Q.a , Kramer, M.A.a , Ching, S.b
An active method for tracking connectivity in temporally changing brain networks
(2013) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, art. no. 6610515, pp. 4374-4377. 

a Department of Mathematics and Statistics, Boston University, Boston, MA, United States
b Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The inference of connectivity in brain networks has typically been performed using passive measurements of ongoing activity across recording sites. Passive measures of connectivity are harder to interpret, however, in terms of causality - how evoked activity in one region might induce activity in another. To obviate this issue, recent work has proposed the use of active stimulation in conjunction with network estimation. By actively stimulating the network, more accurate information can be gleaned regarding evoked connectivity. The assumption in these previous works, however, was that the underlying networks were static and do not change in time. Such an assumption may be limiting in situations of clinical relevance, where the introduction of a drug or of brain pathology, might change the underlying networks structure. Here, an extension of the evoked connectivity paradigm is introduced that enables tracking networks that change in time. © 2013 IEEE.

Document Type: Conference Paper
Source: Scopus

Smith, K.a , Politte, D.a , Reiker, G.a , Nolan, T.S.a , Hildebolt, C.a , Mattson, C.b , Tucker, D.b , Prior, F.a , Turovets, S.b , Larson-Prior, L.J.a
Automated measurement of skull circumference, cranial index, and braincase volume from pediatric computed tomography
(2013) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, art. no. 6610416, pp. 3977-3980. 

a Washington University School of Medicine, St. Louis, MO 63110, United States
b Neuroinformatics Center, University of Oregon, Eugene, OR 97403, United States

Abstract
Normative values of pediatric skull circumference, cranial index, and braincase volume would inform multiple disciplines including neurosurgery, plastic surgery and anthropology. Semi-automated methods exist for obtaining these data but are time consuming and require expertise. We report on a new method for automated extraction of in vivo measures of pediatric crania based on x-ray computed tomography scans (CT). Data were obtained from a clinical image repository for pediatric populations in whom no pathology was noted. The automated process showed good agreement with semi-automated measures, although there was a small bias for both braincase volume and circumference. We developed an open source program to automatically extract measures of skull circumference, cranial index, and braincase volume that are likely to prove useful in multiple disciplines. © 2013 IEEE.

Document Type: Conference Paper
Source: Scopus

Anderson, N.R.a , Blakely, T.b , Brunner, P.c , Krusienski, D.J.d , Moran, D.W.e , Leuthardt, E.C.f
High-frequency spectral changes in Dorsolateral Prefrontal Cortex for potential neuoroprosthetics
(2013) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, art. no. 6609984, pp. 2247-2250. 

a Cortech Solutions, Wilmington, NC, United States
b Department of Biomedical Engineering, University of Washington, Seattle, United States
c Laboratory of Neural Injury and Repair, Wadsworth Center, Albany, NY, United States
d Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
f Departments of Neurological Surgery and Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Dorsolateral Prefrontal Cortex (DLPFC) has been associated with goal encoding in primates. Thus far, the majority of research involving DLPFC, including all electrophysiology studies, has been performed in non-human primates. In this paper, we explore the possibility of utilizing the cortical activity in DLPFC in humans for use in Brain-Computer Interfaces (BCIs). Electrocorticographic signals were recorded from seven patients with intractable epilepsy who had electrode coverage over DLPFC. These subjects performed a visuomotor target-based task to assess DLPFC's involvement in planning, execution, and accomplishment of the simple motor task. These findings demonstrate that there is a distinct high-frequency spectral component in DLPFC associated with accomplishment of the task. It is envisioned that these signals could potentially provide a novel verification of task accomplishment for a BCI. © 2013 IEEE.

Document Type: Conference Paper
Source: Scopus

Finger, S.
Obituary: Christopher Smith (1930-2013).
(2013) Journal of the history of the neurosciences, 22 (2), pp. 216-218. 

Department of Psychology, Programs in Neuroscience and Philosophy-Neuroscience-Psychology, Washington University, Saint Louis, MO 63130-4899, USA.

Document Type: Article
Source: Scopus

Remke, M.a b c , Ramaswamy, V.a b c , Peacock, J.a b c , Shih, D.J.H.a b c , Koelsche, C.d e , Northcott, P.A.f , Hill, N.a b , Cavalli, F.M.G.a b , Kool, M.f , Wang, X.a b c , Mack, S.C.a b c , Barszczyk, M.a , Morrissy, A.S.a b , Wu, X.a b , Agnihotri, S.a , Luu, B.a b , Jones, D.T.W.f , Garzia, L.a b , Dubuc, A.M.a b c , Zhukova, N.a , Vanner, R.a , Kros, J.M.g , French, P.J.h , Van Meir, E.G.i , Vibhakar, R.j , Zitterbart, K.k , Chan, J.A.l , Bognár, L.m , Klekner, A.m , Lach, B.n , Jung, S.o , Saad, A.G.p , Liau, L.M.q , Albrecht, S.r , Zollo, M.s t , Cooper, M.K.u , Thompson, R.C.v , Delattre, O.O.w , Bourdeaut, F.w , Doz, F.F.x , Garami, M.y , Hauser, P.y , Carlotti, C.G.z , Van Meter, T.E.aa , Massimi, L.ab , Fults, D.ac , Pomeroy, S.L.ad , Kumabe, T.ae , Ra, Y.S.af , Leonard, J.R.ag , Elbabaa, S.K.ah , Mora, J.ai , Rubin, J.B.aj , Cho, Y.-J.be , McLendon, R.E.al , Bigner, D.D.al , Eberhart, C.G.am , Fouladi, M.an , Wechsler-Reya, R.J.ao , Faria, C.C.ap aq , Croul, S.E.c , Huang, A.ar , Bouffet, E.ar , Hawkins, C.E.as , Dirks, P.B.ap , Weiss, W.A.ak , Schüller, U.at , Pollack, I.F.au , Rutkowski, S.av , Meyronet, D.aw bd , Jouvet, A.aw bd , Fèvre-Montange, M.ax , Jabado, N.ay , Perek-Polnik, M.az , Grajkowska, W.A.ba , Kim, S.-K.bb , Rutka, J.T.ap , Malkin, D.ar , Tabori, U.ar , Pfister, S.M.f bc , Korshunov, A.d e , von Deimling, A.d e , Taylor, M.D.a b c ap
TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma
(2013) Acta Neuropathologica, pp. 1-13. Article in Press. 

a The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada
b Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
c Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
d Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
e Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
f Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
g Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
h Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands
i Departments of Neurosurgery and Hematology and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, United States
j Department of Pediatrics, University of Colorado Denver, Aurora, United States
k Department of Pediatric Oncology, School of Medicine, Masaryk University and University Hospital Brno, Brno, Czech Republic
l Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada
m Department of Neurosurgery, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
n Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
o Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwas, Chonnam, South Korea
p Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, United States
q Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, United States
r Department of Pathology, McGill University, Montreal, Canada
s Dipartimento di Medicina Molecolare e Biotecnologie Mediche, University of Naples, Naples, Italy
t CEINGE Biotecnologie Avanzate, Naples, Italy
u Department of Neurology, Vanderbilt Medical Center, Nashville, United States
v Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, United States
w Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France
x Department of Pediatric Oncology, Institut Curie and University Paris Descartes, Sorbonne Paris Cité, Paris, France
y 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
z Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
aa Pediatric Hematology-Oncology, School of Medicine, Virginia Commonwealth University, Richmond, United States
ab Pediatric Neurosurgery, Catholic University Medical School, Rome, Italy
ac Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, United States
ad Department of Neurology, Harvard Medical School, Children's Hospital Boston, Boston, United States
ae Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
af Department of Neurosurgery, Asan Medical Center, University of Ulsan, Seoul, South Korea
ag Division of Pediatric Neurosurgery, Department of Neurosurgery, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, United States
ah Division of Pediatric Neurosurgery, Department of Neurological Surgery, Saint Louis University School of Medicine, Saint Louis, United States
ai Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Spain
aj Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, United States
ak Department of Neurology, University of California, San Francisco, San Francisco, United States
al Department of Pathology, Duke University, Durham, United States
am Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, United States
an Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
ao Sanford-Burnham Medical Research Institute, La Jolla, United States
ap Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children and The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada
aq Division of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte EPE, Lisbon, Portugal
ar Division of Haematology and Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
as Department of Pathology, The Hospital for Sick Children, Toronto, Canada
at Center for Neuropathology and Prion Research, University of Munich, Munich, Germany
au Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, United States
av Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
aw Neuro-oncology and Neuro-inflammation Team, Inserm U1028, CNRS UMR 5292, Neuroscience Center, University Lyon 1, Lyon, 69000, France
ax Centre de Recherche en Neurosciences, INSERM U1028, CNRS UMR5292, Université de Lyon, Lyon, France
ay Division of Experimental Medicine, McGill University, Montreal, Canada
az Department of Oncology, The Children's Memorial Health Institute, Warsaw, Poland
ba Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland
bb Division of Pediatric Neurosurgery, Department of Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea
bc Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany
bd Hospices Civils de Lyon, Centre de Pathologie et de Neuropathologie Est, Lyon, 69003, France
be Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, United States

Abstract
Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. © 2013 The Author(s).

Author Keywords
Adult;  Medulloblastoma;  SHH pathway;  TERT promoter mutations

Document Type: Article in Press
Source: Scopus

Stevens, J.A., Sukhum, K.V., Carlson, B.A.
Independent Evolution of Visual and Electrosensory Specializations in Different Lineages of Mormyrid Electric Fishes
(2013) Brain, Behavior and Evolution, pp. 185-198. Article in Press. 

Department of Biology, Washington University in St. Louis, St. Louis, Mo., USA

Abstract
African mormyrid fishes are by far the most diverse group of osteoglossomorph (bony tongue) fishes. Mormyrids communicate using pulses of electricity, and they process electric communication signals in the midbrain exterolateral nucleus (EL). In its ancestral form, the EL is relatively small and homogenous. In two different lineages, however, the EL expanded in size and increased in cytological complexity. This evolutionary change established the perceptual ability to distinguish variation in electric pulse waveform, which plays an important role in species recognition and mate choice. However, the sensory basis of social behavior in species with a small, homogenous EL remains unknown. Using published species descriptions, we found that species in one of these lineages have relatively large eyes. Using sectioned brains, we measured the volume of a major visual region, the optic tectum (OT), and found that this same lineage also has an enlarged OT. We also found that eye size and OT size are highly correlated across species. Phylogenetic analysis suggests that a reduced visual system evolved with the origins of an active electrosense, and that this one particular lineage secondarily evolved an enlarged visual system. Behavioral tests revealed that this enlargement of the visual system established increased visual acuity. Thus, our findings demonstrate that different lineages of mormyrids have evolved visual or electrosensory specializations, but that no lineages have specialized in both. This sensory divergence likely reflects fundamentally different ecologies and suggests that vision may play an especially important role in the social behavior of mormyrids that cannot detect variation in electric signal waveform. Our findings provide an example of evolutionary change in multiple sensory systems among closely related species that lays a foundation for relating ecological adaptation to evolutionary change in multisensory perception and social behavior. © 2013 S. Karger AG, Basel.

Document Type: Article in Press
Source: Scopus

Huang, V.J., Stein, K.C., True, H.L.
Spontaneous Variants of the [RNQ+] Prion in Yeast Demonstrate the Extensive Conformational Diversity Possible with Prion Proteins
(2013) PLoS ONE, 8 (10), art. no. e79582, . 

Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Prion strains (or variants) are structurally distinct amyloid conformations arising from a single polypeptide sequence. The existence of prion strains has been well documented in mammalian prion diseases. In many cases, prion strains manifest as variation in disease progression and pathology, and in some cases, these prion strains also show distinct biochemical properties. Yet, the underlying basis of prion propagation and the extent of conformational possibilities available to amyloidogenic proteins remain largely undefined. Prion proteins in yeast that are also capable of maintaining multiple self-propagating structures have provided much insight into prion biology. Here, we explore the vast structural diversity of the yeast prion [RNQ+] in Saccharomyces cerevisiae. We screened for the formation of [RNQ+] in vivo, allowing us to calculate the rate of spontaneous formation as ~2.96x10-6, and successfully isolate several different [RNQ+] variants. Through a comprehensive set of biochemical and biological analyses, we show that these prion variants are indeed novel. No individual property or set of properties, including aggregate stability and size, was sufficient to explain the physical basis and range of prion variants and their resulting cellular phenotypes. Furthermore, all of the [RNQ+] variants that we isolated were able to facilitate the de novo formation of the yeast prion [PSI+], an epigenetic determinant of translation termination. This supports the hypothesis that [RNQ+] acts as a functional amyloid in regulating the formation of [PSI+] to produce phenotypic diversity within a yeast population and promote adaptation. Collectively, this work shows the broad spectrum of available amyloid conformations, and thereby expands the foundation for studying the complex factors that interact to regulate the propagation of distinct aggregate structures. © 2013 Huang et al.

Document Type: Article
Source: Scopus

Sareen, D.a b , O'Rourke, J.G.a , Meera, P.c , Muhammad, A.K.M.G.a , Grant, S.a , Simpkinson, M.a , Bell, S.a , Carmona, S.a , Ornelas, L.a , Sahabian, A.a , Gendron, T.d , Petrucelli, L.d , Baughn, M.e , Ravits, J.e , Harms, M.B.f , Rigo, F.g , Frank Bennett, C.g , Otis, T.S.c , Svendsen, C.N.a b , Baloh, R.H.a h
Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion
(2013) Science Translational Medicine, 5 (208), art. no. 208ra149, . 

a Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, United States
b Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
c Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, United States
d Mayo Clinic, Jacksonville, FL 32224, United States
e Department of Neurology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, United States
f Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
g Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States
h Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States

Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat-containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-α, suggesting that theymay be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.

Document Type: Article
Source: Scopus

Lester, R.
Back from the edge of existence: A critical anthropology of trauma
(2013) Transcultural Psychiatry, 50 (5), pp. 753-762. 

Department of Anthropology, Washington University in St. Louis, Campus Box 1114, 1 Brookings Drive, St. Louis, MO 63130, United States

Document Type: Note
Source: Scopus

Makris, A.a , Darcey, V.L.a , Rosenbaum, D.L.a , Komaroff, E.b , Vander Veur, S.S.a , Collins, B.N.b , Klein, S.c , Wyatt, H.R.d , Foster, G.D.a
Similar effects on cognitive performance during high- and low-carbohydrate obesity treatment
(2013) Nutrition and Diabetes, 3 (SEPTEMBER), art. no. e89, . 

a Center for Obesity Research and Education, Temple University, 3223 North Broad Street, Philadelphia, PA 19140, United States
b College of Health Professions and Social Work, Department of Public Health, Temple University, Philadelphia, PA, United States
c Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, United States
d Division of Endocrinology, Metabolism and Diabetes, Anschutz Health and Wellness Center, University of Colorado, Aurora, CO, United States

Abstract
OBJECTIVE: Low-carbohydrate (L-CHO) diets are often used for weight loss but their effects on cognitive function are not well understood. The present study compared the effects of a L-CHO and high-carbohydrate (H-CHO) weight-loss diet on cognitive function adults. DESIGN: Participants were randomized to either a L-CHO (n=22) or H-CHO (n=25) weight-loss diet. Cognitive function was evaluated by four computerized cognitive tasks (Stroop Task, Continuous Performance Task, Word Recall and Wisconsin Card Sorting Task) presented in random order before and at 1, 4, 12 and 24 weeks after the initiation of the L-CHO or H-CHO diet. PARTICIPANTS: Forty-seven adults (25 males) with a mean±s.d. age of 47.4±8.7 years and body mass index of 35.3±3.4 kgm-2. RESULTS: There were no significant differences in weight loss between groups at any time point. There were significant improvements on color Stroop task accuracy over time in both diet groups (P&lt;0.05), but there were no differences in performance between groups on this or any other cognitive task at any time period. CONCLUSION: These findings suggest that weight loss has neither a positive nor a negative effect on cognitive function and that L-CHO and H-CHO weight-loss diets have similar effects on cognitive performance. © 2013 Macmillan Publishers Limited All rights reserved.

Author Keywords
Cognitive function;  Diet;  Low carbohydrate;  Obesity;  Weight loss

Document Type: Article
Source: Scopus

Storkel, H.L.a , Bontempo, D.E.a , Aschenbrenner, A.J.a b , Maekawa, J.a , Lee, S.-Y.a c
The effect of incremental changes in phonotactic probability and neighborhood density on word learning by preschool children
(2013) Journal of Speech, Language, and Hearing Research, 56 (5), pp. 1689-1700. 

a University of Kansas, Lawrence, United States
b Washington University, St. Louis, United States
c Woosong University, Daejeon, South Korea

Abstract
Purpose: Phonotactic probability or neighborhood density has predominately been defined through the use of gross distinctions (i.e., low vs. high). In the current studies, the authors examined the influence of finer changes in probability (Experiment 1) and density (Experiment 2) on word learning. Method: The authors examined the full range of probability or density by sampling 5 nonwords from each of 4 quartiles. Three and 5-year-old children received training on nonword-nonobject pairs. Learning was measured in a picture-naming task immediately following training and 1 week after training. Results were analyzed through the use of multilevel modeling. Results: A linear spline model best captured nonlinearities in phonotactic probability. Specifically, word learning improved as probability increased in the lowest quartile, worsened as probability increased in the mid-low quartile, and then remained stable and poor in the 2 highest quartiles. An ordinary linear model sufficiently described neighborhood density. Here, word learning improved as density increased across all quartiles. Conclusion: Given these different patterns, phonotactic probability and neighborhood density appear to influence different word learning processes. Specifically, phonotactic probability may affect recognition that a sound sequence is an acceptable word in the language and is a novel word for the child, whereas neighborhood density may influence creation of a new representation in long-term memory. © American Speech-Language-Hearing Association.

Author Keywords
Neighborhood density;  Phonotactic probability;  Spline regression;  Vocabulary;  Word learning

Document Type: Article
Source: Scopus

Mesa, R., Bassnett, S.
UV-B-induced DNA damage and repair in the mouse lens
(2013) Investigative Ophthalmology and Visual Science, 54 (10), pp. 6789-6797. 

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Purpose. Epidemiologic studies have linked UV-B exposure to development of cortical cataracts, but the underlying molecular mechanism(s) is unresolved. Here, we used a mouse model to examine the nature and distribution of DNA photolesions produced by ocular UV-B irradiation. Methods. Anesthetized mice, eye globes, or isolated lenses were exposed to UV-B. Antibodies specific for 6-4 photoproducts (6-4 PPs) or cyclobutane pyrimidine dimers (CPDs) were used to visualize DNA adducts. Results. Illumination of intact globes with UV-B-induced 6-4 PP and CPD formation in cells of the cornea, anterior iris, and central lens epithelium. Photolesions were not detected in retina or lens cells situated in the shadow of the iris. Photolesions in lens epithelial cells were produced with radiant exposures significantly below the minimal erythemal dose. Lens epithelial cells rapidly repaired 6-4 PPs, but CPD levels did not markedly diminish, even over extended postirradiation recovery periods in vitro or in vivo. The repair of 6-4 PPs did not depend on the proliferative activity of the epithelial cells, since the repair rate in the mitotically-active germinative zone (GZ) was indistinguishable from that of quiescent cells in the central epithelium. Conclusions. Even relatively modest exposures to UV-B produced 6-4 PP and CPD photolesions in lens epithelial cells. Cyclobutane pyrimidine dimer lesions were particularly prevalent and were repaired slowly if at all. Studies on sun-exposed skin have established a causal connection between photolesions and so-called UV-signature mutations. If similar mechanisms apply in the lens, it suggests that somatic mutations in lens epithelial cells may contribute to the development of cortical cataracts. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

Author Keywords
Cortical cataract;  DNA damage;  UV-B

Document Type: Article
Source: Scopus

Whitman, J.B.a , North, C.S.b , Downs, D.L.a , Spitznagel, E.L.c
A prospective study of the onset of PTSD symptoms in the first month after trauma exposure
(2013) Annals of Clinical Psychiatry, 25 (3), pp. 163-172. 

a Department of Psychiatry, Division of Crisis and Disaster Psychiatry, University of Texas, 6363 Forest Park Road, Dallas, TX 75390, United States
b Department of Psychiatry and Surgery, Division of Emergency Medicine, University of Texas, Dallas, TX, United States
c Department of Mathematics, Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: The course of posttraumatic stress disorder (PTSD) symptoms in the month after trauma exposure has not been determined adequately. Symptom group C (avoidance/numbing) has been identified retrospectively as a marker for PTSD, but prospective studies are needed to determine whether these symptoms can provide substantially earlier identification of those who will have PTSD 1 month after trauma exposure. METHODS: We evaluated 42 patients hospitalized for traumatic injuries over the first post-injury month to track development of posttraumatic symptoms. RESULTS: Symptoms emerged rapidly, with group B (intrusion) and group D (hyperarousal) symptoms occurring earlier than group C symptoms. At 1 week, group C criteria accurately predicted who would develop PTSD by 1 month, and by 2 weeks, group C criteria also predicted who would not develop PTSD by 1 month. CONCLUSIONS: The findings, if replicated, may permit earlier identification of PTSD and more timely, appropriate treatment.

Author Keywords
Emergency medicine;  Posttraumatic stress disorder;  PTSD;  Trauma

Document Type: Article
Source: Scopus

Thompson, T., Rodebaugh, T.L., Pérez, M., Schootman, M., Jeffe, D.B.
Perceived social support change in patients with early stage breast cancer and controls.
(2013) Health psychology : official journal of the Division of Health Psychology, American Psychological Association, 32 (8), pp. 886-895. 

George Warren Brown School of Social Work, Washington University in St Louis, St Louis, MO 63130-4899, USA.

Abstract
Variables associated with levels of, and change in, social support were identified in a cohort of early stage breast cancer patients and age-matched controls. Telephone interviews measuring perceived social support and other demographic and psychosocial variables were conducted at 4 to 6 weeks and 6, 12, and 24 months after surgery (patients) or a normal/benign screening mammogram (controls). We modeled the intercept (starting point) and slope (changing) aspects of social support. Participants included 542 controls and 541 patients (77% White, 23% African American; mean age 57.7 years [SD = 10.6]). Most participants reported high social support. Patients reported significantly higher levels of social support at baseline than controls. For patients, social support had a significant negative slope that significantly varied between individuals; the intercept of social support also varied significantly. Predictors of lower social support intercept in patients included not being married/partnered, being White, having lower perceived general health, and having higher negative affect (a latent variable defined by anxiety and depression symptom severity). Patients who were African American (vs. White) or had mastectomy (vs. lumpectomy) had steeper social support declines, and participants with both these characteristics had lower starting points as well as steeper declines. Social support among controls did not change significantly. Clinicians might consider psychosocial interventions for patients reporting low social support around the time of diagnosis and surgical treatment, and for patients at risk for steeper declines in support, such as African Americans and women undergoing mastectomy. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Document Type: Article
Source: Scopus

Koopmeiners, A.S.a , Mueller, S.b , Kramer, J.c , Hogan, Q.H.b d
Effect of electrical field stimulation on dorsal root ganglion neuronal function
(2013) Neuromodulation, 16 (4), pp. 304-311. Cited 2 times.

a Department of Pathology, Washington University of St. Louis, St. Louis, MO, United States
b Department of Anesthesiology, Medical College of Wisconsin, 8701 W Watertown Plank, Milwaukee, WI 53226-3548, United States
c Spinal Modulation, Inc., Palo Alto, CA, United States
d Zablocki VA Medical Center, Milwaukee, WI, United States

Abstract
Objectives Neural stimulation may provide analgesia for a variety of painful conditions. Activation of primary sensory neurons, which underlies pain relief by spinal cord stimulation, also may be achieved by stimulation at the level of the dorsal root ganglion (DRG). The DRG also is a site of pain pathogenesis, particularly in neuropathic pain. We therefore examined the hypothesis that field stimulation of the DRG directly suppresses excitability of sensory neurons. Materials and Methods Intercellular Ca2+ level (Fura-2 microfluorimetry) and membrane potential were recorded in excised rat DRGs with ganglionic field stimulation (GFS) delivered by wire electrodes in the bath solution adjacent to the DRG. Neuronal excitability was evaluated by number of action potentials (APs) generated during neuronal depolarization, conduction velocity during axonal stimulation, and AP propagation failure. These were measured before and after 90 sec of GFS at 60 Hz. Data analysis employed chi-square, paired t-test, and analysis of variance. Results GFS using 400-μsec pulses and 30 V generated Ca2+ influx, indicative of DRG neuronal activation. Fewer neurons were able to fire one or more APs after GFS (N = 23) than in control neurons without GFS (N = 24, p &lt; 0.05), and fewer neurons were able to generate multiple APs after GFS compared with time controls (p &lt; 0.05). GFS significantly reduced conduction velocity compared with baseline before GFS (N = 16, p &lt; 0.05) while there was no change in the controls (N = 18). The peak rate at which APs could be propagated was reduced in 9 of 16 neurons by GFS, but propagation efficiency was reduced in only 4 of 18 control neurons (p &lt; 0.05), and the total number of APs generated in an ensemble of stimuli at different frequencies was reduced by GFS (N = 16, p &lt; 0.05) but not in time controls (N = 18). Conclusions Our findings indicate that direct excitation of the DRG by electrical fields reduces neuronal excitability and may provide a new analgesic approach. © 2013 International Neuromodulation Society.

Author Keywords
Electrode placement;  neuropathic pain;  neurostimulation;  peripheral nerve stimulation;  rats;  stimulation

Document Type: Article
Source: Scopus

Poldrack, R.A.a , Barch, D.M.b , Mitchell, J.P.c , Wager, T.D.d , Wagner, A.D.e , Devlin, J.T.f , Cumba, C.a , Koyejo, O.a , Milham, M.P.g
Towards open sharing of task-based fMRI data: The OpenfMRI project
(2013) Frontiers in Neuroinformatics, 7 (JUNE), . Cited 1 time.

a University of Texas at Austin, United States
b Washington University, St. Louis, United States
c Harvard University, United States
d University of Colorado, United States
e Stanford University, United Kingdom
f University College, London, United Kingdom
g Child Mind Institute, United States

Abstract
The large-scale sharing of task-based functional neuroimaging data has the potential to allow novel insights into the organization of mental function in the brain, but the eld of neuroimaging has lagged behind other areas of bioscience in the development of data sharing resources. This paper describes the OpenFMRI project (accessible online at http://www.openfmri.org), which aims to provide the neuroimaging community with a resource to support open sharing of task-based fMRI studies. We describe the motivation behind the project, focusing particularly on how this project addresses some of the well-known challenges to sharing of task-based fMRI data. Results from a preliminary analysis of the current database are presented, which demonstrate the ability to classify between task contrasts with high generalization accuracy across subjects, and the ability to identify individual subjects from their activation maps with moderately high accuracy. Clustering analyses show that the similarity relations between statistical maps have a somewhat orderly relation to the mental functions engaged by the relevant tasks. These results highlight the potential of the project to support large-scale multivariate analyses of the relation between mental processes and brain function. © 2013 Poldrack, Barch, Mitchell, Wager, Wagner, Devlin, Cumba, Koyejo and Milham.

Document Type: Article
Source: Scopus

Whitman, J.B.a , North, C.S.b , Downs, D.L.a , Spitznagel, E.L.c
A prospective study of the onset of PTSD symptoms in the first month after trauma exposure
(2013) Annals of Clinical Psychiatry, 25 (2), pp. E8-E17. 

a Department of Psychiatry, Division of Crisis and Disaster Psychiatry, University of Texas Southwestern Medical Center, 6363 Forest Park Road, Dallas, TX 75390, United States
b VA North Texas Health Care System, Departments of Psychiatry and Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States
c Department of Mathematics, Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: The course of posttraumatic stress disorder (PTSD) symptoms in the month after trauma exposure has not been determined adequately. Symptom group C (avoidance/numbing) has been identified retrospectively as a marker for PTSD, but prospective studies are needed to determine whether these symptoms can provide substantially earlier identification of those who will have PTSD 1 month after trauma exposure. METHODS: We evaluated 42 patients hospitalized for traumatic injuries over the first post-injury month to track development of posttraumatic symptoms. RESULTS: Symptoms emerged rapidly, with group B (intrusion) and group D (hyperarousal) symptoms occurring earlier than group C symptoms. At 1 week, group C criteria accurately predicted who would develop PTSD by 1 month, and by 2 weeks, group C criteria also predicted who would not develop PTSD by 1 month. CONCLUSIONS: The findings, if replicated, may permit earlier identification of PTSD and more timely, appropriate treatment.

Author Keywords
Emergency medicine;  Posttraumatic stress disorder;  PTSD;  Trauma

Document Type: Article
Source: Scopus