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WUSTL Neuroscience Publications Archive - September 2015

September 2015

September 23, 2015

Salminen, L.E.a , Schofield, P.R.b c , Pierce, K.D.b , Zhao, Y.d , Luo, X.d , Wang, Y.d , Laidlaw, D.H.e , Cabeen, R.P.e , Conturo, T.E.f , Tate, D.F.g , Akbudak, E.f , Lane, E.M.h , Heaps, J.M.g , Bolzenius, J.D.a , Baker, L.M.a , Cagle, L.M.a , Paul, R.H.ag 
Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition
(2016) Behavioural Brain Research, 296, art. no. 9778, pp. 85-93. 

DOI: 10.1016/j.bbr.2015.08.028

a University of Missouri-St. Louis, Department of Psychological Sciences, 1 University Blvd., Stadler Hall 442A, St. Louis, MO, United States
b Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, Australia
c School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
d Brown University, Department of Biostatistics and Center for Statistical Sciences, Providence, RI, United States
e Brown University, Computer Science Department, Providence, RI, United States
f Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway, St. Louis, MO, United States
g Missouri Institute of Mental Health, 4633 World Parkway Circle, Berkeley, MO, United States
h Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, United States

Abstract
The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n= 27, ThrThr n= 27). Differences in subcortical hyperintensity (SH) volume were also examined between groups. Results indicated that the threonine variant was associated with significantly reduced integrity in the superior longitudinal fasciculus (SLF) and the cingulate gyrus segment of the cingulum bundle (cingulum CG) compared to those with the methionine variant, and poorer cognitive performance on tests of attention/processing speed and language. Despite these associations, integrity of these tracts did not significantly mediate relationships between cognition and genetic status, and SH did not differ significantly between groups. Collectively our results suggest that the threonine variant of M268T is a significant risk factor for abnormalities in specific white matter tracts and cognitive domains in healthy older adults, independent of SH burden. © 2015 Elsevier B.V.

Author Keywords
AGT;  Cognition;  M235T;  M268T;  Rs699;  White matter

Document Type: Article
Source: Scopus
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Noguchi, K.K.a , Cabrera, O.H.b , Swiney, B.S.a , Salinas-Contreras, P.a , Smith, J.K.a , Farber, N.B.a 
Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis
(2015) Neurobiology of Disease, 83, art. no. 3586, . 

DOI: 10.1016/j.nbd.2015.08.020

a Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO, United States
b University of Missouri-St. Louis, Department of Psychological Sciences, One University Boulevard, 325 Stadler Hall, St. Louis, MO, United States

Abstract
The external granule layer (EGL) is a proliferative region that produces over 90% of the neurons in the cerebellum but can also malignantly transform into a cerebellar tumor called the medulloblastoma (the most common malignant brain tumor in children). Current dogma considers Hedgehog stimulation a potent proliferative signal for EGL neural progenitor cells (NPCs) and medulloblastomas. However, the Hedgehog pathway also acts as a survival signal in the neural tube where it regulates dorsoventral patterning by controlling NPC apoptosis. Here we show that Hedgehog stimulation is also a potent survival signal in the EGL and medulloblastomas that produces a massive apoptotic response within hours of signal loss in mice. This toxicity can be produced by numerous Hedgehog antagonists (vismodegib, cyclopamine, and jervine) and is Bax/Bak dependent but p53 independent. Finally, since glucocorticoids can also induce EGL and medulloblastoma apoptosis, we show that Hedgehog's effects on apoptosis can occur independent of glucocorticoid stimulation. This effect may play a major role in cerebellar development by directing where EGL proliferation occurs thereby morphologically sculpting growth. It may also be a previously unknown major therapeutic effect of Hedgehog antagonists during medulloblastoma therapy. Results are discussed in terms of their implications for both cerebellar development and medulloblastoma treatment. © 2015 Elsevier Inc.

Author Keywords
Apoptosis;  Cerebellum;  External granule layer;  Medulloblastoma;  Neural progenitor cell;  Sonic Hedgehog

Document Type: Article
Source: Scopus
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Hänggi, D.a , Etminan, N.a , Macdonald, R.L.b , Steiger, H.J.a , Mayer, S.A.c , Aldrich, F.d , Diringer, M.N.e , Hoh, B.L.f , Mocco, J.g , Strange, P.h i , Faleck, H.J.h , Miller, M.h i 
NEWTON: Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage
(2015) Neurocritical Care, 23 (2), pp. 274-284. Cited 1 time.

DOI: 10.1007/s12028-015-0112-2

a Department of Neurosurgery, Heinrich-Heine-University, Moorenstraße 5, Düsseldorf, Germany
b Division of Neurosurgery, Department of Surgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada
c Institute for Critical Care Medicine, Mount Sinai Hospital, New York, NY, United States
d Neurological Surgery, University of Maryland Medical Center, Baltimore, MD, United States
e Neurological Critical Care, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurosurgery, University of Florida, Gainesville, FL, United States
g Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
h Edge Therapeutics, Berkeley Heights, NJ, United States
i Phase 1 to 4, LLC, Princeton Junction, NJ, United States

Abstract
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. EG-1962 is a sustained-release microparticle formulation of nimodipine that has shown preclinical efficacy when administered intraventricularly or intracisternally to dogs with SAH, without evidence of toxicity at doses in the anticipated therapeutic range. Thus, we propose to administer EG-1962 to humans in order to assess safety and tolerability and determine a dose to investigate efficacy in subsequent clinical studies. Methods: We describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of EG-1962 in patients with aSAH. The study will comprise two parts: a dose escalation period (Part 1) to determine the MTD of EG-1962 and a treatment period (Part 2) to assess the safety and tolerability of the selected dose of EG-1962. Patients with a ruptured saccular aneurysm treated by neurosurgical clipping or endovascular coiling will be considered for enrollment. Patients will be randomized to receive either EG-1962 (study drug: nimodipine microparticles) or oral nimodipine in the approved dose regimen (active control) within 60 h of aSAH. Results: Primary objectives are to determine the MTD and the safety and tolerability of the selected dose of intraventricular EG-1962 as compared to enteral nimodipine. The secondary objective is to determine release and distribution by measuring plasma and CSF concentrations of nimodipine. Exploratory objectives are to determine the incidence of delayed cerebral infarction on computed tomography, clinical features of delayed cerebral ischemia, angiographic vasospasm, and incidence of rescue therapy and clinical outcome. Clinical outcome will be determined at 90 days after aSAH using the extended Glasgow outcome scale, modified Rankin scale, Montreal cognitive assessment, telephone interview of cognitive status, and Barthel index. Conclusion: Here, we describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the MTD and assess the safety and tolerability of EG-1962 in patients with aSAH. © 2015, Springer Science+Business Media New York.

Author Keywords
Cerebral aneurysm;  Clinical trial;  Delayed cerebral ischemia;  Nimodipine;  Subarachnoid hemorrhage;  Sustained drug release

Document Type: Article
Source: Scopus
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Mallon, R.
Performance, self-explanation, and agency
(2015) Philosophical Studies, 172 (10), pp. 2777-2798. 

DOI: 10.1007/s11098-015-0444-y

Department of Philosophy and Philosophy-Neuroscience-Psychology Program, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States

Abstract
Social constructionist explanations of human thought and behavior hold that our representations (e.g. of race, or gender, or mental illness, or emotion) produce and regulate the categories, thoughts, and behaviors of those they represent. Performative versions of constructionist accounts explain these thoughts and behaviors as part of an intentional, strategic performance that is elicited and regulated by our representations of ourselves. This paper has four aims. First, I sketch a causal model of performative social constructionist claims. Second, I articulate a puzzling feature of performative claims that makes them seem especially implausible: the puzzle of intention and ignorance. Like other constructionists, performative constructionists are especially interested in explaining thoughts and behaviors that are widely but mistakenly believed to be the unintentional consequences of membership in a natural kind. But why doesn’t the intentional performance of a category undermine this ignorance? My third aim is to resolve this puzzle. I suggest that a plausible understanding can be found in the failure to locate one’s mental states in a causal explanation of one’s thoughts and actions. Finally, I argue that this model implies that the sorts of theories we (as a community or as a culture) offer of particular behaviors can create or destroy agency and responsibility with regard to those behaviors. © 2015, Springer Science+Business Media Dordrecht.

Author Keywords
Agency;  Gender;  Performance;  Performativity;  Race;  Responsibility;  Self-knowledge;  Social construction

Document Type: Article
Source: Scopus
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Ong, C.J.a , Keyrouz, S.G.b , Diringer, M.N.b 
The Role of Osmotic Therapy in Hemispheric Stroke
(2015) Neurocritical Care, 23 (2), pp. 285-291. 

DOI: 10.1007/s12028-015-0173-2

a Departments of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States
b Department of Neurology and Neurosurgery, Washington University in St. Louis, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States

Abstract
Background: Decompressive hemicraniectomy (DHC) can be lifesaving in hemispheric stroke complicated by cerebral edema. Conversely, osmotic agents have not been shown to improve survival, despite their widespread use. It is unknown whether medical measures can similarly confer survival in certain patient subgroups. We hypothesized that osmotic therapy (OT) without DHC may be associated with a greater likelihood of survival in particular populations depending on demographic, radiologic, or treatment characteristics. Methods: We performed a retrospective cohort analysis of patients with large anterior circulation strokes with an NIH stroke scale (NIHSS) ≥10 who received OT. We compared clinical, radiologic, and treatment characteristics between two groups: (1) those who survived until discharge with only OT (medical management success) and (2) those who required either DHC or died (medical management failure). Results: Thirty patients met eligibility criteria. Median NIHSS was 19 [interquartile range (IQR) 13–24], and median GCS was 10 [IQR 8–14]. Forty-seven percent of the medical management cohort survived to discharge. Demographic characteristics associated with medical management success included NIHSS (p = 0.009) and non-black race (p = 0.003). Of the various interventions, the administration of OT after 24 hours and a smaller hypertonic saline dose was also associated with survival to discharge (p = 0.038 and 0.031 respectively). Conclusion: Our results suggest that patients with moderate size hemispheric infarcts on presentation and those who do not require OT within the first 24 h of stroke may survive until discharge with medical management alone. Black race was also associated with conservative management failure, a finding that may reflect a cultural preference toward aggressive management. Further prospective studies are needed to better establish the utility of medical management of hemispheric edema in the setting of moderate size hemispheric infarcts. © 2015, Springer Science+Business Media New York.

Author Keywords
Cerebrovascular accident;  Hemicraniectomy;  Herniation;  Malignant edema;  Stroke

Document Type: Article
Source: Scopus
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Cho, Y.a , Park, D.b , Cavalli, V.a 
Filamin a is required in injured axons for HDAC5 activity and axon regeneration
(2015) Journal of Biological Chemistry, 290 (37), pp. 22759-22770. 

DOI: 10.1074/jbc.M115.638445

a Dept. of Anatomy and Neurobiology, Washington University, School of Medicine, Campus Box 8108, 660 S. Euclid Ave., St. Louis, MO, United States
b School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea

Abstract
Microtubule dynamics are important for axon growth during development as well as axon regeneration after injury. We have previously identified HDAC5 as an injury-regulated tubulin deacetylase that functions at the injury site to promote axon regeneration. However, the mechanisms involved in the spatial control of HDAC5 activity remain poorly understood. Here we reveal that HDAC5 interacts with the actin binding protein filamin A via its C-terminal domain. Filamin A plays critical roles in HDAC5-dependent tubulin deacetylation because, in cells lacking filamin A, the levels of acetylated tubulin are elevated markedly. We found that nerve injury increases filamin A axonal expression in a protein synthesis-dependent manner. Reducing filamin A levels or interfering with the interaction between HDAC5 and filaminAprevents injury-induced tubulin deacetylation as well as HDAC5 localization at the injured axon tips. In addition, neurons lacking filamin A display reduced axon regeneration. Our findings suggest a model in which filaminAlocal translation following axon injury controls localized HDAC5 activity to promote axon regeneration. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

Document Type: Article
Source: Scopus
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van Den Berg, S.M.a , de Moor, M.H.M.b c d , Verweij, K.J.H.e f , Krueger, R.F.g , Luciano, M.h i , Arias Vasquez, A.j k l m , Matteson, L.K.g , Derringer, J.n , Esko, T.o , Amin, N.p , Gordon, S.D.e , Hansell, N.K.e , Hart, A.B.q , Seppälä, I.r , Huffman, J.E.s , Konte, B.t , Lahti, J.u v , Lee, M.w , Miller, M.g , Nutile, T.x , Tanaka, T.y , Teumer, A.z , Viktorin, A.aa , Wedenoja, J.ab , Abdellaoui, A.b , Abecasis, G.R.ac , Adkins, D.E.ad , Agrawal, A.ae , Allik, J.af ag , Appel, K.ah , Bigdeli, T.B.w , Busonero, F.ai , Campbell, H.aj , Costa, P.T.ak , Smith, G.D.al , Davies, G.h i , de Wit, H.am , Ding, J.bo , Engelhardt, B.E.an , Eriksson, J.G.v ao ap aq ar , Fedko, I.O.b , Ferrucci, L.y , Franke, B.j k l , Giegling, I.t , Grucza, R.ae , Hartmann, A.M.t , Heath, A.C.ae , Heinonen, K.u , Henders, A.K.e , Homuth, G.as , Hottenga, J.-J.b , Iacono, W.G.g , Janzing, J.k , Jokela, M.u , Karlsson, R.aa , Kemp, J.P.al at , Kirkpatrick, M.G.am , Latvala, A.ab ao , Lehtimäki, T.r , Liewald, D.C.h i , Madden, P.A.F.ae , Magri, C.au , Magnusson, P.K.E.aa , Marten, J.s , Maschio, A.ai , Mbarek, H.b , Medland, S.E.e , Mihailov, E.o av , Milaneschi, Y.aw , Montgomery, G.W.e , Nauck, M.ax , Nivard, M.G.b , Ouwens, K.G.b , Palotie, A.ay az , Pettersson, E.aa , Polasek, O.ba , Qian, Y.bo , Pulkki-Råback, L.u , Raitakari, O.T.bb bc , Realo, A.af , Rose, R.J.bd , Ruggiero, D.x , Schmidt, C.O.z , Slutske, W.S.be , Sorice, R.x , Starr, J.M.i bf , St Pourcain, B.al bg bh , Sutin, A.R.y bi , Timpson, N.J.al , Trochet, H.s , Vermeulen, S.l bj , Vuoksimaa, E.ab , Widen, E.az , Wouda, J.a b , Wright, M.J.e , Zgaga, L.aj bk , Generation Scotlandbl , Porteous, D.bm , Minelli, A.au , Palmer, A.A.q am , Rujescu, D.t , Ciullo, M.x , Hayward, C.s , Rudan, I.aj , Metspalu, A.o ag , Kaprio, J.ab ao az , Deary, I.J.h i , Räikkönen, K.u , Wilson, J.F.s aj , Keltikangas-Järvinen, L.u , Bierut, L.J.ae , Hettema, J.M.w , Grabe, H.J.ah bn , Penninx, B.W.J.H.aw , van Duijn, C.M.p , Evans, D.M.al , Schlessinger, D.bo , Pedersen, N.L.aa , Terracciano, A.v y , McGue, M.g bp , Martin, N.G.e , Boomsma, D.I.b 
Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium
(2015) Behavior Genetics, 13 p. Article in Press. 

DOI: 10.1007/s10519-015-9735-5

a Department of Research Methodology, Measurement and Data-Analysis (OMD), Faculty of Behavioural, Management, and Social Sciences, University of Twente, PO Box 217, Enschede, Netherlands
b Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands
c Department of Clinical Child and Family Studies, VU University Amsterdam, Amsterdam, Netherlands
d Department of Methods, VU University Amsterdam, Amsterdam, Netherlands
e QIMR Berghofer Medical Research Institute, Brisbane, Australia
f Department of Developmental Psychology and EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, Netherlands
g Department of Psychology, University of Minnesota, Minneapolis, United States
h Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
i Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
j Donders Institute for Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, Netherlands
k Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
l Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
m Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
n Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL, United States
o Estonian Genome Center, University of Tartu, Tartu, Estonia
p Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
q Department of Human Genetics, University of Chicago, Chicago, IL, United States
r Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland
s MRC Human Genetics Unit, MRC IGMM, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom
t Department of Psychiatry, University of Halle, Halle, Germany
u Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
v Folkhälsan Research Center, Helsinki, Finland
w Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
x Institute of Genetics and Biophysics “A. Buzzati-Traverso” – CNR, Naples, Italy
y National Institute on Aging, NIH, Baltimore, MD, United States
z Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
aa Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
ab Department of Public Health, University of Helsinki, Helsinki, Finland
ac Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, United States
ad Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, VA, United States
ae Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
af Department of Psychology, University of Tartu, Tartu, Estonia
ag Estonian Academy of Sciences, Tallinn, Estonia
ah Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
ai Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy
aj Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
ak Behavioral Medicine Research Center, Duke University School of Medicine, Durham, NC, United States
al Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
am Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, United States
an Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
ao National Institute for Health and Welfare (THL), Helsinki, Finland
ap Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
aq Unit of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
ar Vasa Central Hospital, Vaasa, Finland
as Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
at Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Australia
au Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
av Department of Biotechnology, University of Tartu, Tartu, Estonia
aw Department of Psychiatry, EMGO+ Institute, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands
ax Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
ay Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
az Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
ba Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia
bb Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
bc Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
bd Department of Psychological & Brain Sciences, Indiana University, Bloomington, IN, United States
be Department of Psychological Sciences and Missouri Alcoholism Research Center, University of Missouri, Columbia, MO, United States
bf Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom
bg School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom
bh School of Experimental Psychology, University of Bristol, Bristol, United Kingdom
bi College of Medicine, Florida State University, Tallahassee, FL, United States
bj Department for Health Evidence, Radboud University Medical Center, Nijmegen, Netherlands
bk Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland
bl Scottish Family Health Study, A Collaboration Between the University Medical Schools and NHS, Aberdeen, Dundee, Edinburgh and Glasgow, United Kingdom
bm Medical Genetics Section, Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
bn Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, Stralsund, Germany
bo Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
bp Institute of Public Health, University of Southern Denmark, Odense, Denmark

Abstract
Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion. © 2015 The Author(s)

Author Keywords
Common genetic variants;  Imputation;  Personality;  Phenotype harmonization;  Polygenic risk

Document Type: Article in Press
Source: Scopus
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Best, A.L.a , Alcaraz, K.I.b , McQueen, A.c , Cooper, D.L.b , Warren, R.C.d , Stein, K.b 
Examining the mediating role of cancer-related problems on spirituality and self-rated health among African American cancer survivors: A report from the American Cancer Society's Studies of Cancer Survivors-II
(2015) Psycho-Oncology, 24 (9), pp. 1051-1059. 

DOI: 10.1002/pon.3720

a HEALing Community Center, Research and Community Health, 2600 Martin Luther King, Jr. Drive, Atlanta, GA, United States
b American Cancer Society, Behavioral Research Center, United States
c Washington University School of Medicine, United States
d Tuskegee University, National Center for Bioethics in Research and Health Care, United States

Abstract
Objective African American (AA) cancer survivors report poorer self-rated health (SRH) compared to other racial/ethnic groups. Spirituality is often linked to positive health outcomes, with AAs reporting greater levels of spirituality. This study examined the potential mediating role of cancer-related problems in the relationship between spirituality and SRH among AA cancer survivors compared to non-African American (non-AA) survivors. Methods We analyzed data on 9006 adult cancer survivors from the American Cancer Society's Study of Cancer Survivors-II. Preliminary analyses compared characteristics of AAs and non-AAs and identified significant covariates of SRH. We tested a path model using multi-group structural equation modeling (SEM), and then examined race as a moderator. Results Of the three domains of spirituality assessed, AAs had higher levels of peace (p < .001) and faith (p < .001), but not meaning, compared to non-AAs; and of four domains of cancer-related problems assessed, AAs had greater physical distress (p < .001), emotional distress (p < .001), and employment/finance problems (p < .001), but not fear of recurrence. In SEM analyses adjusting for number of comorbidities and income, race moderated the impact of spirituality and cancer-related problems on SRH. Specifically, spirituality had significantly stronger associations with cancer-related problems among AAs than non-AAs. Spirituality was positively associated with all four domains of cancer-related problems, but only physical distress was associated with SRH among AAs. Conclusions The negative effects of physical distress may attenuate the positive effects of spirituality on AA's SRH. Future studies should consider racial/ethnic differences in the determinants and conceptualization of SRH, which is a known predictor of survival. © 2014 John Wiley & Sons, Ltd.

Author Keywords
cancer;  disparities;  oncology;  self-rated health;  spirituality;  survivors

Document Type: Article
Source: Scopus
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Valenta, K.a b , Brown, K.A.c , Rafaliarison, R.R.d , Styler, S.A.e , Jackson, D.f , Lehman, S.M.a , Chapman, C.A.b g , Melin, A.D.h 
Sensory integration during foraging: the importance of fruit hardness, colour, and odour to brown lemurs
(2015) Behavioral Ecology and Sociobiology, 11 p. Article in Press. 

DOI: 10.1007/s00265-015-1998-6

a Department of Anthropology, 19 Russell Street, University of Toronto, Toronto, ON, Canada
b Department of Anthropology, McGill University, 855 Sherbrooke Street West, Montreal, QC, Canada
c Dalla Lana School of Public Health, University of Toronto, 155 College Street, Toronto, ON, Canada
d Department of Paleontology, University of Antananarivo, Antananarivo, Madagascar, Madagascar
e Leibniz Institute for Tropospheric Research, Permoserstraße 15, Leipzig, Germany
f Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada
g Wildlife Conservation Society, Bronx, NY, United States
h Department of Anthropology, Washington University, One Brooking Drive, Campus Box 1114, St. Louis, MO, United States

Abstract
Animal reliance on fruit signals, such as hardness, colour, and odour, during foraging is poorly understood. Here, we present data on fruit foraging behaviour and efficiency (rate of fruit ingestion) of three groups of wild, frugivorous brown lemurs (Eulemur fulvus, N = 29 individuals) in Ankarafantsika National Park, Madagascar. We quantify fruit hardness using a modified force gauge, fruit colour using spectroscopy, and fruit odour using volatile organic compound (VOC) sampling with gas chromatography-mass spectrometry. We relate lemur foraging behaviour to fruit traits by calculating touching, visual inspection, and sniffing indices and relate lemur foraging efficiency to fruit traits by calculating acceptance indices. The use of different sensory modalities by lemurs is marginally predicted in one case by fruit traits—fruits with higher overall smell signals are sniffed less than fruits with lower overall smell signals. When controlling for all fruit traits, fruit size is the only significant predictor of fruit foraging efficiency—lemurs forage more rapidly on smaller fruits relative to larger fruits. © 2015 Springer-Verlag Berlin Heidelberg

Author Keywords
Brown lemurs;  Colour vision;  Frugivory;  Fruit choice;  Madagascar;  Olfaction;  Volatile Organic Compounds

Document Type: Article in Press
Source: Scopus
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Baker, C.A., Huck, K.R., Carlson, B.A.
Peripheral sensory coding through oscillatory synchrony in weakly electric fish
(2015) eLife, 4 (AUGUST2015), art. no. e08163, 26 p. 

DOI: 10.7554/eLife.08163

Department of Biology, Washington University in St. Louis, St. Louis, United States

Abstract
Adaptations to an organism’s environment often involve sensory system modifications. In this study, we address how evolutionary divergence in sensory perception relates to the physiological coding of stimuli. Mormyrid fishes that can detect subtle variations in electric communication signals encode signal waveform into spike-timing differences between sensory receptors. In contrast, the receptors of species insensitive to waveform variation produce spontaneously oscillating potentials. We found that oscillating receptors respond to electric pulses by resetting their phase, resulting in transient synchrony among receptors that encodes signal timing and location, but not waveform. These receptors were most sensitive to frequencies found only in the collective signals of groups of conspecifics, and this was correlated with increased behavioral responses to these frequencies. Thus, different perceptual capabilities correspond to different receptor physiologies. We hypothesize that these divergent mechanisms represent adaptations for different social environments. Our findings provide the first evidence for sensory coding through oscillatory synchrony. © Baker et al.

Document Type: Article
Source: Scopus
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Sheahan, T.D.a b , Copits, B.A.a , Golden, J.P.a , Gereau, R.W., IVa b 
Voluntary exercise training: Analysis of mice in uninjured, inflammatory, and nerve-injured pain states
(2015) PLoS ONE, 10 (7), art. no. e0133191, . 

DOI: 10.1371/journal.pone.0133191

a Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Washington University Program in Neuroscience, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Both clinical and animal studies suggest that exercise may be an effective way to manage inflammatory and neuropathic pain conditions. However, existing animal studies commonly use forced exercise paradigms that incorporate varying degrees of stress, which itself can elicit analgesia, and thus may complicate the interpretation of the effects of exercise on pain. We investigated the analgesic potential of voluntary wheel running in the formalin model of acute inflammatory pain and the spared nerve injury model of neuropathic pain in mice. In uninjured, adult C57BL/6J mice, 1 to 4 weeks of exercise training did not alter nociceptive thresholds, lumbar dorsal root ganglia neuronal excitability, or hindpaw intraepidermal innervation. Further, exercise training failed to attenuate formalin-induced spontaneous pain. Lastly, 2 weeks of exercise training was ineffective in reversing spared nerve injury-induced mechanical hypersensitivity or in improving muscle wasting or hindpaw denervation. These findings indicate that in contrast to rodent forced exercise paradigms, short durations of voluntary wheel running do not improve pain-like symptoms in mouse models of acute inflammation and peripheral nerve injury. © 2015 Sheahan et al.

Document Type: Article
Source: Scopus
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Mackay, D.S., Bennett, T.M., Shiels, A.
Exome sequencing identifies a missense variant in efemp1 co-segregating in a family with autosomal dominant primary open-angle glaucoma
(2015) PLoS ONE, 10 (7), art. no. e0132529, . 

DOI: 10.1371/journal.pone.0132529

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

Abstract
Primary open-angle glaucoma (POAG) is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp) in exon-5 of the gene coding for epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H) on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic. Copyright: © 2015 Mackay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus
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Calì, T.a , Lopreiato, R.b , Shimony, J.c , Vineyard, M.d , Frizzarin, M.b , Zanni, G.e , Zanotti, G.b , Brini, M.a , Shinawi, M.d , Carafoli, E.f 
A novel mutation in isoform 3 of the plasma membrane Ca2+ pump impairs cellular Ca2+ homeostasis in a patient with cerebellar ataxia and laminin subunit 1α mutations
(2015) Journal of Biological Chemistry, 290 (26), pp. 16132-16141. 

DOI: 10.1074/jbc.M115.656496

a Department of Biology, University of Padova, Padova, Italy
b Department of Biomedical Sciences, University of Padova, Padova, Italy
c Mallinckrodt Institute of Radiology, Division of Genetics and Genomic Medicine, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University, School of Medicine, St. Louis, MO, United States
e Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
f Venetian Institute of Molecular Medicine (VIMM), Padova, Italy

Abstract
The particular importance of Ca2+ signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca2+ ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca2+. A genetic defect of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation in the ATP2B3 gene in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca2+ ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca2+ transients generated by cell stimulation and impairs its Ca2+ extrusion function under conditions of low resting cytosolic Ca2+ as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca2+-bound state. The patient also carries two missense mutations in LAMA1, encoding laminin subunit 1α. Onthe basis of the family pedigree of the patient, the presence of both PMCA3 and laminin subunit 1α mutations appears to be necessary for the development of the disease. Considering the observed defect in cellularCa2+ homeostasisandthe previous finding that PMCAs act as digenic modulators in Ca2+-linked pathologies, the PMCA3 dysfunction along with LAMA 1 mutations could act synergistically to cause the neurological phenotype. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

Document Type: Article
Source: Scopus
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Naidoo, S.D.a , Skolnick, G.B.a , Patel, K.B.a , Woo, A.S.a , Cheng, A.-L.b 
Long-term outcomes in treatment of deformational plagiocephaly and brachycephaly using helmet therapy and repositioning: a longitudinal cohort study
(2015) Child's Nervous System, 31 (9), pp. 1547-1552. 

DOI: 10.1007/s00381-015-2769-4

a Cleft Palate and Craniofacial Deformities Institute, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8238, St. Louis, MO, United States
b School of Nursing and Health Studies, University of Missouri–Kansas City, 2464 Charlotte, Kansas City, MO, United States

Abstract
Objectives: Deformational plagiocephaly and/or brachycephaly (DPB) is a misshapen head presenting at birth or shortly thereafter, caused by extrinsic forces on an infant’s malleable cranium. There are two treatment methods available for DPB: helmeting and repositioning. Little is known about the long-term outcomes of these two treatment options. The purpose of this study was to examine children who received helmeting or repositioning therapy for DPB as infants and compare the long-term head shape outcomes of the two groups. Methods: A longitudinal cohort study design was used to evaluate change in head shape of the two groups. One hundred children (50 helmeted, 50 repositioned) were initially evaluated at 6 months or younger for DPB. Anthropometric skull measurements taken as infants before treatment were compared with measurements taken for this study. Inclusion criteria included initial clinic visit at age 6 months or younger, evaluation by the same practitioner, and current age 2–10 years. Cephalic index and cranial vault asymmetry were calculated based on caliper measurements. Results: Data from 100 children were evaluated for this study. Significant differences between the treatment groups in the mean change in cephalic index (p = 0.003) and cranial vault asymmetry (p < 0.001) were found; the children that used helmet therapy demonstrated greater improvement. Conclusions: This is one of the larger published long-term outcome studies comparing children that used helmets and repositioning to treat their DPB as infants. The data suggest that infants will have more improvement in head shape with a helmet than with repositioning. © 2015, Springer-Verlag Berlin Heidelberg.

Author Keywords
Brachycephaly;  Deformational plagiocephaly;  Long-term outcomes;  Non-synostotic plagiocephaly;  Plagiocephaly treatment;  Positional plagiocephaly

Document Type: Article
Source: Scopus
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Vinberg, F., Kefalov, V.
Simultaneous ex vivo functional testing of two retinas by in vivo electroretinogram system
(2015) Journal of Visualized Experiments, 2015 (99), art. no. e52855, 7 p. 

DOI: 10.3791/52855

Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, United States

Abstract
An In vivo electroretinogram (ERG) signal is composed of several overlapping components originating from different retinal cell types, as well as noise from extra-retinal sources. Ex vivo ERG provides an efficient method to dissect the function of retinal cells directly from an intact isolated retina of animals or donor eyes. In addition, ex vivo ERG can be used to test the efficacy and safety of potential therapeutic agents on retina tissue from animals or humans. We show here how commercially available in vivo ERG systems can be used to conduct ex vivo ERG recordings from isolated mouse retinas. We combine the light stimulation, electronic and heating units of a standard in vivo system with customdesigned specimen holder, gravity-controlled perfusion system and electromagnetic noise shielding to record low-noise ex vivo ERG signals simultaneously from two retinas with the acquisition software included in commercial in vivo systems. Further, we demonstrate how to use this method in combination with pharmacological treatments that remove specific ERG components in order to dissect the function of certain retinal cell types. © 2015 Journal of Visualized Experiments.

Author Keywords
a-wave;  b-wave;  Cone;  Drug testing;  Electrophysiology;  Electroretinogram;  ERG;  ex vivo ERG;  Issue 99;  Neuroscience;  Photoreceptor;  Retina;  Rod

Document Type: Article
Source: Scopus
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Poinsatte, K.a , Selvaraj, U.M.a , Ortega, S.B.a , Plautz, E.J.a , Kong, X.a , Gidday, J.M.b , Stowe, A.M.a 
Quantification of neurovascular protection following repetitive hypoxic preconditioning and transient middle cerebral artery occlusion in mice
(2015) Journal of Visualized Experiments, 2015 (99), art. no. e52675, 10 p. 

DOI: 10.3791/52675

a Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, United States
b Department of Neurological Surgery, Washington University School of Medicine, United States

Abstract
Experimental animal models of stroke are invaluable tools for understanding stroke pathology and developing more effective treatment strategies. A 2 week protocol for repetitive hypoxic preconditioning (RHP) induces long-term protection against central nervous system (CNS) injury in a mouse model of focal ischemic stroke. RHP consists of 9 stochastic exposures to hypoxia that vary in both duration (2 or 4 hr) and intensity (8% and 11% O<inf>2</inf>). RHP reduces infarct volumes, blood-brain barrier (BBB) disruption, and the post-stroke inflammatory response for weeks following the last exposure to hypoxia, suggesting a long-term induction of an endogenous CNS-protective phenotype. The methodology for the dual quantification of infarct volume and BBB disruption is effective in assessing neurovascular protection in mice with RHP or other putative neuroprotectants. Adult male Swiss Webster mice were preconditioned by RHP or duration-equivalent exposures to 21% O<inf>2</inf> (i.e. room air). A 60 min transient middle cerebral artery occlusion (tMCAo) was induced 2 weeks following the last hypoxic exposure. Both the occlusion and reperfusion were confirmed by transcranial laser Doppler flowmetry. Twenty-two hr after reperfusion, Evans Blue (EB) was intravenously administered through a tail vein injection. 2 hr later, animals were sacrificed by isoflurane overdose and brain sections were stained with 2,3,5- triphenyltetrazolium chloride (TTC). Infarcts volumes were then quantified. Next, EB was extracted from the tissue over 48 hr to determine BBB disruption after tMCAo. In summary, RHP is a simple protocol that can be replicated, with minimal cost, to induce long-term endogenous neurovascular protection from stroke injury in mice, with the translational potential for other CNS-based and systemic pro-inflammatory disease states. © 2015 Journal of Visualized Experiments.

Author Keywords
Blood-brain barrier disruption;  Hypoxia;  Issue 99;  Medicine;  Neuroprotection;  Preconditioning;  Stroke;  Transient middle cerebral artery occlusion

Document Type: Article
Source: Scopus
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Seay, K.D.a , Kohl, P.L.b 
The Comorbid and Individual Impacts of Maternal Depression and Substance Dependence on Parenting and Child Behavior Problems
(2015) Journal of Family Violence, 30 (7), pp. 899-910. 

DOI: 10.1007/s10896-015-9721-y

a College of Social Work, DeSaussure College, University of South Carolina, Columbia, SC, United States
b George Warren Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Maternal depression, substance dependence, and the comorbidity of these conditions are highly prevalent risk factors among families involved with Child Protective Services (CPS). Data from the National Survey of Child and Adolescent Well-Being I (NSCAW I) were analyzed to examine the influence of maternal substance dependence, depression, and comorbidity on parenting and child behavior over 36-months among children reported to CPS who remained in the home at all waves. Although neglect and child behavior problems were highest for mothers with comorbidity at baseline, mothers with substance dependence had the poorest self-reported parenting and child behavior problems over time. Results indicate a need for intensive targeted services to address the complex needs of CPS-involved mothers with substance dependence and their in-home children. © 2015, Springer Science+Business Media New York.

Author Keywords
Child abuse and neglect;  Child behavior problems;  Child welfare;  Comorbid conditions;  Maternal depression;  Maternal substance dependence;  Parenting

Document Type: Article
Source: Scopus
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Vulin, A.a , Wein, N.a , Simmons, T.R.a , Rutherford, A.M.a , Findlay, A.R.a d , Yurkoski, J.A.a , Kaminoh, Y.a e , Flanigan, K.M.a b c 
The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development
(2015) Neuromuscular Disorders, . Article in Press. 

DOI: 10.1016/j.nmd.2015.08.005

a The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
b Department of Pediatrics, The Ohio State University, Columbus, OH, USA
c Department of Neurology, The Ohio State University, Columbus, OH, USA
d Department of Neurology, Washington University, St. Louis, MO, USA
e School of Osteopathic Medicine, Ohio University, Athens, OH, USA

Abstract
Exon duplication mutations account for up to 11% of all cases of Duchenne muscular dystrophy (DMD), and a duplication of exon 2 is the most common duplication in patients. For use as a platform for testing of duplication-specific therapies, we developed a mouse model that carries a Dmd exon 2 duplication. By using homologous recombination we duplicated exon 2 within intron 2 at a location consistent with a human duplication hotspot. mRNA analysis confirms the inclusion of a duplicated exon 2 in mouse muscle. Dystrophin expression is essentially absent by immunofluorescent and immunoblot analysis, although some muscle specimens show very low-level trace dystrophin expression. Phenotypically, the mouse shows similarities to mdx, the standard laboratory model of DMD. In skeletal muscle, areas of necrosis and phagocytosis are seen at 3 weeks, with central nucleation prominent by four weeks, recapitulating the "crisis" period in mdx. Marked diaphragm fibrosis is noted by 6 months, and remains unchanged at 12 months. Our results show that the Dup2 mouse is both pathologically (in degree and distribution) and physiologically similar to mdx. As it recapitulates the most common single exon duplication found in DMD patients, this new model will be a useful tool to assess the potential of duplicated exon skipping. © 2015 Elsevier B.V.

Author Keywords
Duchenne muscular dystrophy;  Duplication;  Exon skipping;  Mouse model

Document Type: Article in Press
Source: Scopus
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Godzik, J.a , Ravindra, V.M.b , Ray, W.Z.c , Eskandari, R.d , Dailey, A.T.b 
Primary repair of open neural tube defect in adulthood: Case example and review of management strategies
(2015) Spine Journal, . Article in Press. 

DOI: 10.1016/j.spinee.2015.07.463

a Department of Neurosurgery, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, USA
b Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 N. Medical Drive East, Salt, Lake City, UT 84132, USA
c Department of Neurosurgery, Washington University in St. Louis, 660 S. Euclid, Box 8057, St. Louis, MO 63110, USA
d Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB 301, MSC 606, Charleston, SC 29425-6160, USA

Abstract
Background Context: Neural tube defects are congenital malformations that develop when the neural plate fails to close during embryogenesis. The most common open neural tube defect, myelomeningocele (MMC), is declining in frequency in North America. If identified, an MMC must be closed in the perinatal period to prevent lethal complications. Lesions presenting in older adults are, thus, very uncommon. Purpose: The purpose of this study was to describe the surgical management of an adult with an unrepaired ulcerated lumbosacral MMC who presented with persistent cerebrospinal fluid (CSF) leakage and to review the management strategies for adult patients with unrepaired MMC. Study Design: A case report was used for this study. Methods: The patient was a 62-year-old woman with an unrepaired ulcerated lumbosacral MMC and associated lower extremity weakness. She sought medical care for persistent lumbar tenderness and ulceration after sustaining a fall 4 months before admission. Physical and radiological assessment revealed a lumbosacral MMC at the L5 and S1 levels and a tethered cord. Surgical resection of the placode and de-tethering were performed. Results: One week after repair of the lumbosacral MMC, the patient was readmitted for management of continued CSF leakage and hydrocephalus, requiring external ventricular drainage, wound revision, and placement of lumboperitoneal shunt. The patient experienced complete resolution of back pain without additional episodes of CSF leakage. Conclusions: This rare case and review of management strategies suggests that proper surgical management of open MMC in adulthood can successfully be performed and improve patient symptoms and prevent further complications. © 2015 Elsevier Inc.

Author Keywords
Cerebrospinal fluid;  Hydrocephalus;  Lumboperitoneal shunt;  Myelomeningocele;  Spinal dysraphism;  Tethered cord

Document Type: Article in Press
Source: Scopus
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Brenner, D.S.a b , Golden, J.P.b , Vogt, S.K.b , Gereau, R.W., IVb 
A simple and inexpensive method for determining cold sensitivity and adaptation in mice
(2015) Journal of Visualized Experiments, 2015 (97), art. no. e52640, 12 p. Cited 1 time.

DOI: 10.3791/52640

a MSTP, Washington University, St. Louis, United States
b Washington University Pain Center, Department of Anesthesiology, Washington University, St. Louis, United States

Abstract
Cold hypersensitivity is a serious clinical problem, affecting a broad subset of patients and causing significant decreases in quality of life. The cold plantar assay allows the objective and inexpensive assessment of cold sensitivity in mice, and can quantify both analgesia and hypersensitivity. Mice are acclimated on a glass plate, and a compressed dry ice pellet is held against the glass surface underneath the hindpaw. The latency to withdrawal from the cooling glass is used as a measure of cold sensitivity. Cold sensation is also important for survival in regions with seasonal temperature shifts, and in order to maintain sensitivity animals must be able to adjust their thermal response thresholds to match the ambient temperature. The Cold Plantar Assay (CPA) also allows the study of adaptation to changes in ambient temperature by testing the cold sensitivity of mice at temperatures ranging from 30 °C to 5 °C. Mice are acclimated as described above, but the glass plate is cooled to the desired starting temperature using aluminum boxes (or aluminum foil packets) filled with hot water, wet ice, or dry ice. The temperature of the plate is measured at the center using a filament T-type thermocouple probe. Once the plate has reached the desired starting temperature, the animals are tested as described above. This assay allows testing of mice at temperatures ranging from innocuous to noxious. The CPA yields unambiguous and consistent behavioral responses in uninjured mice and can be used to quantify both hypersensitivity and analgesia. This protocol describes how to use the CPA to measure cold hypersensitivity, analgesia, and adaptation in mice. © 2015 Journal of Visualized Experiments.

Author Keywords
Acetone;  Adaptation;  Behavior;  Cold;  Cold plate;  Issue 97;  Mouse;  Neuroscience;  Neuroscience;  Reflex;  Thermosensation

Document Type: Article
Source: Scopus
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Gold, M.S.a b c d , Badgaiyan, R.D.e , Blum, K.f g h i 
A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry
(2015) Psychiatric Clinics of North America, 38 (3), pp. 419-462. 

DOI: 10.1016/j.psc.2015.05.011

a Departments of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, CA, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
c Rivermend Health Scientific Advisory Board, 2300 Windy Ridge Parkway South East, Suite 210S, Atlanta, GA, United States
d Drug Enforcement Administration (DEA) Educational Foundation, Washington, DC, United States
e Laboratory of Advanced Radiochemistry and Molecular and Functioning Imaging, Department of Psychiatry, College of Medicine, University of Minnesota, Minneapolis, MN, United States
f Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
g Department of Psychiatry, Center for Clinical and Translational Science, Community Mental Health Institute, Burlington, VT, United States
h Division of Applied Clinical Research, Dominion Diagnostics, LLC, 211 Circuit Drive, North Kingstown, RI, United States
i Rivermend Health Scientific Advisory Board, Atlanta, GA, United States

Author Keywords
Dopamine agonistic therapy;  Drug addiction;  Food addiction;  Genetic basis;  Hypodopaminergic state;  Molecular basis;  Psychiatry

Document Type: Review
Source: Scopus
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Fullerton, J.M.a b , Koller, D.L.c , Edenberg, H.J.c d , Foroud, T.c e , Liu, H.f l , Glowinski, A.L.g , Mcinnis, M.G.h , Wilcox, H.C.i j k , Frankland, A.j k , Roberts, G.j k , Schofield, P.R.a b , Mitchell, P.B.j k o , Nurnberger, J.I.c e , Hulvershorn, L.e , Fisher, C.e, Monahan, P.O.l , McInnis, M.m , Kamali, M.m , Brucksch, C.m , Glowinski, A.n , Gershon, E.S.p , Berrettini, W.q 
Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At-Risk Individuals
(2015) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 168 (7), pp. 617-629. 

DOI: 10.1002/ajmg.b.32344

a Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
b School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
c Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
d Department of Biochemistry and Molecular Biology and Center for Medical Genomics, Indiana University, Indianapolis, IN, United States
e Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
g Department of Psychiatry, Washington University, St. Louis, MO, United States
h Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
i Child Psychiatry and Public Health, Johns Hopkins University, Baltimore, MD, United States
j School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
k Black Dog Institute, Prince of Wales Hospital, Sydney, NSW, Australia
l Department of Medicine, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, United States
m Department of Psychiatry, University of Michigan School of Medicine, Ann Arbor, United States
n Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
o Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
p Department of Psychiatry, University of Chicago Pritzker School of Medicine, Chicago, IL, United States
q Department of Psychiatry, University of Pennsylvania Health System, Philadelphia, United States

Abstract
Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n=601) and their adult relatives without BP (n=695). Unrelated adult controls (n=266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12-30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n=367) and psychiatrically screened controls (n=229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P=3.4×10-5, AUC=0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P=0.014, RR=1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ2=5.15, P=0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 Wiley Periodicals, Inc.

Author Keywords
AUC analysis;  Bipolar disorder;  Family;  Polygenic risk;  Prospective

Document Type: Article
Source: Scopus
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Munn-Chernoff, M.A.a b , Grant, J.D.a b , Bucholz, K.K.a b , Agrawal, A.a b , Lynskey, M.T.c , Madden, P.A.F.a b , Heath, A.C.a b , Duncan, A.E.a b d 
Bulimic Behaviors and Early Substance Use: Findings from a Cotwin-Control Study
(2015) Alcoholism: Clinical and Experimental Research, 39 (9), pp. 1740-1748. 

DOI: 10.1111/acer.12829

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom
d George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States

Abstract
Background: Bulimic behaviors (i.e., binge eating and compensatory behaviors) and substance use frequently co-occur. However, the etiology underlying this association is poorly understood. This study evaluated the association between bulimic behaviors and early substance use, controlling for genetic and shared environmental factors. Methods: Participants were 3,540 young adult women from the Missouri Adolescent Female Twin Study. A telephone adaptation of the Semi-Structured Assessment for the Genetics of Alcoholism interview assessed DSM-IV bulimic behaviors, substance use, and other psychological characteristics. Lifetime bulimic behaviors were examined in twin pairs concordant and discordant for early substance use. Logistic regressions were adjusted for the nonindependence of twin data, zygosity, age, body mass index, early menarche (onset before age 12), and early sex (first consensual sexual intercourse before age 15). Results: In the entire study population, women who reported early use of alcohol or nicotine were more likely to engage in bulimic behaviors after adjusting for covariates. In 53 pairs of monozygotic twins discordant for alcohol experimentation before age 15, the twin who reported early alcohol experimentation had 3.21 (95% confidence interval = 1.54 to 6.67) times higher odds of reporting bulimic behaviors than the cotwin who did not report early alcohol experimentation, even after adjustment for covariates. Conclusions: Findings suggest that early alcohol experimentation may contribute to the development of bulimic behaviors via mechanisms extending beyond shared vulnerability, including individual-specific environmental experiences or causal pathways. © 2015 Research Society on Alcoholism.

Author Keywords
Bulimia;  Cotwin-Control Design;  Early Substance Use;  Eating Disorders;  Sexual Intercourse

Document Type: Article
Source: Scopus
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Hancock, D.B.a , Levy, J.L.b , Gaddis, N.C.b , Glasheen, C.a , Saccone, N.L.c , Page, G.P.d , Hulse, G.K.e , Wildenauer, D.e , Kelty, E.A.e , Schwab, S.G.f g , Degenhardt, L.h , Martin, N.G.i , Montgomery, G.W.i , Attia, J.j k , Holliday, E.G.j k , McEvoy, M.j l , Scott, R.J.m n o , Bierut, L.J.p , Nelson, E.C.p , Kral, A.H.q , Johnson, E.O.r 
Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1
(2015) Biological Psychiatry, 78 (7), pp. 474-484. Cited 1 time.

DOI: 10.1016/j.biopsych.2015.01.003

a Behavioral Health Epidemiology Program, Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, 3040 East Cornwallis Road, Research Triangle Park, NC, United States
b Research Computing Division, RTI International, Research Triangle Park, NC, United States
c Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
d Center for Public Health Genomics, RTI International, Atlanta, GA, United States
e School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia
f Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany
g Faculty of Science Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
h National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia
i Queensland Institute of Medical Research, Berghofer Medical Research Institute, Brisbane, QLD, Australia
j Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
k Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, NSW, Australia
l Public Health Research Program, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, NSW, Australia
m Center for Bioinformatics Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, NSW, Australia
n School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
o Division of Genetics, Hunter Area Pathology Service, Newcastle, NSW, Australia
p Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
q Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, San Francisco, CA, United States
r Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, United States

Abstract
Background No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction. Methods We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry. Results Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 × 10-5): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 × 10-5). Meta-analysis across all case-control cohorts resulted in p = 4.3 × 10-8: the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 × 10-6 for rs1799971-A/rs3778150-C and p =.79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 × 10-8 for rs3823010). Conclusions Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction. © 2015 Society of Biological Psychiatry.

Author Keywords
Genetic association study;  Heroin;  Multiancestry;  Opioid;  OPRM1;  Prefrontal cortex

Document Type: Article
Source: Scopus
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Bugg, J.M., Diede, N.T., Cohen-Shikora, E.R., Selmeczy, D.
Expectations and experience: Dissociable bases for cognitive control?
(2015) Journal of Experimental Psychology: Learning Memory and Cognition, 41 (5), pp. 1349-1373. 

DOI: 10.1037/xlm0000106

Department of Psychology, Washington University in St. Louis, United States

Abstract
Classic theories emphasized the role of expectations in the intentional control of attention and action. However, recent theorizing has implicated experience-dependent, online adjustments as the primary basis for cognitive control-adjustments that appear to be implicit (Blais, Harris, Guerrero, & Bunge, 2012). The purpose of the current study was to evaluate whether explicit expectations play any role in cognitive control above and beyond experience. In a novel precued lists paradigm, participants were administered abbreviated lists of Stroop trials. For half of the lists, precues led participants to validly expect lists of varying proportion congruency (e.g., mostly congruent [MC], mostly incongruent [MI]; Experiments 1 to 4). The Stroop effect was greater in cued MC relative to uncued MC lists. By contrast, the Stroop effect was equivalent in cued MI and uncued MI lists. Only when preparation was encouraged via a speed manipulation (Experiment 3) or incentives (Experiment 4) did we find evidence of heightened control when an MI list was expected, in the form of a short-lived reduction in the Stroop effect on the first (experience-free) trial. These patterns suggest (a) expectations play a role in the relaxation of cognitive control, independent of experience (as also shown in Experiment 5, wherein expectations were varied while holding experience constant across lists), but (b) experience is the dominant basis for the sustained heightening of cognitive control (after the first trial). Theoretical implications of dissociating the contributions of expectations and experience to cognitive control are discussed, including interpretations of the list-wide proportion congruence effect. © 2015 American Psychological Association.

Author Keywords
Cognitive control;  Color-word correlations;  Conflict-monitoring;  Conscious expectations;  Stroop

Document Type: Article
Source: Scopus
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Kunkle, B.W.a , Jaworski, J.a , Barral, S.b c d , Vardarajan, B.b c f g , Beecham, G.W.a , Martin, E.R.a , Cantwell, L.S.h , Partch, A.h , Bird, T.D.i j , Raskind, W.H.j k , DeStefano, A.L.l , Carney, R.M.a m , Cuccaro, M.a n , Vance, J.M.a n , Farrer, L.A.k o p qr , Goate, A.M.f g , Foroud, T.s , Mayeux, R.P.b c d e t , Schellenberg, G.D.h , Haines, J.L.u , Pericak-Vance, M.A.a e n 
Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease
(2015) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2015.05.020

a John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
b The Taub Institute of Research on Alzheimer's Disease, College of Physicians and Surgeons, Columbia University, New York, NY, USA
c The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
d Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
e Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
g Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
h Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
i Department of Neurology, University of Washington, Seattle, WA, USA
j Department of Medicine, University of Washington, Seattle, WA, USA
k Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
l Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
m Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA
n Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA
o Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public Health, MA, USA
p Department of Neurology, Boston University School of Medicine and Public Health, MA, USA
q Department of Ophthalmology, Boston University School of Medicine and Public Health, MA, USA
r Department of Epidemiology, Boston University School of Public Health, MA, USA
s Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
t The Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA
u Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA

Abstract
Introduction: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. Methods: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Results: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD*=4.18). The 1-LOD confidence interval forthis region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD. © 2015 The Authors.

Author Keywords
Familial;  Genetics;  High penetrance;  Identity by descent;  Late-onset Alzheimer's disease;  Linkage;  Non-Hispanic white

Document Type: Article in Press
Source: Scopus
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Wixted, J.T.a , Mickes, L.b , Clark, S.E.c , Gronlund, S.D.d , Roediger, H.L., IIIe 
Initial eyewitness confidence reliably predicts eyewitness identification accuracy
(2015) American Psychologist, 70 (6), pp. 515-526. 

DOI: 10.1037/a0039510

a Department of Psychology, University of California, San Diego, United States
b Department of Psychology, Royal Holloway, University of London, United Kingdom
c Department of Psychology, University of California, Riverside, United States
d Department of Psychology, University of Oklahoma, United States
e Department of Psychology, Washington University in St. Louis, United States

Abstract
Eyewitness memory is widely believed to be unreliable because (a) high-confidence eyewitness misidentifications played a role in over 70% of the now more than 300 DNA exonerations of wrongfully convicted men and women, (b) forensically relevant laboratory studies have often reported a weak relationship between eyewitness confidence and accuracy, and (c) memory is sufficiently malleable that, not infrequently, people (including eyewitnesses) can be led to remember events differently from the way the events actually happened. In light of such evidence, many researchers agree that confidence statements made by eyewitnesses in a court of law (in particular, the high confidence they often express at trial) should be discounted, if not disregarded altogether. But what about confidence statements made by eyewitnesses at the time of the initial identification (e.g., from a lineup), before there is much opportunity for memory contamination to occur? A considerable body of recent empirical work suggests that confidence may be a highly reliable indicator of accuracy at that time, which fits with longstanding theoretical models of recognition memory. Counterintuitively, an appreciation of this fact could do more to protect innocent defendants from being wrongfully convicted than any other eyewitness identification reform that has been proposed to date. © 2015 American Psychological Association.

Author Keywords
Accuracy;  Confidence;  Eyewitness memory

Document Type: Article
Source: Scopus
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Jacoby, L.L.a , Wahlheim, C.N.a , Kelley, C.M.b 
Memory consequences of looking back to notice change: Retroactive and proactive facilitation
(2015) Journal of Experimental Psychology: Learning Memory and Cognition, 41 (5), pp. 1282-1297. 

DOI: 10.1037/xlm0000123

a Department of Psychology, Washington University in St. Louis, United States
b Department of Psychology, Florida State University, United States

Abstract
Three experiments contrasted recollection of change with differentiation as means of avoiding retroactive interference and proactive interference. We manipulated the extent to which participants looked back to notice change between pairs of cues and targets (A-B, A-D) and measured the effects on later cued recall of either the first or second response. Two lists of word pairs were presented. Some right-hand members of pairs were changed within List 2, whereas others were changed between lists. Participants in a Within-List Back condition were instructed to detect changes that occurred only during List 2, in an effort to reduce noticing changes in pairs between lists while simultaneously differentiating the 2 lists. In contrast, participants in an N-Back condition were instructed to detect both within-list and between-list changes. Recall of first list responses that changed between lists produced retroactive facilitation for the N-Back condition but not for the Within-List Back condition. Similarly, recall of second list responses that changed between lists produced proactive facilitation for the N-Back condition but not for the Within-List Back condition. The greater extent of looking back increased detection of change and later recollection of change, which produced facilitation. When change was not recollected, detected change produced proactive interference. The recursive reminding produced when change is noticed contrasts with the simple associations of classic interference theory, and memory performance when change is recollected contrasts with the predictions of interference theory. © 2015 American Psychological Association.

Author Keywords
Change;  Interference;  Memory;  Recollection;  Reminding

Document Type: Article
Source: Scopus
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Beebe, J.a , Qiaoan, R.b , Endara, M.A.c , Wysocki, T.d 
Moral Objectivism in Cross-Cultural Perspective
(2015) Journal of Cognition and Culture, 15 (3-4), pp. 386-401. 

DOI: 10.1163/15685373-12342157

a Department of Philosophy, State University of New York at Buffalo, 131 Park Hall, Buffalo, NY, United States
b Sun Yat-sen University, Kanton, China
c Azusa Pacific Online University, Azusa, 901 E. Alosta AvenueCA, United States
d Department of Philosophy, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States

Abstract
Moral psychologists have recently turned their attention to the study of folk metaethical beliefs. We report the results of a cross-cultural study using Chinese, Polish and Ecuadorian participants that seeks to advance this line of investigation. Individuals in all three demographic groups were observed to attribute objectivity to ethical statements in very similar patterns. Differences in participants'strength of opinion about an issue, the level of societal agreement or disagreement about an issue, and participants'age were found to significantly affect their inclination to view the truth of an ethical statement as a matter of objective fact. Implications for theorizing about folk morality are discussed. © Koninklijke Brill NV, Leiden, The Netherlands.

Author Keywords
folk psychology;  moral psychology;  morality;  objectivism;  relativism

Document Type: Review
Source: Scopus
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Luby, J.L.a b 
Povertys most insidious damage: The developing brain
(2015) JAMA Pediatrics, 169 (9), pp. 810-811. 

DOI: 10.1001/jamapediatrics.2015.1682

a Early Emotional Development Program, Washington University School of Medicine in St Louis, St Louis, MO, United States
b Department of Psychiatry (Child), Washington University School of Medicine in St Louis, 660 S Euclid, Box 8511, St Louis, MO, United States

Document Type: Editorial
Source: Scopus
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Vaneckova, M.a , Herman, M.b , Smith, M.P.c , Mechl, M.d , Maravilla, K.R.e , Weichet, J.f , Spampinato, M.V.g , Žižka, J.h , Wippold, F.J., IIi , Baima, J.J.j , Babbel, R.k , Bültmann, E.l , Huang, R.Y.m , Buhk, J.-H.n , Bonafé, A.o , Colosimo, C.p , Lui, S.q, Kirchin, M.A.r , Shen, N.s , Pirovano, G.s , Spinazzi, A.s 
The benefits of high relaxivity for brain tumor imaging: Results of a multicenter intraindividual crossover comparison of gadobenate dimeglumine with gadoterate meglumine (the BENEFIT study)
(2015) American Journal of Neuroradiology, 36 (9), pp. 1589-1598. 

DOI: 10.3174/ajnr.A4468

a Charles University in Prague, First Faculty of Medicine, General University Hospital, Katerinská 30, Prague, Czech Republic
b University Hospital Olomouc, Olomouc, Czech Republic
c Beth Israel Deaconess Medical Center, Boston, MA, United States
d Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czech Republic
e MR Research Laboratory, University of Washington, Seattle, WA, United States
f Na Homolce Hospital, Prague, Czech Republic
g Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, United States
h University Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, Charles University in Prague, Prague, Czech Republic
i Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
j Clinical Radiologists, S.C., Springfield, IL, United States
k Good Samaritan Regional Medical Center, Corvallis, OR, United States
l Institute of Diagnostic and Interventional Neuroradiology, Hannover, Germany
m Harvard Medical School, Brigham and Women's Hospital, Boston, United States
n University Medical Center Hamburg Eppendorf, Hamburg, Germany
o Hopital Gui de Chauliac, Montpellier, France
p Policlinico Agostino Gemelli, Rome, Italy
q West China Hospital of Sichuan University, Chengdu, Sichuan, China
r Global Medical and Regulatory Affairs, Bracco Imaging S.p.A., Milan, Italy
s Global Medical and Regulatory Affairs, Bracco Diagnostics, Monroe, NJ, United States

Abstract
BACKGROUND AND PURPOSE: Gadobenate dimeglumine (MultiHance) has higher r1 relaxivity than gadoterate meglumine (Dotarem) which may permit the use of lower doses for MR imaging applications. Our aim was to compare 0.1- and 0.05-mmol/kg body weight gadobenate with 0.1-mmol/kg body weight gadoterate for MR imaging assessment of brain tumors. MATERIALS AND METHODS: We performed crossover, intraindividual comparison of 0.1-mmol/kg gadobenate with 0.1-mmol/kg gadoterate (Arm 1) and 0.05-mmol/kg gadobenate with 0.1-mmol/kg gadoterate (Arm 2). Adult patients with suspected or known brain tumors were randomized to Arm 1 (70 patients) or Arm 2 (107 patients) and underwent 2 identical examinations at 1.5T. The agents were injected in randomized-sequence order, and the 2 examinations were separated by 2-14 days. MR imaging scanners, imaging sequences (T1-weighted spin-echo and T1-weighted high-resolution gradient-echo), and acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images for diagnostic information (degree of definition of lesion extent, lesion border delineation, visualization of lesion internal morphology, contrast enhancement) and quantitatively for percentage lesion enhancement and lesion-to-background ratio. Safety assessments were performed. RESULTS: In Arm 1, a highly significant superiority (P<.002) of 0.1-mmol/kg gadobenate was demonstrated by all readers for all end points. In Arm 2, no significant differences (P>.1) were observed for any reader and any end point, with the exception of percentage enhancement for reader 2 (P < .05) in favor of 0.05-mmol/kg gadobenate. Study agent-related adverse events were reported by 2/169 (1.2%) patients after gadobenate and by 5/175 (2.9%) patients after gadoterate. CONCLUSIONS: Significantly superior morphologic information and contrast enhancement are demonstrated on brain MR imaging with 0.1-mmol/kg gadobenate compared with 0.1-mmol/kg gadoterate. No meaningful differences were recorded between 0.05-mmol/kg gadobenate and 0.1-mmol/kg gadoterate.

Document Type: Article
Source: Scopus

September 16, 2015

Fallil, Z.a , Pardoe, H.a , Bachman, R.a , Cunningham, B.a , Parulkar, I.b , Shain, C.b , Poduri, A.b , Knowlton, R.c , Kuzniecky, R.a ad , Abou-Khalil, B.d , Alldredge, B.e , Andermann, E.f , Bautista, J.g , Berkovic, S.h , Boro, A.i , Cascino, G.j , Consalvo, D.k , Crumrine, P.l , Devinsky, O.m , Dlugos, D.n , Epstein, M.o , Fiol, M.p , Fountain, N.q , French, J.r , Friedman, D.s , Geller, E.t, Glauser, T.u , Glynn, S.v , Haut, S.w , Hayward, J.x , Helmers, S.y , Kanner, A.z , Kirsch, H.aa , Kossoff, E.ab , Kuperman, R.ac , Lowenstein, D.ae , McGuire, S.af , Motika, P.ag , Novotny, E.ah , Ottman, R.ai , Paolicchi, J.aj , Parent, J.ak , Park, K.al , Risch, N.am , Sadleir, L.an , Scheffer, I.ao , Shellhaas, R.ap , Sherr, E.aq , Shih, J.ar , Shinnar, S.as , Singh, R.at , Sirven, J.au , Smith, M.av , Sullivan, J.aw , Thio, L.L.ax , Venkatasubramanian, A.ay , Vining, E.az , Von Allmen, G.ba , Weisenberg, J.ax , Widdess-Walsh, P.bb , Winawer, M.R.bc , Acton, E.bd , Hagopian, S.bd , Sanchez, S.bd 
Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy
(2015) Epilepsy and Behavior, 51, pp. 321-327. 

DOI: 10.1016/j.yebeh.2015.07.041

a NYU Epilepsy Center, Langone Medical Center, New York University, New York, NY, United States
b Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, United States
c UCSF Epilepsy Center, UCSF, San Francisco, CA, United States
d Data Review Core, Vanderbilt University Medical Center, United States
e AEDCore, University of California, San Francisco, United States
f MNI, McGill University, Canada
g Cleveland Clinic, United States
h The University of Melbourne, Australia
i EEG Core, Albert Einstein College of Medicine, United States
j MRICore, Mayo Clinic College of Medicine RochesterMN, United States
k Hospital General de Agudos José Maria Ramos Mejía, Argentina
l Children's Hospital of Pittsburgh of UPMC, United States
m Phenotyping Core, NewYork University School of Medicine, United States
n EEG Core, Phenotyping Core, The Children's Hospital of Philadelphia, United States
o Data Analysis Core, Emory University School of Medicine, United States
p University of Minnesota Medical Center, United States
q Data Review Core, University of Virginia Health System, United States
r AEDCore, New York University School of Medicine, United States
s NewYork University School of Medicine, United States
t St.Barnabas Health Care System, United States
u AED Core, Cincinnati Children's Hospital Medical Center, United States
v University of Michigan, United States
w Albert Einstein College of Medicine, United States
x Referral Center PI, Kaiser Permanente, Oakland Medical Center, United States
y Emory University School of Medicine, United States
z AEDCore, University of Miami, United States
aa University of California, San Francisco, United States
ab The Johns Hopkins University School of Medicine, United States
ac Local Referral Center PI, Children's Hospital and Research Center Oakland, United States
ad New York University School of Medicine, United States
ae University of California, San Francisco, United States
af Louisiana State University Health Sciences Center, United States
ag Rush University Medical Center, United States
ah Seattle Children's Hospital, United States
ai Phenotyping Core, Data Analysis Core, Columbia University, United States
aj Vanderbilt University Medical Center, United States
ak University of Michigan, United States
al The Children's Hospital Denver, United States
am Data Analysis Core, University of California, San Francisco, United States
an Wellington School of Medicine and Health Sciences, University of Otago, New Zealand
ao Data Review Core, The University of Melbourne, Australia
ap EEG Core, University of Michigan, United States
aq Phenotyping Core, University of California, San Francisco, United States
ar Data Review Core, Mayo Clinic College of Medicine JacksonvilleFL, United States
as Phenotyping Core, Albert Einstein College of Medicine, United States
at University of Michigan, United States
au Mayo Clinic College of Medicine ScottsdaleAZ, United States
av Rush University Medical Center, United States
aw EEGCore, University of California, San Francisco, United States
ax Washington University, St.Louis, United States
ay The Children's Hospital of Philadelphia, United States
az The Johns Hopkins University School of Medicine, United States
ba University of Texas Health Science Center, Houston, United States
bb Data Review Core, St. Barnabas Health Care System, United States
bc Data Review Core, Data Analysis Core, Columbia University, United States
bd The Children's Hospital of Philadelphia, United States

Abstract
Purpose: Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls. We report the clinical characteristics of the largest case series of FLNA-negative patients with seizures and bilateral periventricular heterotopia. Methods: Participants were recruited through the Epilepsy Phenome/Genome Project (EPGP), a multicenter collaborative effort to collect detailed phenotypic data and DNA on a large number of individuals with epilepsy, including a cohort with symptomatic epilepsy related to PVNH. Included subjects had epilepsy, and MRI confirmed bilateral PVNH. Magnetic resonance imaging studies were visually and quantitatively reviewed to investigate the topographic extent of PVNH, symmetry, and laterality. Key findings: We analyzed data on 71 patients with bilateral PVNH. The incidence of febrile seizures was 16.6%. There was at least one other family member with epilepsy in 36.9% of this population. Developmental delay was present in 21.8%. Focal onset seizures were the most common type of seizure presentation (79.3%). High heterotopia burden was strongly associated with female gender and trigonal nodular localization. There was no evidence for differences in brain volume between PVNH subjects and controls. No relationship was observed between heterotopic volume and gender, developmental delay, location of PVNH, ventricular or cerebellar abnormalities, laterality of seizure onset, age at seizure onset, and duration of epilepsy. Significance: A direct correlation was observed between high heterotopia burden, female gender, and trigonal location in this large cohort of FLNA-negative bilateral PVNH patients with epilepsy. Quantitative MRI measurements indicated that this correlation is based on the diffuse nature of the heterotopic nodules rather than on the total volume of abnormal heterotopic tissue. © 2015 Elsevier Inc.

Author Keywords
Epilepsy;  Epilepsy Phenome/Genome Project;  Periventricular nodular heterotopia


Document Type: Article
Source: Scopus


 

Wen, J.a , Yablonskiy, D.A.a , Luo, J.b , Lancia, S.c , Hildebolt, C.a , Cross, A.H.c 
Detection and quantification of regional cortical gray matter damage in multiple sclerosis utilizing gradient echo MRI
(2015) NeuroImage: Clinical, 9, pp. 164-175. 

DOI: 10.1016/j.nicl.2015.08.003

a Department of Radiology, Washington University, St. Louis, MO, United States
b Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, United States
c Department of Neurology, Washington University, St. Louis, MO, United States

Abstract
Cortical gray matter (GM) damage is now widely recognized in multiple sclerosis (MS). The standard MRI does not reliably detect cortical GM lesions, although cortical volume loss can be measured. In this study, we demonstrate that the gradient echo MRI can reliably and quantitatively assess cortical GM damage in MS patients using standard clinical scanners. High resolution multi-gradient echo MRI was used for regional mapping of tissue-specific MRI signal transverse relaxation rate values (R2∗) in 10 each relapsing-remitting, primary-progressive and secondary-progressive MS subjects. A voxel spread function method was used to correct artifacts induced by background field gradients. R2∗ values from healthy controls (HCs) of varying ages were obtained to establish baseline data and calculate ΔR2∗ values - age-adjusted differences between MS patients and HC. Thickness of cortical regions was also measured in all subjects. In cortical regions, ΔR2∗ values of MS patients were also adjusted for changes in cortical thickness. Symbol digit modalities (SDMT) and paced auditory serial addition (PASAT) neurocognitive tests, as well as Expanded Disability Status Score, 25-foot timed walk and nine-hole peg test results were also obtained on all MS subjects. We found that ΔR2∗ values were lower in multiple cortical GM and normal appearing white matter (NAWM) regions in MS compared with HC. ΔR2∗ values of global cortical GM and several specific cortical regions showed significant (p < 0.05) correlations with SDMT and PASAT scores, and showed better correlations than volumetric measures of the same regions. Neurological tests not focused on cognition (Expanded Disability Status Score, 25-foot timed walk and nine-hole peg tests) showed no correlation with cortical GM ΔR2∗ values. The technique presented here is robust and reproducible. It requires less than 10 min and can be implemented on any MRI scanner. Our results show that quantitative tissue-specific R2∗ values can serve as biomarkers of tissue injury due to MS in the brain, including the cerebral cortex, an area that has been difficult to evaluate using standard MRI. © 2015 The Authors. Published by Elsevier Inc.

Author Keywords
Cognitive disability;  Cortical gray matter;  Multiple sclerosis;  Quantitative;  R2


Document Type: Article
Source: Scopus


 

Chetail, F.a , Treiman, R.b , Content, A.a 
Effect of consonant/vowel letter organisation on the syllable counting task: evidence from English
(2015) Journal of Cognitive Psychology, 12 p. Article in Press. 

DOI: 10.1080/20445911.2015.1074582

a Laboratoire Cognition Langage Développement (LCLD), Centre de Recherche Cognition et Neurosciences (CRCN), Université Libre de Bruxelles (ULB), Brussels, Belgium
b Reading and Language Lab, Washington University in Saint Louis, Saint Louis, MO, USA

Abstract
Recent studies in alphabetic writing systems have investigated whether the status of letters as consonants or vowels influences the perception and processing of written words. Here, we examined to what extent the organisation of consonants and vowels within words affects performance in a syllable counting task in English. Participants were asked to judge the number of syllables in written words that were matched for the number of spoken syllables but comprised either 1 orthographic vowel cluster less than the number of syllables (hiatus words, e.g., triumph) or as many vowel clusters as syllables (e.g., pudding). In 3 experiments, we found that readers were slower and less accurate on hiatus than control words, even when phonological complexity (Experiment 1), number of reduced vowels (Experiment 2), and number of letters (Experiment 3) were taken into account. Interestingly, for words with or without the same number of vowel clusters and syllables, participants’ errors were more likely to underestimate the number of syllables than to overestimate it. Results are discussed in a cross-linguistic perspective. © 2015 Taylor & Francis

Author Keywords
consistency;  CV pattern;  foot;  hiatus words;  orthographic units;  syllable counting task


Document Type: Article in Press
Source: Scopus


 

Funk, K.E.a , Mirbaha, H.b , Jiang, H.a , Holtzman, D.M.a , Diamond, M.I.b 
Distinct therapeutic mechanisms of Tau antibodies: Promoting microglial clearance versus blocking neuronal uptake
(2015) Journal of Biological Chemistry, 290 (35), pp. 21652-21662. 

DOI: 10.1074/jbc.M115.657924

a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States

Abstract
Tauopathies are neurodegenerative diseases characterized by accumulation of Tau amyloids, and include Alzheimer disease and certain frontotemporal dementias. Trans-neuronal propagation of amyloid mediated by extracellular Tau may underlie disease progression. Consistent with this, active and passive vaccination studies in mouse models reduce pathology, although by unknown mechanisms. We previously reported that intracerebroventricular administration of three anti-Tau monoclonal antibodies (HJ8.5, HJ9.3, and HJ9.4) reduces pathology in a model overexpressing full-length mutant (P301S) human Tau. We now study effects of these three antibodies and a negative control antibody (HJ3.4) on Tau aggregate uptake into BV2 microglial-like cells and primary neurons. Antibody-independent Tau uptake into BV2 cells was blocked by heparin, consistent with a previously described role for heparan sulfate proteoglycans. Two therapeutic antibodies (HJ8.5 and HJ9.4) promoted uptake of full-length Tau fibrils into microglia via Fc receptors. Surprisingly, HJ9.3 promoted uptake of fibrils composed of the Tau repeat domain or Alzheimer disease-derived Tau aggregates, but failed to influence full-length recombinant Tau fibrils. Size fractionation of aggregates showed that antibodies preferentially promote uptake of larger oligomers (n≥∼20-mer) versus smaller oligomers (n∼10-mer) or monomer. No antibody inhibited uptake of full-length recombinant fibrils into primary neurons, but HJ9.3 blocked neuronal uptake of Tau repeat domain fibrils and Alzheimer disease-derived Tau. Antibodies thus have multiple potential mechanisms, including clearance via microglia and blockade of neuronal uptake. However these effects are epitope- and aggregate size-dependent. Establishing specific mechanisms of antibody activity in vitro may help in design and optimization of agents that are more effective in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
 


Document Type: Article
Source: Scopus


 

Krauss, M.J., Sowles, S.J., Mylvaganam, S., Zewdie, K., Bierut, L.J., Cavazos-Rehg, P.A.
Displays of dabbing marijuana extracts on YouTube
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.08.020

Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA

Abstract
Background: Dabbing involves heating marijuana extracts to a high temperature and inhaling the vapor. Little is known about this new method of using marijuana. YouTube, the most popular platform for sharing online videos, may be a go-to resource for individuals interested in learning about dabbing. Our objective was to explore the content of dabbing-related videos on YouTube. Methods: We searched for dabbing-related videos on YouTube using the search terms "dabbing" and "dabs" on January 22, 2015. For each term, videos were sorted by relevance and view count. A sample of 116 dabbing videos were viewed and coded for content. Results: The 116 videos (published by 75 unique channels) had a total of 9,545,482 views. Most (76%) of the channels had a specific focus on marijuana and 23% were located in California. Eighty-nine percent of the videos showed at least one person dabbing, and 61% of these showed someone dabbing repeatedly. Most dabbers were male (67%) and many appeared to be >25 years old (42%). Approximately 34% of the videos contained a product review, 28% provided instructions on dabbing or other educational information, and 21% contained at least a brief cautionary message. Over half (54%) of the videos referenced medical marijuana, and only 20% of the videos had an age-restriction. Conclusions: Dabbing-related videos are easily found and can be readily viewed on YouTube. As marijuana use becomes more accepted by the general population, the popularity of dabbing-related videos could increase, potentially normalizing this potent form of marijuana use. © 2015 Elsevier Ireland Ltd.

Author Keywords
Cannabis;  Cannabis extract;  Dab;  Dabbing;  Marijuana smoking;  Social media


Document Type: Article in Press
Source: Scopus


 

Rustichini, A.a , Padoa-Schioppa, C.b 
A neuro-computational model of economic decisions
(2015) Journal of Neurophysiology, 114 (3), pp. 1382-1398. 

DOI: 10.1152/jn.00184.2015

a Department of Economics, University of Minnesota, Minneapolis, MN, United States
b Departments of Anatomy and Neurobiology, Economics, and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Neuronal recordings and lesion studies indicate that key aspects of economic decisions take place in the orbitofrontal cortex (OFC). Previous work identified in this area three groups of neurons encoding the offer value, the chosen value, and the identity of the chosen good. An important and open question is whether and how decisions could emerge from a neural circuit formed by these three populations. Here we adapted a biophysically realistic neural network previously proposed for perceptual decisions (Wang XJ. Neuron 36: 955–968, 2002; Wong KF, Wang XJ. J Neurosci 26: 1314–1328, 2006). The domain of economic decisions is significantly broader than that for which the model was originally designed, yet the model performed remarkably well. The input and output nodes of the network were naturally mapped onto two groups of cells in OFC. Surprisingly, the activity of interneurons in the network closely resembled that of the third group of cells, namely, chosen value cells. The model reproduced several phenomena related to the neuronal origins of choice variability. It also generated testable predictions on the excitatory/inhibitory nature of different neuronal populations and on their connectivity. Some aspects of the empirical data were not reproduced, but simple extensions of the model could overcome these limitations. These results render a biologically credible model for the neuronal mechanisms of economic decisions. They demonstrate that choices could emerge from the activity of cells in the OFC, suggesting that chosen value cells directly participate in the decision process. Importantly, Wang’s model provides a platform to investigate the implications of neuroscience results for economic theory. © 2015 the American Physiological Society.

Author Keywords
Dynamic system;  Good-based decisions;  Neural network;  Neuroeconomics;  Orbitofrontal cortex


Document Type: Article
Source: Scopus


 

Dey, A., Sommers, M.S.
Age-related differences in inhibitory control predict audiovisual speech perception
(2015) Psychology and Aging, 30 (3), pp. 634-646. 

DOI: 10.1037/pag0000033

Washington University in St. Louis, Department of Psychology, United States

Abstract
Audiovisual (AV) speech perception is the process by which auditory and visual sensory signals are integrated and used to understand what a talker is saying during face-to-face communication. This form of communication is markedly superior to speech perception in either sensory modality alone. However, there are additional lexical factors that are affected by age-related cognitive changes that may contribute to differences in AV perception. In the current study, we extended an existing model of spoken word identification to the AV domain, and examined the cognitive factors that contribute to age-related and individual differences in AV perception of words varying in lexical difficulty (i.e., on the basis of competing items). Young (n - 49) and older adults (n - 50) completed a series of cognitive inhibition tasks and a spoken word identification task. The words were presented in auditory-only, visual-only, and AV conditions, and were equally divided into lexically hard (words with many competitors) and lexically easy (words with few competitors). Overall, young adults demonstrated better inhibitory abilities and higher identification performance than older adults. However, whereas no relationship was observed between inhibitory abilities and AV word identification performance in young adults, there was a significant relationship between Stroop interference and AV identification of lexically hard words in older adults. These results are interpreted within the framework of existing models of spoken-word recognition with implications for how cognitive deficits in older adults contribute to speech perception. © 2015 American Psychological Association.

Author Keywords
Aging;  Inhibition;  Speech perception


Document Type: Article
Source: Scopus


 

Kumar, G., Ching, S.
Design of optimally sparse dosing strategies for neural pharmacology
(2015) Proceedings of the American Control Conference, 2015-July, art. no. 7172259, pp. 5865-5870. 

DOI: 10.1109/ACC.2015.7172259

Department of Electrical and Systems Engineering, Division of Biology and Biomedical Sciences, Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
Modeling the actions of neuroactive drugs has typically been limited to two classes of mathematical descriptions: the so-called pharmacokinetics model, which describes the diffusion of the drug from the administration site to the effect site, i.e., the brain; and the pharmacodynamics model, which describes the mapping between effect site concentration and behavioral phenotype. Often, a desired behavioral outcome occurs at the end of the admissible concentration range such as unconsciousness induced via a general anesthetic. Here, we develop a dynamical systems-based modeling and design paradigm to optimally construct pharmacologic regimes, i.e., drug selection and dose schedules, to meet phenotypic objectives while minimizing costs and adverse effects. Our framework focuses less on the kinetics of the drug from infusion to effect site, and more on the explicit descriptions of the affinity of the drugs to their respective molecular targets. Through this paradigm, we use methodologies embedded in formal optimal control theory to show how one can, in a principled manner, optimize selection and dosing of synergistic drugs to efficiently achieve a particular phenotype while mitigating paradoxical or undesired states that might otherwise be encountered. © 2015 American Automatic Control Council.
 


Document Type: Conference Paper
Source: Scopus


 

Pan, H.a , Ding, B.a , Zhong, W.b , Kumar, G.c , Kothare, M.V.d 
Designing closed-loop brain-machine interfaces with network of spiking neurons using MPC strategy
(2015) Proceedings of the American Control Conference, 2015-July, art. no. 7171117, pp. 2543-2548. 

DOI: 10.1109/ACC.2015.7171117

a Department of Automation, School of Electronic and Information Engineering, Xian Jiaotong University, Xian, China
b Key Laboratory of Advanced Control and Optimization for Chemical Processes, Ministry of Education, East China University of Science and Technology, Shanghai, China
c Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA, United States

Abstract
Brain-machine interfaces (BMIs) are human-machine integration systems that provide an interface between the brain and a machine to sense cortical neuronal activity for the purpose of restoring impaired motor tasks. In our previous work [1], an optimal design of BMIs based on artificial sensory feedback was developed using model predictive control which relied on neuronal activity in the form of spiking. From a real implementation perspective, a more generalized framework that utilizes spiking is proposed in this paper. Specifically, a charge-balanced intra-cortical micro-stimulation (ICMS) current and a network of spiking neurons are adopted to compensate the lost feedback information. Next, an artificial sensory feedback framework using the network of spiking neurons is designed based on model predictive control (MPC) strategy, and an optimization problem is formulated according to this framework. Since the charge-balanced ICMS current is composed of several integer parameters, the optimization problem also includes some integer decision variables and is hard to be solved. In this paper, a heuristic population-based search algorithm called particle swarm optimization (PSO) algorithm is used to solve this optimization problem. Considering the updated particles may violate the input constraints, additional constraints are designed to guarantee that the decision variables can satisfy the input constraints. Finally, simulation results show the effectiveness of the designed closed-loop BMIs during recovery of natural performance. © 2015 American Automatic Control Council.
 


Document Type: Conference Paper
Source: Scopus

Naismith, R.T., Cross, A.H.
Enhancing our understanding of white matter changes in early multiple sclerosis
(2015) Brain, 138 (9), pp. 2465-2466. 

DOI: 10.1093/brain/awv196

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


Document Type: Review
Source: Scopus


 

Klein, S.E.a , Chu, J.a b , McCormick, J.J.a , Johnson, J.E.a 
Evaluation of Peripheral Neuropathy of Unknown Origin in an Outpatient Foot and Ankle Practice
(2015) Foot and Ankle International, 36 (9), pp. 1058-1063. 

DOI: 10.1177/1071100715583352

a Department of Orthopaedic Surgery, Washington University, School of Medicine, 660 South Euclid Avenue, Campus Box 8233, St Louis, MO, United States
b Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Abstract
Background: The foot and ankle surgeon can see peripheral neuropathy in the treatment of foot and ankle conditions. The purpose of this study was (1) to evaluate the demographics and presenting complaints of patients diagnosed with idiopathic peripheral neuropathy during an examination by a foot and ankle surgeon and (2) to identify the type and frequency of subsequent diagnosis of medical causes of neuropathy. Methods: This was a retrospective study of patients diagnosed with idiopathic peripheral neuropathy in our practice between January 1997 and December 2008. Ninety-five patients were identified, and demographic data, presenting complaints, and medical comorbidities were extracted from the medical record. Examination findings of decreased sensation to Semmes Weinstein 5.07 monofilament testing were documented, and electromyogram and nerve conduction study results were reviewed when available. Laboratory values were noted, as were neurologic evaluations performed to diagnose medical conditions associated with peripheral neuropathy. Results: The most common presentation was foot pain, in 36 patients (38%). Ninety-one patients had Semmes Weinstein 5.07 monofilament testing, with loss of protective sensation reported in 75 of the 91 tested (82%). Only 30 of the 95 patients had electromyogram and nerve conduction study results available, with a test positive for peripheral neuropathy in 20 of the 30 tested. Thirty-two patients were evaluated by a neurologist. A specific cause was identified in 12 of the 32 seen by a neurologist. Of the total group of 95 patients, 31 patients (33%) were diagnosed with a condition that may be associated with peripheral neuropathy. Conclusions: Thirty-three percent of the patients presenting to our clinic and given a diagnosis of idiopathic peripheral neuropathy were ultimately diagnosed with a medical cause of neuropathy - most commonly, diabetes. For those patients with idiopathic neuropathy, a spectrum of disease was encountered, including pain, ulcer, infection, and Charcot neuroarthropathy. Level of Evidence: Level IV, retrospective case series. © American Orthopaedic Foot & Ankle Society. © The Author(s) 2015.

Author Keywords
Charcot arthropathy;  diabetes mellitus;  foot pain;  peripheral neuropathy


Document Type: Article
Source: Scopus


 

Kummer, T.T.a , Magnoni, S.b , MacDonald, C.L.a e , Dikranian, K.c , Milner, E.d , Sorrell, J.a , Conte, V.b , Benetatos, J.J.a , Zipfel, G.J.d , Brody, D.L.a 
Experimental subarachnoid haemorrhage results in multifocal axonal injury
(2015) Brain, 138 (9), pp. 2608-2618. 

DOI: 10.1093/brain/awv180

a Department of Neurology, Washington University, School of Medicine, 660 S Euclid Ave, Saint Louis, MO, United States
b Department of Anaesthesiology and Intensive Care, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Via Francesco Sforza, 33, Milan, Italy
c Department of Anatomy and Neurobiology, Washington University, School of Medicine, 660 S Euclid Ave, Saint Louis, MO, United States
d Department of Neurosurgery, Washington University, School of Medicine, 660 S Euclid Ave, Saint Louis, MO, United States
e Department of Neurological Surgery, University of Washington, School of Medicine, 325 Ninth Avenue, Seattle, WA, United States

Abstract
The great majority of acute brain injury results from trauma or from disorders of the cerebrovasculature, i.e. ischaemic stroke or haemorrhage. These injuries are characterized by an initial insult that triggers a cascade of injurious cellular processes. The nature of these processes in spontaneous intracranial haemorrhage is poorly understood. Subarachnoid haemorrhage, a particularly deadly form of intracranial haemorrhage, shares key pathophysiological features with traumatic brain injury including exposure to a sudden pressure pulse. Here we provide evidence that axonal injury, a signature characteristic of traumatic brain injury, is also a prominent feature of experimental subarachnoid haemorrhage. Using histological markers of membrane disruption and cytoskeletal injury validated in analyses of traumatic brain injury, we show that axonal injury also occurs following subarachnoid haemorrhage in an animal model. Consistent with the higher prevalence of global as opposed to focal deficits after subarachnoid haemorrhage and traumatic brain injury in humans, axonal injury in this model is observed in a multifocal pattern not limited to the immediate vicinity of the ruptured artery. Ultrastructural analysis further reveals characteristic axonal membrane and cytoskeletal changes similar to those associated with traumatic axonal injury. Diffusion tensor imaging, a translational imaging technique previously validated in traumatic axonal injury, from these same specimens demonstrates decrements in anisotropy that correlate with histological axonal injury and functional outcomes. These radiological indicators identify a fibre orientation-dependent gradient of axonal injury consistent with a barotraumatic mechanism. Although traumatic and haemorrhagic acute brain injury are generally considered separately, these data suggest that a signature pathology of traumatic brain injury - axonal injury - is also a functionally significant feature of subarachnoid haemorrhage, raising the prospect of common diagnostic, prognostic, and therapeutic approaches to these conditions. © 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Author Keywords
axonal injury;  brain haemorrhage;  diffusion tensor imaging;  subarachnoid haemorrhage;  traumatic brain injury


Document Type: Article
Source: Scopus


 

Abdelmalek, D.a , Arroyo-Plasencia, A.a , Schwarz, E.S.a , Weber, J.b , Sampson, C.S.c , Thornton, S.L.d , Mullins, M.E.a 
Factitious snake envenomation and narcotic-seeking behavior
(2015) American Journal of Emergency Medicine, 33 (9), pp. 1331e5-1331e6. 

DOI: 10.1016/j.ajem.2015.03.020

a Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Missouri Regional Poison Center, SSM Cardinal Glennon Children's Hospital, St. Louis, MO, United States
c Department of Emergency Medicine, University of Missouri School of Medicine, Columbia, MO, United States
d Department of Emergency Medicine, University of Kansas School of Medicine, Kansas City, KS, United States

Abstract
United States Poison Control Centers (PCCs) recorded nearly 7000 snakebites in 2013. We present a case of a factitious snakebite in a patient with a pattern of similar emergency department (ED) visits. A 47-year-old man presented to the ED with 5 snakebites on both forearms. He reported being bittenwhile milking venomfroman eastern diamondback rattlesnake for the zoo. On ED arrival, he had punctures on both forearms, swelling on the right forearm, tachycardia, and leukocytosis. He requested CroFab (Crotalidae Polyvalent Immune Fab) and pain medication. Contact with the PCC revealed numerous similar visits at other EDs across the state and an adjacent state. In a series of at least 12 encounters, he received a total of at least 42 vials of antivenom without documented allergic reaction. The PCC recommendations curtailed his receipt of antivenom in later visits. This is an unusual case of repeated factitious snake envenomation. His misuse of epinephrine autoinjectors mimicked symptoms of envenomation. CroFab is an expensive antidote with a potential risk of sensitization with multiple exposures and is best reserved for patientswith true pit viper envenomation. Astute PCC specialists detected the repetitive pattern of his ED visits and helped to reduce unnecessary treatment in later visits.Our patient had factitious disorder and narcotic-seeking behaviorwith repeated ED visits and hospital admissions for alleged pit viper bites. Poison Control Centers play an essential role in detecting patterns of abuse in individuals who change location frequently. © 2015 Published by Elsevier Inc.
 


Document Type: Article
Source: Scopus


 

Honig, L.S.a b c , Kang, M.S.a , Cheng, R.a , Eckfeldt, J.H.d , Thyagarajan, B.d, Leiendecker-Foster, C.d , Province, M.A.e , Sanders, J.L.f , Perls, T.g , Christensen, K.h , Lee, J.H.a b i , Mayeux, R.a b c i j , Schupf, N.a b j 
Heritability of telomere length in a study of long-lived families
(2015) Neurobiology of Aging, 36 (10), pp. 2785-2790. 

DOI: 10.1016/j.neurobiolaging.2015.06.017

a Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
b Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, United States
c Department of Neurology, Columbia University Medical Center, New York, NY, United States
d Department Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States
e Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Epidemiology, Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, PA, United States
g Section of Geriatrics, Department of Medicine, Boston Medical Center, Boston, MA, United States
h The Danish Aging Research Center, University of Southern Denmark, Odense, Denmark
i Department of Epidemiology, Columbia University Medical Center, New York, NY, United States
j Department of Psychiatry, Columbia University Medical Center, New York, NY, United States

Abstract
Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h2 = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process. © 2015 Elsevier Inc.

Author Keywords
Aging;  Heritability;  Longevity;  Telomere


Document Type: Article
Source: Scopus


 

Sansing, L.H.a , Wu, G.F.b 
Immunologic mechanisms in neurological diseases
(2015) Current Immunology Reviews, 11 (2), p. 75. 
 

a Department of Neurology, Yale University School of Medicine, United States
b Department of Neurology, Washington University School of Medicine, United States
 
 


Document Type: Editorial
Source: Scopus


 

Sinclair, K.C., Miner, J.J., Kim, A.H.J.
Immunological mechanisms of Neuropsychiatric Lupus
(2015) Current Immunology Reviews, 11 (2), pp. 93-106. 
 

Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a clinical syndrome characterized by various neurologic phenotypes in patients with systemic lupus erythematosus (SLE). Mechanisms of NPSLE pathogenesis are not well understood although aberrant activation of both innate and adaptive immune pathways is thought to play a role. Animal models suggest a variety of factors that may instigate these neuropsychiatric events, including production of pathogenic autoantibodies, release of proinflammatory cytokines, disruption of the blood-brain barrier, and dysregulation of innate immune responses. © 2015 Bentham Science Publishers.

Author Keywords
Autoantibodies;  Blood-brain barrier;  Cytokines;  Neuropsychiatric lupus;  Systemic lupus erythematosus


Document Type: Article
Source: Scopus

MacCotta, L.a c , Moseley, E.D.a b , Benzinger, T.L.b , Hogan, R.E.a b 
In response: From the CA1 subfield, and beyond!
(2015) Epilepsia, 56 (9), pp. 1471-1472. 

DOI: 10.1111/epi.13079

a Department of Neurology, Washington University, St. Louis, Missouri, United States
b Department of Radiology, Washington University, St. Louis, Missouri, United States
c Department of Neurological Surgery, Washington University, St. Louis, Missouri, United States
 
 


Document Type: Letter
Source: Scopus


 

Hipólito, L.a g , Wilson-Poe, A.a , Campos-Jurado, Y.b , Zhong, E.a , Gonzalez-Romero, J.a , Virag, L.a , Whittington, R.a , Comer, S.D.c , Carlton, S.M.d , Walker, B.M.e , Bruchas, M.R.f , Morón, J.A.a h 
Inflammatory pain promotes increased opioid self-administration: Role of dysregulated ventral tegmental area µ opioid receptors
(2015) Journal of Neuroscience, 35 (35), . 

DOI: 10.1523/JNEUROSCI.1053-15.2015

a Department of Anesthesiology, Columbia University, New York, NY, United States
b Departament de Farmàcia i Tecnología Farmacèutica, Universitat de Farmàcia, Burjassot, València, Spain
c Department of Psychiatry, Division on Substance Abuse, New York State Psychiatric Institute College of Physicians and Surgeons of Columbia University, New York, NY, United States
d Department of Neuroscience and Cell Biology, University of Texas Medical Branch Galveston, Galveston, TX, United States
e Department of Psychology, Washington State University, Pullman, WA, United States
f Department of Anesthesiology and Department of Anatomy and Neurobiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
g Departament de Farmàcia i Tecnología Farmacèutica, Universitat de València, Avda, Vicente Andrés Estellés s/n, Burjassot, Valencia, Spain
h Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, Box 8054, St. Louis, MO, United States

Abstract
Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund’s adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbicDAtransmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbicMORfunction suggested byDAmicrodialysis. Consistent with the reduction in low doseFRheroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss ofMORfunction in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. © 2015 the authors.

Author Keywords
Dopamine;  Opioids;  Pain;  Self-administration;  VTA;  µ opioid receptor


Document Type: Article
Source: Scopus


 

Azevedo, D.C.a , Van Dillen, L.R.b , De Oliveira Santos, H.c , Oliveira, D.R.d , Ferreira, P.H.d , Costa, L.O.P.e 
Movement system impairment–based classification versus general exercise for chronic low back pain: Protocol of a randomized controlled trial
(2015) Physical Therapy, 95 (9), pp. 1287-1294. 

DOI: 10.2522/ptj.20140555

a Universidade Cidade de São Paulo and Physical Therapy Department, Pontifícia Universidade Católica de Minas Gerais, Dom José Gaspar 500, Belo Horizonte, MG, Brazil
b Washington University School of Medicine, St Louis, MO, United States
c Physical Therapy Department, Pontifícia Universidade Católica de Minas Gerais, Australia
d University of Sydney, Sydney, Australia
e Universidade Cidade de São Paulo and Musculoskeletal Division, The George Institute for Global Health, Sydney, Australia

Abstract
Background. Low back pain (LBP) is an important health problem in all developed countries and is associated with high levels of disability. Evidence-based clinical practice guidelines usually recommend different physical therapy interventions to manage this condition. However, those interventions usually result in small to moderate clinical effects. Recent studies suggest that interventions based on subgroup classifications may improve the effect sizes compared with rehabilitation programs where the same interventions were applied to all patients. Objective. This study will investigate the efficacy of treatment based on a Movement System Impairment (MSI)–based classification model for patients with chronic LBP compared with general exercise. The primary outcomes will be pain intensity and disability at 2 months after randomization. Design. The study is a 2-arm, prospectively registered, randomized controlled trial with a blinded assessor. Setting. The study setting will be a university physical therapy clinic in Brazil. Participants. A total of 148 individuals with chronic LBP will participate in the study. Intervention. Included individuals will be randomly allocated to participate in an 8-week treatment program based on the MSI-based classification or a general exercise program of stretching and strengthening exercises. Measurements. Pain intensity, disability, and global impression of recovery will be assessed by a blinded assessor at baseline and at follow-up appointments after treatment (2 months) and 4 and 6 months after randomization. Limitations. Therapists will not be blinded. Conclusions. The results of this study may contribute to a better understanding of the efficacy of treatments based on classification of participants with chronic LBP into subgroups. © 2015 American Physical Therapy Association.
 


Document Type: Article
Source: Scopus


 

Ritt, J.T.a , Ching, S.b 
Neurocontrol: Methods, models and technologies for manipulating dynamics in the brain
(2015) Proceedings of the American Control Conference, 2015-July, art. no. 7171915, pp. 3765-3780. 

DOI: 10.1109/ACC.2015.7171915

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

Abstract
This paper accompanies a tutorial session at the 2015 American Control Conference, and provides a survey of emerging technologies and research problems at the boundary between systems engineering, neuroscience and neural medicine. Emphasis will be placed on both recent theoretical developments - for example, system identification and controllability in neuronal networks - and real-world constraints in applications such as clinical deep brain stimulation, or optical stimulation in experimental neuroscience. Discussion will extend to how these constrains may necessitate the development of entirely new paradigms in systems and control theory that respond to the unprecedented challenges facing neural scientists and engineers. © 2015 American Automatic Control Council.
 


Document Type: Conference Paper
Source: Scopus

Xiao, Q.a , Yan, P.a , Ma, X.b d , Liu, H.b d , Perez, R.a , Zhu, A.a , Gonzales, E.a , Tripoli, D.L.a , Czerniewski, L.a , Ballabio, A.e , Cirrito, J.R.a , Diwan, A.b cd , Lee, J.-M.a 
Neuronal-targeted TFEB accelerates lysosomal degradation of app, reducing Aβ generation and amyloid plaque pathogenesis
(2015) Journal of Neuroscience, 35 (35), pp. 12137-12151. 

DOI: 10.1523/JNEUROSCI.0705-15.2015

a Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
b Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
d John Cochran VA Medical Center, St. Louis, MO, United States
e Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy

Abstract
In AD, an imbalance between Aβ production and removal drives elevated brain Aβ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- and γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aβ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adenoassociated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and β C-terminal APP fragments (CTFs), and in the steady-state Aβ levels in the brain interstitial fluid. In aged mice, total Aβ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and β-CTFs, and attenuated Aβ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aβ generation. Activation of TFEB in neurons is an effective strategy to attenuate Aβ generation and attenuate amyloid plaque deposition in AD. © 2015 the authors.

Author Keywords
Alzheimer’s disease;  Amyloid;  Amyloid precursor protein;  Lysosome;  TFEB


Document Type: Article
Source: Scopus

Conen, K.E.a , Padoa-Schioppa, C.a b c 
Neuronal variability in orbitofrontal cortex during economic decisions
(2015) Journal of Neurophysiology, 114 (3), pp. 1367-1381. 

DOI: 10.1152/jn.00231.2015

a Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Economics, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Neuroeconomic models assume that economic decisions are based on the activity of offer value cells in the orbitofrontal cortex (OFC), but testing this assertion has proven difficult. In principle, the decision made on a given trial should correlate with the stochastic fluctuations of these cells. However, this correlation, measured as a choice probability (CP), is small. Importantly, a neuron’s CP reflects not only its individual contribution to the decision (termed readout weight), but also the intensity and the structure of correlated variability across the neuronal population (termed noise correlation). A precise mathematical relation between CPs, noise correlations, and readout weights was recently derived by Haefner and colleagues (Haefner RM, Gerwinn S, Macke JH, Bethge M. Nat Neurosci 16: 235–242, 2013) for a linear decision model. In this framework, concurrent measurements of noise correlations and CPs can provide quantitative information on how a population of cells contributes to a decision. Here we examined neuronal variability in the OFC of rhesus monkeys during economic decisions. Noise correlations had similar structure but considerably lower strength compared with those typically measured in sensory areas during perceptual decisions. In contrast, variability in the activity of individual cells was high and comparable to that recorded in other cortical regions. Simulation analyses based on Haefner’s equation showed that noise correlations measured in the OFC combined with a plausible readout of offer value cells reproduced the experimental measures of CPs. In other words, the results obtained for noise correlations and those obtained for CPs taken together support the hypothesis that economic decisions are primarily based on the activity of offer value cells. © 2015 the American Physiological Society.

Author Keywords
Neoroeconomics;  Subjective value;  Value-based decision


Document Type: Article
Source: Scopus


 

Wu, G.F.a b , Harp, C.R.P.b , Shindler, K.S.c 
Optic neuritis: A model for the immuno-pathogenesis of central nervous system inflammatory Demyelinating Diseases
(2015) Current Immunology Reviews, 11 (2), pp. 85-92. 
 

a Departments of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States

Abstract
Evidence for the tenuous regulation between the immune system and central nervous system (CNS) can be found with examples of interaction between these organ systems gone awry. Multiple sclerosis (MS) is the prototypical inflammatory disease of the CNS and is characterized by widely distributed inflammatory demyelinating plaques that can involve the brain, spinal cord and/or optic nerves. Optic neuritis (ON), inflammatory injury of the optic nerve that frequently occurs in patients with MS, has been the focus of intense study in part given the readily accessible nature of clinical outcome measures. Exploring the clinical and pathological features of ON in relation to other inflammatory demyelinating conditions of the CNS, namely MS and neuromyelitis optica, provides an opportunity to glean common and distinct mechanisms of disease. Emerging data from clinical studies along with various animal models involving ON implicate innate and adaptive immune responses directed at glial targets, including myelin oligodendrocyte glycoprotein and aquaporin 4. Resolution of inflammation in ON is commonly observed both clinically and experimentally, but persistent nerve injury is also one emerging hallmark of ON. One hypothesis seeking evaluation is that, in comparison to other sites targeted in MS, the optic nerve is a highly specialized target within the CNS predisposing to unique immunologic processes that generate ON. Overall, ON serves as a highly relevant entity for understanding the pathogenesis of other CNS demyelinating conditions, most notably MS. © 2015 Bentham Science Publishers.

Author Keywords
Demyelination;  Multiple sclerosis;  Neuro-immunology;  Optic neuritis;  Pathogenesis


Document Type: Article
Source: Scopus


 

Ju, Y.-E.
Souse the mouse
(2015) Science Translational Medicine, 7 (303), . 

DOI: 10.1126/scitranslmed.aad1828

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


Document Type: Short Survey
Source: Scopus


 

Costello, M.C.a , Bloesch, E.K.b , Davoli, C.C.b , Panting, N.D.a , Abrams, R.A.c , Brockmole, J.R.d 
Spatial representations in older adults are not modified by action: Evidence from tool use
(2015) Psychology and Aging, 30 (3), pp. 656-668. 

DOI: 10.1037/pag0000029

a Indiana University South Bend, Department of Psychology, United States
b Central Michigan University, Department of Psychology, United States
c Washington University in St. Louis, Department of Psychology, United States
d University of Notre Dame, Department of Psychology, United States

Abstract
Theories of embodied perception hold that the visual system is calibrated by both the body schema and the action system, allowing for adaptive action-perception responses. One example of embodied perception involves the effects of tool use on distance perception, in which wielding a tool with the intention to act upon a target appears to bring that object closer. This tool-based spatial compression (i.e., tool-use effect) has been studied exclusively with younger adults, but it is unknown whether the phenomenon exists with older adults. In this study, we examined the effects of tool use on distance perception in younger and older adults in 2 experiments. In Experiment 1, younger and older adults estimated the distances of targets just beyond peripersonal space while either wielding a tool or pointing with the hand. Younger adults, but not older adults, estimated targets to be closer after reaching with a tool. In Experiment 2, younger and older adults estimated the distance to remote targets while using either a baton or a laser pointer. Younger adults displayed spatial compression with the laser pointer compared to the baton, although older adults did not. Taken together, these findings indicate a generalized absence of the tool-use effect in older adults during distance estimation, suggesting that the visuomotor system of older adults does not remap from peripersonal to extrapersonal spatial representations during tool use. © 2015 American Psychological Association.

Author Keywords
Aging;  Distance perception;  Embodiment;  Perception;  Tool use


Document Type: Article
Source: Scopus


 

Alpert, K.a , Kogan, A.a , Parrish, T.b , Marcus, D.c , Wang, L.a b 
The Northwestern University Neuroimaging Data Archive (NUNDA)
(2015) NeuroImage, . Article in Press. 

DOI: 10.1016/j.neuroimage.2015.05.060

a Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
b Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
c Neuroinformatics Research Group (NRG) at the Washington University School of Medicine, St. Louis, MO, USA

Abstract
The Northwestern University Neuroimaging Data Archive (NUNDA), an XNAT-powered data archiving system, aims to facilitate secure data storage; centralized data management; automated, standardized data processing; and simple, intuitive data sharing. NUNDA is a federated data archive, wherein individual project owners regulate access to their data. NUNDA supports multiple methods of data import, enabling data collection in a central repository. Data in NUNDA are available by project to any authorized user, allowing coordinated data management and review across sites. With NUNDA pipelines, users capitalize on existing procedures or standardize custom routines for consistent, automated data processing. NUNDA can be integrated with other research databases to simplify data exploration and discovery. And data on NUNDA can be confidently shared for secure collaboration. © 2015 Elsevier Inc.

Author Keywords
Data processing and analysis;  Data sharing;  Data storage;  Neuroinformatics;  XNAT


Document Type: Article in Press
Source: Scopus


 

Marquardt, L.M., Sakiyama-Elbert, S.E.
Effect of GDNF on schwann cell differentiation and interaction with neurons in vitro
(2014) Proceedings of the IEEE Annual Northeast Bioengineering Conference, NEBEC, 2014-December, art. no. 6972867, . 

DOI: 10.1109/NEBEC.2014.6972867

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Schwann cells (SCs) are known to provide chemical and physical cues to enhance regeneration following peripheral nerve injury, yet it remains to be shown the effect that specific SC phenotypes (motor or sensory) have on axonal regeneration and functional recovery. In particular, the difference between motor and sensory SC phenotypes may encourage specific motor or sensory axonal guidance in cell transplantation therapies. Thus, the goal of this study was to determine whether phenotypically matched combinations of neurons and SCs stimulate greater neurite extension over mismatched combinations and whether treatment with glial cell line-derived neurotrophic factor (GDNF) affects this SC-neuronal interaction. Our aim is to study the effects of secreted, soluble factors without the interference of cell-to-cell contact cues using microfluidic devices. By elimination of cell-cell contact, we can isolate soluble factors secreted by motor or sensory SCs and determine differential expression of growth factors that induce a particular response from phenotypically matched SCs. Results demonstrated statistically greater neurite extension when neurons were cultured with phenotypically matched SCs, however, mismatched cultures could be compensated for when SCs were pre-treated with GDNF. In addition, exogenous GDNF treatment increased endogenous GDNF mRNA and protein expression levels. As sensory autografts are often used to bridge motor nerve defects, motor axons may not regenerate correctly without transplantation of motor SCs. However, these results suggest that treatment of SCs with GDNF prior to transplantation could enhance their ability to promote proper reinnervation even with mismatched transplanted SCs or graft phenotypes. © 2014 IEEE.

Author Keywords
Gene expression;  Growth factors;  Microdevices;  Nerve regeneration;  SiRNA


Document Type: Conference Paper
Source: Scopus

September 9, 2015

Cavazos-Rehg, P.A., Krauss, M.J., Sowles, S., Connolly, S., Rosas, C., Bharadwaj, M., Bierut, L.J.
A content analysis of depression-related tweets
(2016) Computers in Human Behavior, 54, art. no. 3650, pp. 351-357. 

DOI: 10.1016/j.chb.2015.08.023

Department of Psychiatry, Washington University School of Medicine, St. LouisMO, United States

Abstract
This study examines depression-related chatter on Twitter to glean insight into social networking about mental health. We assessed themes of a random sample (n = 2000) of depression-related tweets (sent 4-11 to 5-4-14). Tweets were coded for expression of DSM-5 symptoms for Major Depressive Disorder (MDD). Supportive or helpful tweets about depression was the most common theme (n = 787, 40%), closely followed by disclosing feelings of depression (n = 625; 32%). Two-thirds of tweets revealed one or more symptoms for the diagnosis of MDD and/or communicated thoughts or ideas that were consistent with struggles with depression after accounting for tweets that mentioned depression trivially. Health professionals can use our findings to tailor and target prevention and awareness messages to those Twitter users in need. © 2015 Elsevier Ltd.

Author Keywords
Depression;  Social media

Document Type: Article
Source: Scopus
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Alaimo, J.T.a , Barton, L.V.b , Mullegama, S.V.a , Wills, R.D.a , Foster, R.H.c d , Elsea, S.H.a b 
Individuals with Smith-Magenis syndrome display profound neurodevelopmental behavioral deficiencies and exhibit food-related behaviors equivalent to Prader-Willi syndrome
(2015) Research in Developmental Disabilities, 47, pp. 27-38. 

DOI: 10.1016/j.ridd.2015.08.011

a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
b Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
c Department of Psychology, St. Louis Children's Hospital, St. Louis, MO, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder associated with intellectual disability, sleep disturbances, early onset obesity and vast behavioral deficits. We used the Behavior Problems Inventory-01 to categorize the frequency and severity of behavioral abnormalities in a SMS cohort relative to individuals with intellectual disability of heterogeneous etiology. Self-injurious, stereotyped, and aggressive/destructive behavioral scores indicated that both frequency and severity were significantly higher among individuals with SMS relative to those with intellectual disability. Next, we categorized food behaviors in our SMS cohort across age using the Food Related Problems Questionnaire (FRPQ) and found that problems began to occur in SMS children as early as 5-11 years old, but children 12-18 years old and adults manifested the most severe problems. Furthermore, we evaluated the similarities of SMS adult food-related behaviors to those with intellectual disability and found that SMS adults had more severe behavioral problems. Many neurodevelopmental disorders exhibit syndromic obesity including SMS. Prader-Willi syndrome (PWS) is the most frequent neurodevelopmental disorder with syndromic obesity and has a well-established management and treatment plan. Using the FRPQ we found that SMS adults had similar scores relative to PWS adults. Both syndromes manifest weight gain early in development, and the FRPQ scores highlight specific areas in which behavioral similarities exist, including preoccupation with food, impaired satiety, and negative behavioral responses. SMS food-related behavior treatment paradigms are not as refined as PWS, suggesting that current PWS treatments for prevention of obesity may be beneficial for individuals with SMS. © 2015 Elsevier Ltd.

Author Keywords
Behavior Problems Inventory;  Food Related Problems Questionnaire;  Intellectual disability;  Neurodevelopmental disorders;  Obesity;  Prader-Willi syndrome;  Smith-Magenis syndrome

Document Type: Article
Source: Scopus
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Davidge, K.M.a , Gontre, G.a , Tang, D.a , Boyd, K.U.b , Yee, A.a , Damiano, M.S.a , Mackinnon, S.E.a 
The “hierarchical” Scratch Collapse Test for identifying multilevel ulnar nerve compression
(2015) Hand, 10 (3), pp. 388-395. 

DOI: 10.1007/s11552-014-9721-z

a Division of Plastic Surgery, Washington University of St. Louis, 660 S. Euclid Avenue, Campus Box 8,238, St. Louis, MO, United States
b Division of Plastic Surgery, University of Ottawa, The Ottawa Hospital, 1,053 Carling Avenue Box 213, Ottawa, ON, Canada

Abstract
Background: The Scratch Collapse Test (SCT) is used to assist in the clinical evaluation of patients with ulnar nerve compression. The purpose of this study is to introduce the hierarchical SCT as a physical examination tool for identifying multilevel nerve compression in patients with cubital tunnel syndrome. Methods: A prospective cohort study (2010–2011) was conducted of patients referred with primary cubital tunnel syndrome. Five ulnar nerve compression sites were evaluated with the SCT. Each site generating a positive SCT was sequentially “frozen out” with a topical anesthetic to allow determination of both primary and secondary ulnar nerve entrapment points. The order or “hierarchy” of compression sites was recorded. Results: Twenty-five patients (mean age 49.6 ± 12.3 years; 64 % female) were eligible for inclusion. The primary entrapment point was identified as Osborne’s band in 80 % and the cubital tunnel retinaculum in 20 % of patients. Secondary entrapment points were also identified in the following order in all patients: (1) volar antebrachial fascia, (2) Guyon’s canal, and (3) arcade of Struthers. Conclusion: The SCT is useful in localizing the site of primary compression of the ulnar nerve in patients with cubital tunnel syndrome. It is also sensitive enough to detect secondary compression points when primary sites are sequentially frozen out with a topical anesthetic, termed the hierarchical SCT. The findings of the hierarchical SCT are in keeping with the double crush hypothesis described by Upton and McComas in 1973 and the hypothesis of multilevel nerve compression proposed by Mackinnon and Novak in 1994. © 2015, American Association for Hand Surgery.

Author Keywords
Cubital tunnel syndrome;  Multilevel nerve compression;  Scratch collapse test

Document Type: Article
Source: Scopus
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Phillips, B.Z.a , Stockburger, C.b , Mackinnon, S.E.a 
Ulnar nerve transection during Tommy John surgery: novel findings and approach to treatment
(2015) Hand, 10 (3), pp. 555-558. 

DOI: 10.1007/s11552-014-9690-2

a Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Article
Source: Scopus
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Ruzycki, P.A.a c , Tran, N.M.a c d , Kefalov, V.J.a , Kolesnikov, A.V.a , Chen, S.a b c 
Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies
(2015) Genome Biology, 16 (1), art. no. 171, . 

DOI: 10.1186/s13059-015-0732-z

a Washington University School of Medicine, Department of Ophthalmology and Visual Sciences, Saint Louis, MO, United States
b Washington University School of Medicine, Department of Developmental Biology, Saint Louis, MO, United States
c Washington University School of Medicine, Division of Biology and Biomedical Sciences, Saint Louis, MO, United States
d Harvard University, Department of Molecular and Cellular Biology, NW 335.30, 52 Oxford St, Cambridge, MA, United States

Abstract
Background: Mutations in the cone-rod-homeobox protein CRX are typically associated with dominant blinding retinopathies with variable age of onset and severity. Five well-characterized mouse models carrying different Crx mutations show a wide range of disease phenotypes. To determine if the phenotype variability correlates with distinct changes in CRX target gene expression, we perform RNA-seq analyses on three of these models and compare the results with published data. Results: Despite dramatic phenotypic differences between the three models tested, graded expression changes in shared sets of genes are detected. Phenotype severity correlates with the down-regulation of genes encoding key rod and cone phototransduction proteins. Interestingly, in increasingly severe mouse models, the transcription of many rod-enriched genes decreases decrementally, whereas that of cone-enriched genes increases incrementally. Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity. Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration. Conclusions: Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies. © 2015 Ruzycki et al.

Document Type: Article
Source: Scopus
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Vande Voort, J.L.a , Singh, A.b , Bernardi, J.c , Wall, C.A.d , Swintak, C.C.a , Schak, K.M.a , Jensen, P.S.e 
Treatments and Services Provided to Children Diagnosed with Bipolar Disorder
(2015) Child Psychiatry and Human Development, 9 p. Article in Press. 

DOI: 10.1007/s10578-015-0582-7

a Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN, United States
b Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
c Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d PrairieCare Medical Group, University of Minnesota Medical School Affiliate, Rochester, MN, United States
e The REACH Institute, New York, NY, United States

Abstract
To better understand the types and quantity of mental health services and medication usage for youth diagnosed with bipolar disorder (BD) within an integrated healthcare system, medical records were reviewed from 2000 to 2011. Eighty-five youth diagnosed with BD were identified and healthcare services (medication and psychotherapy follow-up appointments, emergency room (ER) visits, admissions, phone contacts) and visit-related details (medication usage) were abstracted for 2 years after initial BD diagnosis. Despite complex medication regimens (91.7 and 81.2 % received mood stabilizers and antipsychotic agents, respectively), medication appointments were infrequent, averaging 1 visit every 2 months. Only 36 (42 %) of 85 youth were noted to receive psychotherapy services following BD diagnosis, also averaging 1 visit every 2 months. Most (58.8 %) patients needed one or more hospitalizations during the follow-up period; nearly half (48.2 %) had psychiatric ER visits. The relative lack of psychotherapy and infrequent follow-up visits suggests need for improvement to optimize healthcare delivery. © 2015 Springer Science+Business Media New York

Author Keywords
Pediatric bipolar disorder;  Quality of care;  Services;  Treatments

Document Type: Article in Press
Source: Scopus
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Keven, N.
Events, narratives and memory
(2015) Synthese, 21 p. Article in Press. 

DOI: 10.1007/s11229-015-0862-6

Philosophy-Neuroscience-Psychology Program, Department of Philosophy, Washington University in St.Louis, One Brookings Drive, St. Louis, MO, United States

Abstract
Whether non-human animals can have episodic memories remains the subject of extensive debate. A number of prominent memory researchers defend the view that animals do not have the same kind of episodic memory as humans do, whereas others argue that some animals have episodic-like memory—i.e., they can remember what, where and when an event happened. Defining what constitutes episodic memory has proven to be difficult. In this paper, I propose a dual systems account and provide evidence for a distinction between event memory and episodic memory. Event memory is a perceptual system that evolved to support adaptive short-term goal processing, whereas episodic memory is based on narratives, which bind event memories into a retrievable whole that is temporally and causally organized around subject’s goals. I argue that carefully distinguishing event memory from episodic memory can help resolve the debate. © 2015 Springer Science+Business Media Dordrecht

Author Keywords
Animal cognition;  Episodic memory;  Episodic-like;  Event segmentation;  Mental time travel;  Uniqueness debate

Document Type: Article in Press
Source: Scopus
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Behrman-Lay, A.M.a , Paul, R.H.a b , Heaps-Woodruff, J.a b , Baker, L.M.a , Usher, C.a , Ances, B.M.c d e 
Human immunodeficiency virus has similar effects on brain volumetrics and cognition in males and females
(2015) Journal of NeuroVirology, 11 p. Article in Press. 

DOI: 10.1007/s13365-015-0373-8

a Department of Psychology, University of Missouri- Saint Louis, St. Louis, MO, United States
b Missouri Institute of Mental Health, St. Louis, MO, United States
c Department of Neurology, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO, United States
d Department of Radiology, Washington University in Saint Louis, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, United States

Abstract
Most studies that have examined neuropsychological impairments associated with human immunodeficiency virus (HIV) have focused on males, yet females represent one of the largest groups of newly infected patients. Further, few studies have examined neuropsychological performance and neuroimaging outcomes among females compared to males in the modern era of highly active anti-retroviral therapy (HAART). The present study investigated neuropsychological performance and brain volumetrics among HIV+ males (n = 93) and females (n = 44) on stable HAART compared to HIV seronegative (HIV−) males (n = 42) and females (n = 49). Results revealed a significant effect of HIV on neuropsychological performance and neuroimaging measures. An effect of gender, independent of HIV status, was also observed for neuroimaging measures but not neuropsychological performance. Additionally, no significant differences in neuropsychological performance or brain volumetrics were seen between HIV+ males and females. No significant interaction was observed between HIV and gender on either neuropsychological or neuroimaging indices. Our results suggest that both HIV+ males and females treated with HAART experience similar outcomes in terms of brain integrity. © 2015 Journal of NeuroVirology, Inc.

Author Keywords
Cognition;  Gender;  HIV;  Neuroimaging;  Neuropsychology;  Volumetrics

Document Type: Article in Press
Source: Scopus
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Singh, M.F.a b , Zald, D.H.a c 
A simple transfer function for nonlinear dendritic integration
(2015) Frontiers in Computational Neuroscience, 9 (AUGUST), art. no. 98, 12 p. 

DOI: 10.3389/fncom.2015.00098

a Department of Psychology, Vanderbilt University, Nashville, TN, United States
b Department of Psychiatry, Vanderbilt University, Nashville, TN, United States
c Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Relatively recent advances in patch clamp recordings and iontophoresis have enabled unprecedented study of neuronal post-synaptic integration (“dendritic integration”). Findings support a separate layer of integration in the dendritic branches before potentials reach the cell's soma. While integration between branches obeys previous linear assumptions, proximal inputs within a branch produce threshold nonlinearity, which some authors have likened to the sigmoid function. Here we show the implausibility of a sigmoidal relation and present a more realistic transfer function in both an elegant artificial form and a biophysically derived form that further considers input locations along the dendritic arbor. As the distance between input locations determines their ability to produce nonlinear interactions, models incorporating dendritic topology are essential to understanding the computational power afforded by these early stages of integration. We use the biophysical transfer function to emulate empirical data using biophysical parameters and describe the conditions under which the artificial and biophysically derived forms are equivalent. © 2015 Singh and Zald.

Author Keywords
Dendrite;  Neural network;  NMDA spike;  Pyramidal cell;  Transfer function

Document Type: Article
Source: Scopus
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McNeely, M.E.a c , Duncan, R.P.a c , Earhart, G.M.a b c 
Impacts of dance on non-motor symptoms, participation, and quality of life in Parkinson disease and healthy older adults
(2015) Maturitas, . Article in Press. 

DOI: 10.1016/j.maturitas.2015.08.002

a Program in Physical Therapy, Washington University in St. Louis School of Medicine, St. Louis, MO 63108, USA
b Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63108, USA
c Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO 63108, USA

Abstract
Evidence indicates exercise is beneficial for motor and non-motor function in older adults and people with chronic diseases including Parkinson disease (PD). Dance may be a relevant form of exercise in PD and older adults due to social factors and accessibility. People with PD experience motor and non-motor symptoms, but treatments, interventions, and assessments often focus more on motor symptoms. Similar non-motor symptoms also occur in older adults. While it is well-known that dance may improve motor outcomes, it is less clear how dance affects non-motor symptoms. This review aims to describe the effects of dance interventions on non-motor symptoms in older adults and PD, highlights limitations of the literature, and identifies opportunities for future research. Overall, intervention parameters, study designs, and outcome measures differ widely, limiting comparisons across studies. Results are mixed in both populations, but evidence supports the potential for dance to improve mood, cognition, and quality of life in PD and healthy older adults. Participation and non-motor symptoms like sleep disturbances, pain, and fatigue have not been measured in older adults. Additional well-designed studies comparing dance and exercise interventions are needed to clarify the effects of dance on non-motor function and establish recommendations for these populations. © 2015 Elsevier Ireland Ltd.

Author Keywords
Cognition;  Dance;  Exercise;  Mood;  Parkinson disease;  Quality of life

Document Type: Article in Press
Source: Scopus
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Sasaki, Y., Margolin, Z., Borgo, B., Havranek, J.J., Milbrandt, J.
Characterization of Leber congenital amaurosis-associated NMNAT1 mutants
(2015) Journal of Biological Chemistry, 290 (28), pp. 17228-17238. 

DOI: 10.1074/jbc.M115.637850

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

Abstract
Leber congenital amaurosis 9 (LCA9) is an autosomal recessive retinal degeneration condition caused by mutations in the NAD+ biosynthetic enzyme NMNAT1. This condition leads to early blindness but no other consistent deficits have been reported in patients with NMNAT1 mutations despite its central role in metabolism and ubiquitous expression. To study how these mutations affect NMNAT1 function and ultimately lead to the retinal degeneration phenotype, we performed detailed analysis of LCA-associated NMNAT1 mutants, including the expression, nuclear localization, enzymatic activity, secondary structure, oligomerization, and promotion of axonal and cellular integrity in response to injury. In many assays, most mutants produced results similar to wild type NMNAT1. Indeed, NAD+ synthetic activity is unlikely to be a primary mechanism underlying retinal degeneration as most LCA-associated NMNAT1 mutants had normal enzymatic activity. In contrast, the secondary structure of many NMNAT1 mutants was relatively less stable as they lost enzymatic activity after heat shock, whereas wild type NMNAT1 retains significant activity after this stress. These results suggest that LCA-associated NMNAT1 mutants are more vulnerable to stressful conditions that lead to protein unfolding, a potential contributor to the retinal degeneration observed in this syndrome. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus
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Luo, J.a , Feng, J.a , Liu, S.a , Walters, E.T.b , Hu, H.a 
Erratum: Molecular and cellular mechanisms that initiate pain and itch (Cellular and Molecular Life Sciences DOI: 10.1007/s00018-015-1904-4)
(2015) Cellular and Molecular Life Sciences, 72 (18), pp. 3587-3588. 

DOI: 10.1007/s00018-015-1979-y

a Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine, 660 S. Euclid Ave., St, Louis, MO, United States
b Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, United States

Document Type: Erratum
Source: Scopus
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Tian, L.a , Xia, Y.a , Flores, H.P.a , Campbell, M.C.a b , Moerlein, S.M.b , Perlmutter, J.S.a b c d e 
Neuroimaging analysis of the dopamine basis for apathetic behaviors in an MPTP-lesioned primate model
(2015) PLoS ONE, 10 (7), art. no. e0132064, . 

DOI: 10.1371/journal.pone.0132064

a Department of Neurology, Washington University, St. Louis, MO, United States
b Department of Radiology, Washington University, St. Louis, MO, United States
c Department of Neurobiology, Washington University, St. Louis, MO, United States
d Program of Occupational Therapy, Washington University, St. Louis, MO, United States
e Program of PhysicaTherapy, Washington University, St. Louis, MO, United States

Abstract
Apathy commonly occurs in Parkinson disease (PD) patients; however, the role of dopamine in the pathophysiology of apathy remains elusive. We previously demonstrated that dopaminergic dysfunction within the ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathway contributes to the manifestation of apathetic behaviors in monkeys treated with the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now extend these studies to identify dopaminergic dysfunction in cortical regions that correlate with development of apathetic behaviors. Specifically, we measured the effects of MPTP on monkeys' willingness to attempt goal directed behaviors, which is distinct from their ability to perform tasks. A total of 16 monkeys had baseline magnetic resonance imaging (MRI) and positron emission tomography (PET), using 6-[ 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2β-[11C]carbomethoxy-3β-(4-fluorophenyl)tropane (CFT). The monkeys received unilateral infusion of different doses of MPTP (0 - 0.31mg/kg) to produce a wide range of severity of motor parkinsonism. Eight weeks after MPTP, PET scans were repeated and animals were euthanized. Apathetic behavior and motor impairments were assessed blindly both pre- and post-MPTP infusion. Apathy scores were compared to in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with PET measures of dopaminergic terminals (DTBZ or CFT) in dorsal lateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), and insular cortex (IC). Among all the cortical regions assessed, forward stepwise regression analyses indicated that only stereologic cell counts in VTA, and not counts in the substantia nigra (SN), predict dopamine transporter changes in IC. Our findings suggest that dopaminergic dysfunction within the VTA-IC pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. © 2015 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus
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Gadel, S.a , Friedel, C.a , Kharasch, E.D.a b 
Differences in methadone metabolism by CYP2B6 variants
(2015) Drug Metabolism and Disposition, 43 (7), pp. 994-1001. 

DOI: 10.1124/dmd.115.064352

a Department of Anesthesiology, Division of Clinical and Translational Research, Campus Box 8054, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Methadone is a long-acting opioid with considerable unexplained interindividual variability in clearance. Cytochrome P450 2B6 (CYP2B6) mediates clinical methadone clearance and metabolic inactivation via N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Retrospective studies suggest that individuals with the CYP2B66 allelic variant have higher methadone plasma concentrations. Catalytic activities of CYP2B6 variants are highly substrate- and expression-system dependent. This investigation evaluated methadone N-demethylation by expressed human CYP2B6 allelic variants in an insect cell coexpression system containing P450 reductase. Additionally, the influence of coexpressing cytochrome b<inf>5</inf>, whose role in metabolism can be inhibitory or stimulatory depending on the P450 isoform and substrate, on methadone metabolism, was evaluated. EDDP formation from therapeutic (0.25-1 μM) R- and S-methadone concentrations was CYP2B6.4 ≥ CYP2B6.1 ≥ CYP2B6.5 >> CYP2B6.9 ≈ CYP2B6.6, and undetectable from CYP2B6.18. Coexpression of b<inf>5</inf> had small and variant-specific effects at therapeutic methadone concentrations but at higher concentrations stimulated EDDP formation by CYP2B6.1, CYP2B6.4, CYP2B6.5, and CYP2B6.9 but not CYP2B6.6. In vitro intrinsic clearances were generally CYP2B6.4 ≥ CYP2B6.1 > CYP2B6.5 > CYP2B6.9 ≥ CYP2B6.6. Stereoselective methadone metabolism (S>R) was maintained with all CYP2B6 variants. These results show that methadone N-demethylation by CYP2B6.4 is greater compared with CYP2B6.1, whereas CYP2B6.9 and CYP2B6.6 (which both contain the 516G>T, Q172H polymorphism), are catalyt-ically deficient. The presence or absence of b<inf>5</inf> in expression systems may explain previously reported disparate catalytic activities of CYP2B6 variants for specific substrates. Differences in methadone metabolism by CYP2B6 allelic variants provide a mechanistic understanding of pharmacogenetic variability in clinical methadone metabolism and clearance. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Document Type: Article
Source: Scopus
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Bergen, A.W.a , Michel, M.b , Nishita, D.a , Krasnow, R.a , Javitz, H.S.a , Conneely, K.N.c , Lessov-Schlaggar, C.N.d , Hops, H.e , Zhu, A.Z.X.f , Baurley, J.W.g , McClure, J.B.h , Hall, S.M.i , Baker, T.B.j , Conti, D.V.k , Benowitz, N.L.l , Lerman, C.m , Tyndale, R.F.n , Swan, G.E.e o 
Drug metabolizing enzyme and transporter gene variation, nicotine metabolism, prospective abstinence, and cigarette consumption
(2015) PLoS ONE, 10 (7), art. no. e126113, . 

DOI: 10.1371/journal.pone.0126113

a Center for Health Sciences, SRI International, Menlo Park, CA, United States
b Academic Research Systems, University of California San Francisco, San Francisco, CA, United States
c Department of Human Genetics, Emory University, School of Medicine, Atlanta, GA, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Oregon Research Institute, Eugene, OR, United States
f Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
g BioRealm, LLC, Monument, CO, United States
h Group Health Research Institute, Seattle, WA, United States
i Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States
j Center for Tobacco Research and Intervention, Department of Medicine, University of Wisconsin, Madison, WI, United States
k Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
l Departmentof Medicine and of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, United States
m Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States
n Cambell Family Mental Health Research Institute, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
o Stanford Prevention Research Center, Department of Medicine, Stanford University, Palo Alto, CA, United States

Abstract
The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 P<inf>ACT</inf>=4.1E-7, rs4803381 P<inf>ACT</inf>=4.5E-5, rs1137115, P<inf>ACT</inf>=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis. © 2015 Bergen et al.

Document Type: Article
Source: Scopus
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O'Neill, P.R.a , Gautam, N.a b 
Optimizing optogenetic constructs for control over signaling and cell behaviours
(2015) Photochemical and Photobiological Sciences, 14 (9), pp. 1578-1585. 

DOI: 10.1039/c5pp00171d

a Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
b Genetics, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Optogenetic tools have recently been developed that enable dynamic control over the activities of select signaling proteins. They provide the unique ability to rapidly turn signaling events on or off with subcellular control in living cells and organisms. This capability is leading to new insights into how the spatial and temporal coordination of signaling events governs dynamic cell behaviours such as migration and neurite outgrowth. These tools can also be used to dissect a protein's signaling functions at different organelles. Here we review the properties of photoreceptors from diverse organisms that have been leveraged to control signaling in mammalian cells. We emphasize recent engineering approaches that have been used to create optogenetic constructs with optimized spectral, kinetic, and signaling properties for controlling cell behaviours. This journal is © The Royal Society of Chemistry and Owner Societies.

Document Type: Review
Source: Scopus
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Feng, J.a , Yang, W.a , Xie, Z.a , Xiang, F.a , Cao, Z.a b , Li, W.a b , Hu, H.c , Chen, Z.a , Wu, Y.a b 
Kv channel S1-S2 linker working as a binding site of human β-defensin 2 for channel activation modulation
(2015) Journal of Biological Chemistry, 290 (25), pp. 15487-15495. 

DOI: 10.1074/jbc.M115.639500

a State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
b Center for BioDrug Research, Wuhan University, Wuhan, China
c Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Among the three extracellular domains of the tetrameric voltage-gated K+ (Kv) channels consisting of six membrane-spanning helical segments named S1-S6, the functional role of the S1-S2 linker still remains unclear because of the lack of a peptide ligand. In this study, the Kv1.3 channel S1-S2 linker was reported as a novel receptor site for human β-defensin 2 (hBD2). hBD2 shifts the conductance-voltage relationship curve of the human Kv1.3 channel in a positive direction by nearly 10.5 mV and increases the activation time constant for the channel. Unlike classical gating modifiers of toxin peptides from animal venoms, which generally bind to the Kv channel S3-S4 linker, hBD2 only targets residues in both the N and C termini of the S1-S2 linker to influence channel gating and inhibit channel currents. The increment and decrement of the basic residue number in a positively charged S4 sensor of Kv1.3 channel yields conductance-voltage relationship curves in the positive direction by 31.2 mV and 2-4 mV, which suggests that positively charged hBD2 is anchored in the channel S1-S2 linker and is modulating channel activation through electrostatic repulsion with an adjacent S4 helix. Together, these findings reveal a novel peptide ligand that binds with the Kv channel S1-S2 linker to modulate channel activation. These findings also highlight the functional importance of the Kv channel S1-S2 linker in ligand recognition and modification of channel activation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus
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Checkoway, H.a , Nielsen, S.S.b , Racette, B.A.c d 
Environmental Exposures and Risks for Parkinson's Disease
(2015) Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders, pp. 253-265. 

DOI: 10.1016/B978-0-12-800228-5.00012-1

a Family and Preventive Medicine, University of California, San Diego, La Jolla, CA, United States
b Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States
c Department of Neurology,, Washington University, St Louis, MO, United States
d School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa

Abstract
Parkinson disease (PD) is a degenerative movement disorder that affects up to 2% of persons older than age 60. The etiology of PD remains poorly understood, despite extensive research during the past 50. years. Some genetic factors are consistently associated with PD risk, as is tobacco smoking, which appears protective. Additional lifestyle factors, comorbid conditions, and environmental exposures are likely to play important etiologic roles. Environmental epidemiologic research has been guided by mechanistic considerations, toxicological evidence, and clinical case reports among persons with characteristically high-dose exposures. Agents that have received the most attention are pesticides, metals, and solvents. To date, no agent that can account for a sizable fraction of PD incidence has been identified. Future research should prioritize longitudinal studies of selected occupational or environmental high-dose groups to characterize dose-response relationships for disease risk and progression. © 2015 Elsevier Inc. All rights reserved.

Author Keywords
Environmental exposures;  Epidemiology;  Metals;  Occupations;  Parkinson disease;  Parkinsonism;  Pesticides;  Solvents

Document Type: Book Chapter
Source: Scopus
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Semenkovich, K.a , Patel, P.P.a , Pollock, A.B.b , Beach, K.A.a , Nelson, S.c , Masterson, J.J.d , Hershey, T.e f g , Arbeláez, A.M.a 
Academic abilities and glycaemic control in children and young people with Type 1 diabetes mellitus
(2015) Diabetic Medicine, . Article in Press. 

DOI: 10.1111/dme.12854

a Departments of Pediatrics Washington University School of Medicine St. Louis, MO USA
b Department of Occupational Therapy Washington University School of Medicine St. Louis, MO USA
c Department of Biostatistics Washington University School of Medicine St. Louis, MO USA
d Department of Communication Sciences and Disorders Missouri State University Springfield, MO USA
e Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
f Department of Neurology Washington University School of MedicineSt. Louis, MO USA
g Department of Radiology Washington University School of Medicine St. Louis, MO USA

Abstract
Aims: To determine if children and young people aged < 23 years with Type 1 diabetes differ in academic ability from age-matched control subjects without Type 1 diabetes and whether academic scores are related to glycaemic control. Methods: Using a cross-sectional study design, we administered cognitive and academic tests (Woodcock-Johnson III Spatial Relations, General Information, Letter-Word Recognition, Calculation and Spelling tests) to young people with Type 1 diabetes (n=61) and control subjects (n=26) aged 9-22 years. The groups did not differ in age or gender. Participants with Type 1 diabetes had a disease duration of 5-17.7 years. History of glycaemic control (HbA<inf>1c</inf>, diabetic ketoacidosis and severe hypoglycaemic episodes) was obtained via medical records and interviews. Results: The participants with Type 1 diabetes had a lower mean estimated verbal intelligence (IQ) level compared with those in the control group (P=0.04). Greater exposure to hyperglycaemia over time was associated with lower spelling abilities within the group with Type 1 diabetes (P=0.048), even after controlling for age, gender, socio-economic status, blood glucose level at time of testing and verbal IQ (P=0.01). History of severe hypoglycaemia or ketoacidosis was not associated with differences in academic abilities. Conclusions: In children and young people, Type 1 diabetes was associated with a lower verbal IQ. Moreover, increased exposure to hyperglycaemia was associated with lower spelling performance. These results imply that hyperglycaemia can affect cognitive function and/or learning processes that may affect academic achievement. © 2015 Diabetes UK.

Document Type: Article in Press
Source: Scopus
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Morley, J.E.a , Morris, J.C.b , Berg-Weger, M.c , Borson, S.d , Carpenter, B.D.b , del Campo, N.e , Dubois, B.f , Fargo, K.g , Fitten, L.J.h , Flaherty, J.H.i , Ganguli, M.j , Grossberg, G.T.k , Malmstrom, T.K.l , Petersen, R.D.m , Rodriguez, C.n , Saykin, A.J.o , Scheltens, P.p , Tangalos, E.G.q , Verghese, J.r , Wilcock, G.s , Winblad, B.t , Woo, J.u , Vellas, B.v 
Brain Health: The Importance of Recognizing Cognitive Impairment: An IAGG Consensus Conference
(2015) Journal of the American Medical Directors Association, 16 (9), pp. 731-739. Cited 1 time.

DOI: 10.1016/j.jamda.2015.06.017

a Divisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, St Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
c Division of Geriatric Medicine, School of Social Work, Saint Louis University, St Louis, MO, United States
d Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, United States
e Institute of Aging, University Hospital of Toulouse, Toulouse, France
f Department of Neurology, Université Pierreet Marie Curie, Salpetriere Hospital, Paris, France
g Scientific Programs and Outreach, Alzheimer's Association, Chicago, IL, United States
h Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA and Geriatric Psychiatry, Greater Los Angeles VA, Sepulveda Campus, Los Angeles, CA, United States
i Division of Geriatric Medicine, Saint Louis University School of Medicine, St Louis, MO, United States
j Departments of Psychiatry, Neurology and Epidemiology, University of Pittsburgh School of Medicine, Graduate School of Public Health, Pittsburgh, PA, United States
k Department of Neurology and Psychiatry, Geriatric Psychiatry, Saint Louis University School of Medicine, St Louis, MO, United States
l Department of Neurology and Psychiatry, Saint Louis University School of Medicine, St Louis, MO, United States
m Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, United States
n Public Policy and Communications, Alzheimer's Association, St Louis, MO, United States
o Department of Radiology and Imaging Sciences, The Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, United States
p VU University Medical Center, Alzheimer Center, Amsterdam, Netherlands
q Department of Medicine, Mayo Clinic, Rochester, MN, United States
r Division of Geriatrics, Albert Einstein College of Medicine, Bronx, NY, United States
s Nuffield Department of Clinical Medicine, Oxford Institute of Population Ageing, Oxford, United Kingdom
t Division for Neurogeriatrics, Care Sciences and Society, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden
u Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
v Department of Geriatrics, CHU Toulouse, Toulouse, France

Abstract
Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline. © 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Author Keywords
Alzheimer disease;  Case finding;  Cognitive frailty;  Cognitive impairment;  MCI

Document Type: Article
Source: Scopus
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Sherman, E.D.a , Miller, J.D.b , Few, L.R.c , Campbell, W.K.b , Widiger, T.A.d , Crego, C.d , Lynam, D.R.a 
Development of a short form of the Five-Factor Narcissism Inventory: The FFNI-SF
(2015) Psychological Assessment, 27 (3), pp. 1110-1116. 

a Department of Psychological Sciences, Purdue University, United States
b Department of Psychology, University of Georgia, United States
c Department of Psychiatry, Washington University School of Medicine, United States
d Department of Psychology, University of Kentucky, United States

Abstract
The Five-Factor Narcissism Inventory (FFNI; Glover, Miller, Lynam, Crego, & Widiger, 2012) is a 148-item self-report inventory of 15 traits designed to assess the basic elements of narcissism from the perspective of a 5-factor model. The FFNI assesses both vulnerable (i.e., cynicism/distrust, need for admiration, reactive anger, and shame) and grandiose (i.e., acclaim seeking, arrogance, authoritativeness, entitlement, exhibitionism, exploitativeness, grandiose fantasies, indifference, lack of empathy, manipulativeness, and thrill seeking) variants of narcissism. The present study reports the development of a short-form version of the FFNI in 4 diverse samples (i.e., 2 undergraduate samples, a sample recruited from MTurk, and a clinical community sample) using item response theory. The validity of the resultant 60-item short form was compared against the validity of the full scale in the 4 samples at both the subscale level and the level of the grandiose and vulnerable composites. Results indicated that the 15 subscales remain relatively reliable, possess a factor structure identical to the structure of the long-form scales, and manifest correlational profiles highly similar to those of the long-form scales in relation to a variety of criterion measures, including basic personality dimensions, other measures of grandiose and vulnerable narcissism, and indicators of externalizing and internalizing psychopathology. Grandiose and vulnerable composites also behave almost identically across the short- and long-form versions. It is concluded that the FFNI-Short Form (FFNI-SF) offers a well-articulated assessment of the basic traits comprising grandiose and vulnerable narcissism, particularly when assessment time is limited. © 2015 American Psychological Association.

Author Keywords
FFNI;  Five-factor model;  Grandiose narcissism;  Vulnerable narcissism

Document Type: Article
Source: Scopus
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Al-Hasani, R.a , McCall, J.G.a i , Shin, G.b , Gomez, A.M.a , Schmitz, G.P.a , Bernardi, J.M.c , Pyo, C.-O.d , Park, S.I.b , Marcinkiewcz, C.M.e , Crowley, N.A.e , Krashes, M.J.f g h , Lowell, B.B.h , Kash, T.L.e , Rogers, J.A.b d , Bruchas, M.R.a i 
Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward
(2015) Neuron, 87 (5), pp. 1063-1077. 

DOI: 10.1016/j.neuron.2015.08.019

a Departments of Anesthesiology, Division of Basic Research, Anatomy and Neurobiology, Division of Biomedical Engineering and Washington University Pain Center, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Materials Science and Engineering, Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, United States
c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Electrical and Computer Engineering, Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, United States
e Department of Pharmacology and Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, NC, United States
f Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
g National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States
h Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
i Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease. © 2015 Elsevier Inc.

Document Type: Article
Source: Scopus
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Constantino, J.N.a b , Zhang, Y.a , Holzhauer, K.c , Sant, S.a , Long, K.a , Vallorani, A.d , Malik, L.a , Gutmann, D.H.d 
Distribution and Within-Family Specificity of Quantitative Autistic Traits in Patients with Neurofibromatosis Type i
(2015) Journal of Pediatrics, 167 (3), pp. 621-626.e1. Cited 1 time.

DOI: 10.1016/j.jpeds.2015.04.075

a Department of Psychiatry, 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 University of Illinois, Chicago, IL, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. Study design Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. Results Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. Conclusions Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity. © 2015 Elsevier Inc.

Document Type: Article
Source: Scopus
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Chaturvedi, S.a , Turan, T.N.b , Lynn, M.J.c , Derdeyn, C.P.d , Fiorella, D.e , Janis, L.S.f , Chimowitz, M.I.b 
Do Patient Characteristics Explain the Differences in Outcome between Medically Treated Patients in SAMMPRIS and WASID?
(2015) Stroke, 46 (9), pp. 2562-2567. 

DOI: 10.1161/STROKEAHA.115.009656

a Department of Neurology, University of Miami, Miller School of Medicine, 1120 NW 14th St, Miami, FL, United States
b Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States
c Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA, United States
d Mallinckrodt Institute of Radiology, Department of Neurology and Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
e Department of Neurosurgery, State University of New York, Stony Brook, NY, United States
f National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, United States

Abstract
Background and Purpose - The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) medical group had a much lower primary end point rate than predicted from the preceding Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. This result has been attributed to the aggressive medical therapy used in SAMMPRIS, but an alternative hypothesis is that SAMMPRIS patients were at lower risk. We undertook analyses to evaluate these competing hypotheses. Methods - Using proportional hazards regression, we compared the SAMMPRIS primary end point between SAMMPRIS medical patients and WASID patients meeting the same qualifying criteria adjusted for confounding baseline characteristics. Results - The unadjusted comparison of the SAMMPRIS primary end point showed a significantly higher risk for WASID patients (P=0.009, logrank test) with 12 month Kaplan-Meier estimates of 21.9% in WASID and 12.6% in SAMMPRIS and hazard ratio 1.9 (95% confidence interval =1.2-3.0). The analyses identified the following confounding factors that varied between the studies and that conferred a higher risk: lack of statin use at enrollment (hazard ratio =1.8, 95% confidence interval =1.1-2.9, P=0.027) that was more prevalent among WASID patients (39% versus 14%, P<0.0001) and prior infarcts in the territory of the symptomatic vessel (hazard ratio =1.8, 95% confidence interval =1.1-2.9, P=0.023) that was more prevalent among SAMMPRIS patients (34% versus 22%, P=0.015).The hazard ratio for WASID versus SAMMPRIS adjusted for these 2 characteristics was 1.9 (95% confidence interval =1.1-3.2). Conclusions - After adjustment for confounding baseline characteristics, WASID patients had an almost 2-fold higher risk of the SAMMPRIS primary end point, which supports the hypothesis that the lower rate of the primary end point in the medical arm of SAMMPRIS compared with WASID patients was as a result of the aggressive medical management used in SAMMPRIS. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693. © 2015 American Heart Association, Inc.

Author Keywords
atherosclerosis;  dyslipidemia;  intracranial atherosclerosis;  stroke;  warfarin

Document Type: Article
Source: Scopus
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Chen, Y.-H., Gianino, S.M., Gutmann, D.H.
Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways
(2015) Genes and Development, 29 (16), pp. 1677-1682. 

DOI: 10.1101/gad.261677.115

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

Abstract
Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disordercaused byimpaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, wereport that neurofibromindifferentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways. While PI3K/ AKT governs neurofibromin-regulated NSC proliferation, multilineage differentiation is MEK-dependent. Moreover, whereas MEK-regulated multilineage differentiation requires Smad3-induced Jagged-1 expression and Notch activation, MEK/Smad3-regulated Hes1 induction is only responsible for astrocyte and neuronal differentiation.Collectively, these findings establish distinct roles for theRAS effector pathways in regulating brain NSC function. © 2015 Chen et al.

Author Keywords
AKT;  Astrocyte;  Jagged1;  MEK;  Neurofibromin;  Neuroglial progenitor;  Notch

Document Type: Article
Source: Scopus
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Siddiqi, S.H.a , Creech, M.L.b , Black, K.J.a b c 
Orthostatic stability with intravenous levodopa
(2015) PeerJ, 2015 (8), art. no. 1198, . 

DOI: 10.7717/peerj.1198

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Anatomy and Neurobiology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson's disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo-after oral carbidopa-in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase. © 2015 Siddiqi et al.

Author Keywords
Blood pressure;  Carbidopa;  Heart rate;  Intravenous;  Levodopa;  Randomized controlled trial;  Tourette syndrome

Document Type: Article
Source: Scopus
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Mousavi, F.a , Rozsa, S.a d , Nilsson, T.b , Archer, T.a c , Anckarsäter, H.b , Garcia, D.a b d 
Personality and intelligence: Persistence, not self-directedness, cooperativeness or self-transcendence, is related to twins' cognitive abilities
(2015) PeerJ, 2015 (8), art. no. 1195, . 

DOI: 10.7717/peerj.1195

a Network for Empowerment and Well-Being, Sweden
b Institute of Neuroscience and Physiology, Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden
c Department of Psychology, University of Gothenburg, Gothenburg, Sweden
d Center for Well-Being, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Background. A person-centered approach focusing on the interaction of an individual's temperament-character-life events is essential in the path of individuals' well-being. In this context, three character traits, Self-directedness (e.g., self-acceptance, self-control, goal-directed behavior), Cooperativeness (e.g., social affiliation, social tolerance, empathy and helpfulness) and Self-transcendence (e.g., spiritual acceptance, transpersonal identification), measured using Cloninger's model of personality are suggested to help the individual to regulate and resolve the conflicts derived from her/his temperament combinations as a reaction to life events. However, if character is related to the individual's cognitive ability, then this association might limit any intervention that focuses on character development. We used data from the Child and Adolescent Twin Study in Sweden (CATSS) to investigate the relationship between personality and cognitive ability. Method. The sample consisted of 370 15-year-old twins (159 girls/211 boys), 192 of whomscreen-positive with various types of mental health problems. We used the Temperament and Character Inventory to measure personality and the Wechsler Intelligence Scales for Children (WISC-IV) to measure intelligence. The relationship was investigated using correlation analyses using random-selected twins from each dyad and separately for monozygotic and dizygotic twins. Additional analyses investigated the genetic and environmental effects on personality and cognitive ability in this specific sample. Results. There were no significant correlations between the WISC-IV indices and any of the character traits (i.e., Self-directedness, Cooperativeness, and Self-transcendence). Persistence was significantly related, if weak, to four WISC-IV indices: Verbal Comprehension, Perceptual Reasoning, Working Memory, and the Full WISC-IV Scale. Post-hoc cross-twin/cross-trait analyses showed that the Persistence-cognitive ability correlation might depend on common genetic effects. The WISC-IV indices showed a relatively large genetic influence, while earlier findings about the etiology of temperament and character traits using the whole CATSS sample were replicated in this sub-sample of twins. Conclusions. The results indicate that what individuals make of themselves intentionally (i.e., their character) was not associated to intelligence. Persistence, a temperament dimension that measures heritable individual differences in eagerness of effort, ambition, perfectionism, and resistance to discouragement despite frustration and fatigue, was weakly linked to intelligence. Suggesting that, at least during adolescence, interventions targeting character development are not limited by the individual's intelligence. © 2015 Mousavi et al.

Author Keywords
Cognitive ability;  Cooperativeness;  Intelligence;  Self-directedness;  Temperament and character inventory;  Twins

Document Type: Article
Source: Scopus
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Magnoni, S.a , Mac Donald, C.L.b , Esparza, T.J.c , Conte, V.a , Sorrell, J.c , MacRì, M.d , Bertani, G.e , Biffi, R.f , Costa, A.f , Sammons, B.c , Snyder, A.Z.g , Shimony, J.S.g , Triulzi, F.f , Stocchetti, N.a d , Brody, D.L.c h 
Quantitative assessments of traumatic axonal injury in human brain: Concordance of microdialysis and advanced MRI
(2015) Brain, 138 (8), pp. 2263-2277. 

DOI: 10.1093/brain/awv152

a Department of Anaesthesiology and Intensive Care, Fondazione IRCCS, Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy
b Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, United States
c Department of Neurology, Washington University, St Louis, MO, United States
d Milan University, Milano, Italy
e Department of Neurosurgery, Fondazione IRCCS, Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy
f Department of Neuroradiology, Fondazione IRCCS, Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy
g Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, United States
h Hope Centre for Neurological Disorders, Washington University, St Louis, MO, United States

Abstract
Axonal injury is a major contributor to adverse outcomes following brain trauma. However, the extent of axonal injury cannot currently be assessed reliably in living humans. Here, we used two experimental methods with distinct noise sources and limitations in the same cohort of 15 patients with severe traumatic brain injury to assess axonal injury. One hundred kilodalton cut-off microdialysis catheters were implanted at a median time of 17 h (13-29 h) after injury in normal appearing (on computed tomography scan) frontal white matter in all patients, and samples were collected for at least 72 h. Multiple analytes, such as the metabolic markers glucose, lactate, pyruvate, glutamate and tau and amyloid-β proteins, were measured every 1-2 h in the microdialysis samples. Diffusion tensor magnetic resonance imaging scans at 3 T were performed 2-9 weeks after injury in 11 patients. Stability of diffusion tensor imaging findings was verified by repeat scans 1-3 years later in seven patients. An additional four patients were scanned only at 1-3 years after injury. Imaging abnormalities were assessed based on comparisons with five healthy control subjects for each patient, matched by age and sex (32 controls in total). No safety concerns arose during either microdialysis or scanning. We found that acute microdialysis measurements of the axonal cytoskeletal protein tau in the brain extracellular space correlated well with diffusion tensor magnetic resonance imaging-based measurements of reduced brain white matter integrity in the 1-cm radius white matter-masked region near the microdialysis catheter insertion sites. Specifically, we found a significant inverse correlation between microdialysis measured levels of tau 13-36 h after injury and anisotropy reductions in comparison with healthy controls (Spearman's r = -0.64, P = 0.006). Anisotropy reductions near microdialysis catheter insertion sites were highly correlated with reductions in multiple additional white matter regions. We interpret this result to mean that both microdialysis and diffusion tensor magnetic resonance imaging accurately reflect the same pathophysiological process: traumatic axonal injury. This cross-validation increases confidence in both methods for the clinical assessment of axonal injury. However, neither microdialysis nor diffusion tensor magnetic resonance imaging have been validated versus post-mortem histology in humans. Furthermore, future work will be required to determine the prognostic significance of these assessments of traumatic axonal injury when combined with other clinical and radiological measures. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Author Keywords
diffusion tensor imaging;  microdialysis;  tau;  traumatic axonal injury;  traumatic brain injury

Document Type: Article
Source: Scopus
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Abadin, S.S.a , Zoellner, N.L.a , Schaeffer, M.a , Porcelli, B.b , Gutmann, D.H.c , Johnson, K.J.a d 
Racial/Ethnic Differences in Pediatric Brain Tumor Diagnoses in Patients with Neurofibromatosis Type 1
(2015) Journal of Pediatrics, 167 (3), pp. 613-620.e2. Cited 1 time.

DOI: 10.1016/j.jpeds.2015.04.076

a Brown School, Washington University, 237 Goldfarb Hall, Campus Box 1196, One Brookings Dr, St. Louis, MO, United States
b School of Medicine, Washington University, St. Louis, MO, United States
c Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
d Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO, United States

Abstract
Objective To evaluate evidence for differences in pediatric brain tumor diagnoses by race and ethnicity using a cross-sectional study design in individuals with neurofibromatosis type 1 (NF1). Study design Subjects with NF1 were ascertained from the NF1 Patient Registry Initiative and through a clinical record database of patients at a large academic medical center. Logistic regression was employed to calculate ORs and 95% CIs to analyze differences in the odds of brain tumor diagnosis by race (White, Black, Asian, other/unknown) and ethnic (Hispanic vs non-Hispanic) groups. Results Data from a total of 1546, 629, and 2038 individuals who were ascertained from the NF1 Patient Registry Initiative, clinical records, and pooled datasets were analyzed, respectively. After adjusting for birth year, we observed a significantly reduced odds of brain tumor diagnoses in individuals self-identified or clinically reported as Black (OR = 0.13, 95% CI 0.05-0.31), Asian (OR = 0.15, 95% CI 0.04-0.64), and other/unknown (OR = 0.61, 95% CI 0.41-0.93) race compared with those with reported as White race. There was no significant difference in the odds of pediatric brain tumor diagnosis by Hispanic ethnicity. Conclusions Consistent with prior smaller studies, these data suggest that pediatric brain tumor diagnoses vary by race in individuals with NF1. Reasons underlying observed differences by race warrant further investigation. © 2015 Elsevier Inc.

Document Type: Article
Source: Scopus
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Godzik, J.a , Holekamp, T.F.b , Limbrick, D.D.b , Lenke, L.G.a , Park, T.S.b , Ray, W.Z.b , Bridwell, K.H.a , Kelly, M.P.a 
Risks and outcomes of spinal deformity surgery in Chiari malformation, Type 1, with syringomyelia versus adolescent idiopathic scoliosis
(2015) Spine Journal, 15 (9), pp. 2002-2008. 

DOI: 10.1016/j.spinee.2015.04.048

a Department of Orthopaedic Surgery, Washington University School of Medicine, Campus-Box 8233, 660 S Euclid Ave., St Louis, MO, United States
b Department of Neurological Surgery, Washington University School of Medicine, 660 S Euclid Ave., St Louis, MO, United States

Abstract
Background context Chiari malformation, Type 1, with syringomyelia (CIM+SM) is often associated with spinal deformity. The safety of scoliosis surgery this population is controversial and has never been directly compared with adolescent idiopathic scoliosis (AIS). Purpose The purpose of this study was to compare the safety and subjective outcomes of spinal deformity surgery between patients with Chiari malformation Type 1-associated scoliosis and a matched AIS cohort. Study design This study is based on a retrospective matched cohort analysis. Patient sample Patients with CIM+SM and treated with spinal fusion for spinal deformity were identified in the surgical records of a single institution and were matched, 1:1, with AIS patients undergoing spinal fusion at the same institution. Outcome measures The outcome measures were neurological monitoring data quality and integrity, radiographic parameters, and Scoliosis Research Society Questionnaire-22 (SRS-22) scores. Methods A clinical database was reviewed for patients undergoing spinal reconstruction for CIM+SM-associated spinal deformity at our institution from 2000 to 2012. Thirty-six CIM+SM patients were identified and matched to an AIS cohort (1:1) based on age, gender, major curve magnitude, fusion length, and revision status. Demographics, deformity morphology, surgical details, neuromonitoring data, and preoperative and postoperative SRS-22 scores were recorded at a minimum of 2-year follow-up. Changes in SRS-22 scores were compared within and between groups. Complications and neurological monitoring data issues were compared between groups. Results Mean age was 14.5±5 years (CIM+SM: 14.6±5; AIS: 14.4±5), and 42% of patients were male. Preoperative mean major coronal Cobb measured 58°±25°versus 57°±17°(p=.84) with mean kyphosis 52°±17°versus 41°±20°(p=.018). An average of 10.4±2.6 vertebral levels were fused (10.4±2.8 vs. 10.4±2.3, p=.928). No differences existed in surgical approach (p=.336), estimated blood loss (680±720 vs. 660±310 mL, p=.845), or duration of surgery (6.0±2.2 vs. 5.6±2 hours, p=.434). Complication rate was comparable between the two groups (33% vs. 14%, p=.052). Chiari malformation, Type 1, with syringomyelia experienced more neurological complications (11% vs. 0%, p=.04) and neuromonitoring difficulties (28% vs. 3%, p=.007) than the AIS cohort. Mean curve correction was comparable at 2 years (58% CIM+SM vs. 64% AIS, p=.2). At follow-up, both CIM+SM and AIS groups demonstrated improved cumulative SRS-22 outcome subscores (CIM+SM: +0.4, p=.027; AIS: +0.3, p<.001). No difference in outcome subscores existed between CIM+SM and AIS groups. Conclusions Although CIM+SM patients undergoing spine reconstruction can expect similar deformity corrections and outcome scores to AIS patients, they also experience higher rates of neuromonitoring difficulties and neurological complications related to surgery. Surgeons should be prepared for these difficulties, particularly in children with larger syrinx size. © 2015 Elsevier Inc.

Author Keywords
Adolescent idiopathic scoliosis;  Chiari malformation;  Chiari-associated spinal deformity;  Kyphosis;  Scoliosis;  Spinal deformity;  Syringomyelia

Document Type: Article
Source: Scopus
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Agrawal, A.a , Bogdan, R.b 
Risky Business: Pathways to Progress in Biologically Informed Studies of Psychopathology
(2015) Psychological Inquiry, 26 (3), pp. 231-238. 

DOI: 10.1080/1047840X.2015.1039930

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

Document Type: Note
Source: Scopus
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Warrington, N.M.a , Sun, T.a , Rubin, J.B.a b 
Targeting brain tumor cAMP: The case for sex-specific therapeutics
(2015) Frontiers in Pharmacology, 6 (JUL), art. no. 153, . 

DOI: 10.3389/fphar.2015.00153

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

Abstract
A relationship between cyclic adenosine 3', 5'-monophosphate (cAMP) levels and brain tumor biology has been evident for nearly as long as cAMP and its synthetase, adenylate cyclase (ADCY) have been known. The importance of the pathway in brain tumorigenesis has been demonstrated in vitro and in multiple animal models. Recently, we provided human validation for a cooperating oncogenic role for cAMP in brain tumorigenesis when we found that SNPs in ADCY8 were correlated with glioma (brain tumor) risk in individuals with Neurofibromatosis type 1 (NF1). Together, these studies provide a strong rationale for targeting cAMP in brain tumor therapy. However, the cAMP pathway is well-known to be sexually dimorphic, and SNPs in ADCY8 affected glioma risk in a sex-specific fashion, elevating the risk for females while protecting males. The cAMP pathway can be targeted at multiple levels in the regulation of its synthesis and degradation. Sex differences in response to drugs that target cAMP regulators indicate that successful targeting of the cAMP pathway for brain tumor patients is likely to require matching specific mechanisms of drug action with patient sex. © 2015 Warrington, Sun and Rubin.

Author Keywords
Brain tumors;  CAMP;  PDE;  Primary cilia;  Sex differences

Document Type: Article
Source: Scopus
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Baer, M.a , Evans, K.a , Oldham, G.R.b , Boasso, A.c 
The social network side of individual innovation: A meta-analysis and path-analytic integration
(2015) Organizational Psychology Review, 5 (3), art. no. A001, pp. 191-223. 

DOI: 10.1177/2041386614564105

a Washington University in St. Louis, United States
b Tulane University, United States
c Thync Inc, United States

Abstract
The current study provides a comprehensive analysis and integration of the literature on the social network correlates of individual innovation. Reviewing the extant literature, we cluster existing network measures into five general properties—size, strength, brokerage, closure, and diversity. Using meta-analysis, we estimate the population effect sizes between these network properties and innovation. Results showed that brokerage had the strongest positive relation to innovation, followed by size, diversity, and strength. Closure, by contrast, had a weak, negative association with innovation. In addition, we offer a path-analytic integration of the literature proposing and testing the direct and indirect effects of the five properties on innovation. We suggest that network size and strength impact innovation through a web of relations with the more proximal features of brokerage, closure, and diversity. Our path-analytic integration considers the two dominant perspectives on the effects of social networks—brokerage versus closure—simultaneously allowing us to establish their relative efficacy in predicting innovation. In addition, our model highlights that network strength can have both negative and positive effects (via different direct and indirect pathways) and thus inherently involves a tradeoff. We discuss the implications of these results for future research and practice. © 2015, SAGE Publications Inc. All Rights Reserved.

Author Keywords
Creativity and innovation;  Diversity and relational demography;  Social networks

Document Type: Article
Source: Scopus
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Hoben, G.a , Yan, Y.a , Iyer, N.b , Newton, P.a , Hunter, D.A.a , Moore, A.M.a , Sakiyama-Elbert, S.E.a b , Wood, M.D.a , Mackinnon, S.E.a 
Comparison of acellular nerve allograft modification with Schwann cells or VEGF
(2015) Hand, 10 (3), pp. 396-402. 

DOI: 10.1007/s11552-014-9720-0

a Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, Campus Box 8238, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University, Campus Box 1097, One Brookings Drive, St. Louis, MO, United States

Abstract
Background: Individual contributions of exogenous Schwann cells (SCs) and vascular endothelial growth factor (VEGF) were evaluated in acellular nerve allografts (ANAs). ANA processing removes SCs and vasculature, likely contributing to reduced regeneration compared to autografts. Exogenous SCs may improve the regenerative microenvironment, and VEGF has been shown to stimulate angiogenesis. Replacing these components in ANAs may improve regeneration. Methods: A rat sciatic nerve transection model was used to study 20-mm grafts. Four graft types were studied: (1) isograft, (2) ANA, (3) ANA-SCs, and (4) ANA-VEGF. After 10 weeks in vivo, the midgraft and distal nerve to the grafts were analyzed for axonal regeneration using histomorphometry to assess total myelinated axon counts, density, width, and percent neural tissue. Results: The most axons in the distal nerve were regenerated in the isograft followed by the ANA- SC group, with 9171 ± 1822 and 7103 ± 1576 regenerated axons respectively. Both the ANA and ANA-VEGF groups had significantly fewer regenerated axons compared to the isograft (p < 0.05) with 5225 ± 2994 and 5709 ± 2657 regenerated axons, respectively. The ANA and ANA-VEGF groups also had significantly reduced fiber density and percent nerve compared to the isograft; the isograft and ANA-SC groups were not significantly different (p < 0.05). Conclusions: These results show that SCs improve axonal regeneration in a 20 mm ANA to a greater extent than VEGF. VEGF treatment showed a trend toward increased axonal regeneration but was not significantly different compared to the untreated ANA. The role of VEGF may be clearer in longer grafts where ischemia is a greater factor. © 2014, American Association for Hand Surgery.

Author Keywords
Nerve allografts;  Nerve grafts;  Nerve regeneration;  Peripheral nerve;  Schwann cell;  Vascular endothelial growth factor;  VEGF

Document Type: Article
Source: Scopus
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Kallianpur, A.R.a b , Jia, P.c , Ellis, R.J.d , Zhao, Z.c , Bloss, C.e , Wen, W.f , Marra, C.M.g , Hulgan, T.f , Simpson, D.M.h , Morgello, S.h , McArthur, J.C.i , Clifford, D.B.j , Collier, A.C.k , Gelman, B.B.l , McCutchan, J.A.m , Franklin, D.n , Samuels, D.C.o , Rosario, D.n , Holzinger, E.o , Murdock, D.G.o , Letendre, S.m , Grant, I.p 
Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy
(2014) PLoS ONE, 9 (8), art. no. e103123, . 

DOI: 10.1371/journal.pone.0103123

a Department of Genomic Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
b Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
c Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, United States
d Department of Neurology, University of California San Diego, San Diego, CA, United States
e Scripps Genomic Medicine, Scripps Translational Science Institute, Scripps Health, San Diego, CA, United States
f Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
g Department of Neurology, University of Washington, Seattle, WA, United States
h Department of Neurology, Icahn School of Medicine of Mt. Sinai, New York, NY, United States
i Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
j Department of Neurology, Washington University, Saint Louis, MO, United States
k Department of Medicine, University of Washington, Seattle, WA, United States
l Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
m Department of Medicine, University of California San Diego, San Diego, CA, United States
n HIV Neurobehavioral Research Center, CHARTER Center, University of California San Diego, San Diego, CA, United States
o Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, United States
p Department of Psychiatry, University of California San Diego, San Diego, CA, United States

Abstract
HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP. © 2014 Kallianpur et al.

Document Type: Article
Source: Scopus
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Strappini, F.a b h , Pitzalis, S.c d , Snyder, A.Z.e , McAvoy, M.P.e , Sereno, M.I.f , Corbetta, M.a e g , Shulman, G.L.a 
Eye position modulates retinotopic responses in early visual areas: a bias for the straight-ahead direction
(2015) Brain Structure and Function, 220 (5), pp. 2587-2601. 

DOI: 10.1007/s00429-014-0808-7

a Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States
b Department of Psychology, Sapienza University of Rome, Rome, Italy
c Neuropsychology Research Centre, Scientific Institute for Research, Hospitalization, and Health Care (IRCCS, Istituto di Ricovero e Cura a Carattere Scientifico), Fondazione Santa Lucia, Rome, Italy
d Department of Motor, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy
e Department of Radiology, Washington University, School of Medicine, Saint Louis, MO, United States
f Birkbeck-UCL Centre for NeuroImaging, London, United Kingdom
g Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO, United States
h Neurobiology Department, Weizmann Institute of Science, 234 Herzl St., Rehovot, Israel

Abstract
Even though the eyes constantly change position, the location of a stimulus can be accurately represented by a population of neurons with retinotopic receptive fields modulated by eye position gain fields. Recent electrophysiological studies, however, indicate that eye position gain fields may serve an additional function since they have a non-uniform spatial distribution that increases the neural response to stimuli in the straight-ahead direction. We used functional magnetic resonance imaging and a wide-field stimulus display to determine whether gaze modulations in early human visual cortex enhance the blood-oxygenation-level dependent (BOLD) response to stimuli that are straight-ahead. Subjects viewed rotating polar angle wedge stimuli centered straight-ahead or vertically displaced by ±20° eccentricity. Gaze position did not affect the topography of polar phase-angle maps, confirming that coding was retinotopic, but did affect the amplitude of the BOLD response, consistent with a gain field. In agreement with recent electrophysiological studies, BOLD responses in V1 and V2 to a wedge stimulus at a fixed retinal locus decreased when the wedge location in head-centered coordinates was farther from the straight-ahead direction. We conclude that stimulus-evoked BOLD signals are modulated by a systematic, non-uniform distribution of eye-position gain fields. © 2014, The Author(s).

Author Keywords
Gain field;  Gaze;  Retinotopy;  Vertical meridian;  Wide-field

Document Type: Article
Source: Scopus
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Stewart, R.S., Kiss, I.M., Wilkinson, R.S.
Visualization of endosome dynamics in living nerve terminals with four-dimensional fluorescence imaging
(2014) Journal of Visualized Experiments, (86), art. no. e51477, . 

DOI: 10.3791/51477

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

Abstract
Four-dimensional (4D) light imaging has been used to study behavior of small structures within motor nerve terminals of the thin transversus abdominis muscle of the garter snake. Raw data comprises time-lapse sequences of 3D z-stacks. Each stack contains 4-20 images acquired with epifluorescence optics at focal planes separated by 400-1, 500 nm. Steps in the acquisition of image stacks, such as adjustment of focus, switching of excitation wavelengths, and operation of the digital camera, are automated as much as possible to maximize image rate and minimize tissue damage from light exposure. After acquisition, a set of image stacks is deconvolved to improve spatial resolution, converted to the desired 3D format, and used to create a 4D "movie" that is suitable for variety of computer-based analyses, depending upon the experimental data sought. One application is study of the dynamic behavior of two classes of endosomes found in nerve terminals-macroendosomes (MEs) and acidic endosomes (AEs)-whose sizes (200-800 nm for both types) are at or near the diffraction limit. Access to 3D information at each time point provides several advantages over conventional time-lapse imaging. In particular, size and velocity of movement of structures can be quantified over time without loss of sharp focus. Examples of data from 4D imaging reveal that MEs approach the plasma membrane and disappear, suggesting that they are exocytosed rather than simply moving vertically away from a single plane of focus. Also revealed is putative fusion of MEs and AEs, by visualization of overlap between the two dye-containing structures as viewed in each three orthogonal projections.

Author Keywords
3D;  4D;  Deconvolution;  Endocytosis;  Endosome;  Epifluorescence;  Fluorescence;  Issue 86;  Lysosome;  Microscopy;  Nerve;  Neuroscience

Document Type: Article
Source: Scopus
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Salvay, D.M.a , Padhye, L.V.a , Huecker, J.B.a , Gordon, M.O.a , Viets, R.b , Sharma, A.b , Van Stavern, G.P.a c 
Correlation between papilledema grade and diffusion-weighted magnetic resonance imaging in idiopathic intracranial hypertension
(2014) Journal of Neuro-Ophthalmology, 34 (4), pp. 331-335. 

DOI: 10.1097/WNO.0000000000000150

a Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, 660 South Euclid Avenue, Saint Louis, MO, United States
b Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School, Saint Louis, MO, United States
c Department of Neurology, Washington University, Saint Louis, MO, United States

Abstract
Background: To explore the relationship between diffusion-weighted magnetic resonance imaging (DWI) hyperintensity of the optic nerve head (ONH) and papil-ledema grade in patients with idiopathic intracranial hypertension (IIH).

Methods: A retrospective chart review was conducted of patients with definitively diagnosed IIH by clinical examination and visual field (VF) analysis who underwent orbital magnetic resonance imaging (MRI) within 4 weeks of diagnosis. A neuroradiologist masked to the diagnosis assessed the results of DWI for each eye independently and graded the signal intensity of the ONH into none, mild, and prominent categories. DWI grading was compared with papilledema grade and visual field mean deviation (VFMD) by Spearman rank correlation analysis and t-tests.

Results: Forty-two patients were included in the study. A statistically significant difference (P = 0.0195) was found between papilledema grade and patients with prominent DWI findings (n = 16; mean papilledema grade 3.75 ± 1.25) vs mild or no ONH hyperintensity (n = 26; mean pap-illedema grade 2.79 ± 1.24) at the time of initial diagnosis. DWI hyperintensity of the ONH at diagnosis was also found to be significantly correlated with the degree of papilledema at follow-up (r = 0.39, P = 0.0183) but not with VFMD.

Conclusions: We found a significant correlation between the severity of papilledema and ONH hyperintensity on DWI in patients with IIH but not with VF loss or other visual parameters. These findings may offer insight into the pathophysiology of papilledema in IIH and provide a surro-gate marker for the presence and severity of papilledema. © 2014 by North American Neuro-Ophthalmology Society.

Document Type: Article
Source: Scopus

September 3, 2015

Johnson, C.H.a , Patti, G.J.b , Courade, J.-P.c , Shriver, L.P.d , Hoang, L.T.a , Manchester, M.e , Siuzdak, G.a f
Alterations in Spinal Cord Metabolism during Treatment of Neuropathic Pain
(2015) Journal of Neuroimmune Pharmacology, 10 (3), pp. 396-401. 

DOI: 10.1007/s11481-015-9624-y


a Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, United States
b Departments of Chemistry, Genetics and Medicine, Washington University, St. Louis, MO, United States
c UCB Biopharma, UCB New Medicines, Chemin du Foriest, Braine-l’Alleud, Belgium
d Departments of Chemistry and Biology, University of Akron, Akron, OH, United States
e Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States
f Departments of Chemistry, Molecular, and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, United States


Abstract
Therapeutic options for neuropathic pain have improved over the last 20 years yet still only provide partial relief with numerous side effects. Recently, metabolomics revealed that the concentration of the endogenous metabolite N,N-dimethylsphingosine (DMS) is increased in the spinal cord in a model of neuropathic pain. Additionally, it was shown that introduction of DMS to the central nervous system (CNS) resulted in mechanical allodynia. Here, we have examined two compounds; pregabalin (Lyrica®), a drug used to treat neuropathic pain, and N-oleoylethanolamine (NOE), an endogenous endocannabinoid-like compound that is known to affect multiple lipid pathways. We found that the concentration of DMS in the spinal cord was not significantly altered upon pregabalin treatment of rats suffering from neuropathic pain. We further explored whether modulating lipid metabolism may impact neuropathic pain by testing NOE as a potential novel therapeutic. © 2015, Springer Science+Business Media New York.


Author Keywords
Antimetabolite;  Metabolomics;  N,N-dimethylsphingosine;  N-oleoylethanolamine;  Neuropathic pain;  Pregabalin


Document Type: Article
Source: Scopus




Van Unen, J.d , Woolard, J.e , Rinken, A.g , Hoffmann, C.f , Hill, S.J.e , Goedhart, J.d , Bruchas, M.R.c , Bouvier, M.b , Adjobo-Hermans, M.J.W.a
A perspective on studying G-protein-coupled receptor signaling with resonance energy transfer biosensors in living organisms
(2015) Molecular Pharmacology, 88 (3), pp. 589-595. Cited 3 times.

DOI: 10.1124/mol.115.098897


a Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, Nijmegen, Netherlands
b Department of Biochemistry, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada
c Department of Anesthesiology, Washington University, St. Louis, MO, United States
d Swammerdam Institute for Life Sciences, Section of Molecular Cytology, University of AmsterdamAmsterdam, Netherlands
e Cell Signalling Research Group, School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom
f Bio-Imaging-Center/Rudolf-Virchow-Zentrum, Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany
g And Institute of Chemistry, University of Tartu, Tartu, Estonia


Abstract
The last frontier for a complete understanding of G-protein-coupled receptor (GPCR) biology is to be able to assess GPCR activity, interactions, and signaling in vivo, in real time within biologically intact systems. This includes the ability to detect GPCR activity, trafficking, dimerization, protein-protein interactions, second messenger production, and downstream signaling events with high spatial resolution and fast kinetic readouts. Resonance energy transfer (RET)-based biosensors allow for all of these possibilities in vitro and in cell-based assays, but moving RET into intact animals has proven difficult. Here, we provide perspectives on the optimization of biosensor design, of signal detection in living organisms, and the multidisciplinary development of in vitro and cell-based assays that more appropriately reflect the physiologic situation. In short, further development of RET-based probes, optical microscopy techniques, and mouse genome editing hold great potential over the next decade to bring real-time in vivo GPCR imaging to the forefront of pharmacology. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus




Monk, K.R.a , Hamann, J.b , Langenhan, T.c , Nijmeijer, S.d , Schöneberg, T.e , Liebscher, I.e
Adhesion G protein-coupled receptors: From in vitro pharmacology to in vivo mechanisms
(2015) Molecular Pharmacology, 88 (3), pp. 617-623. Cited 3 times.

DOI: 10.1124/mol.115.098749


a Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Experimental Immunology, Academic Medical Center, University of AmsterdamAmsterdam, Netherlands
c Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany
d Department of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU UniversityAmsterdam, Netherlands
e Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig, Germany


Abstract
The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in humans. aGPCRs are characterized by their enormous size and complex modular structures. While the physiologic importance of many aGPCRs has been clearly demonstrated in recent years, the underlying molecular functions have only recently begun to be elucidated. In this minireview, we present an overview of our current knowledge on aGPCR activation and signal transduction with a focus on the latest findings regarding the interplay between ligand binding, mechanical force, and the tethered agonistic Stachel sequence, as well as implications on translational approaches that may derive from understanding aGPCR pharmacology. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus




Bohn, L.M.a , Lohse, M.J.b , Nitabach, M.N.c , Taghert, P.H.d , Smit, M.J.e
Exploring the biology of G protein-coupled receptors from in vitro to in vivo
(2015) Molecular Pharmacology, 88 (3), pp. 534-535. 

DOI: 10.1124/mol.115.100750


a Scripps Research Institute, Jupiter, FL, United States
b University of Würzburg, Würzburg, Germany
c Yale University, New Haven, CT, United States
d Washington University Medical School, St. Louis, MO, United States
e VU University Amsterdam, Amsterdam, Netherlands


Abstract
In August 2014, an international group of researchers gathered for 5 days at the Lorentz Center in Leiden, The Netherlands, to explore the technical and conceptual issues associated with the analysis of G protein-coupled receptor functions utilizing information from crystal structure models to the use of model organisms. This collection of review articles evolved from the 5-day meeting, with brief presentations and structured discussion periods that were designed to identify key questions remaining in understanding G protein-coupled receptor function and to propose novel strategies by integrating scientific disciplines to guide future research. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus




Langenhan, T.a , Barr, M.M.c , Bruchas, M.R.d e , Ewer, J.g , Griffith, L.C.h , Maiellaro, I.b , Taghert, P.H.e , White, B.H.i , Monk, K.R.f
Model organisms in G protein-coupled receptor research
(2015) Molecular Pharmacology, 88 (3), pp. 596-603. Cited 3 times.

DOI: 10.1124/mol.115.098764


a Institute of Physiology, Department of Neurophysiology, University of Würzburg, Röntgenring 9, Würzburg, Germany
b Institute of Pharmacology and Toxicology, Rudolf Virchow Center, University of Würzburg, Germany, Würzburg, Germany
c Department of Genetics, Rutgers, State University of New Jersey, Piscataway, NJ, United States
d Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
e Division of Biological and Biomedical Sciences, Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Developmental Biology, Hope Center for Neurologic Disorders, Washington University School of Medicine, St. Louis, MO, United States
g Centro Interdisciplinario de Neurociencia, Universidad de Valparaiso, Valparaiso, Chile
h National Center of Behavioral Genomics, Department of Biology, Brandeis University, Waltham, MA, United States
i Laboratory of Molecular Biology, National Institutes of Health National Institute of Mental Health, Bethesda, MD, United States


Abstract
The study of G protein-coupled receptors (GPCRs) has benefited greatly from experimental approaches that interrogate their functions in controlled, artificial environments. Working in vitro, GPCR receptorologists discovered the basic biologic mechanisms by which GPCRs operate, including their eponymous capacity to couple to G proteins; their molecular makeup, including the famed serpentine transmembrane unit; and ultimately, their three-dimensional structure. Although the insights gained from working outside the native environments of GPCRs have allowed for the collection of low-noise data, such approaches cannot directly address a receptor's native (in vivo) functions. An in vivo approach can complement the rigor of in vitro approaches: as studied in model organisms, it imposes physiologic constraints on receptor action and thus allows investigators to deduce the most salient features of receptor function. Here, we briefly discuss specific examples in which model organisms have successfully contributed to the elucidation of signals controlled through GPCRs and other surface receptor systems. We list recent examples that have served either in the initial discovery of GPCR signaling concepts or in their fuller definition. Furthermore, we selectively highlight experimental advantages, shortcomings, and tools of each model organism.


Document Type: Article
Source: Scopus




Chang, S.D.a b , Mascarella, S.W.f , Spangler, S.M.b e , Gurevich, V.V.g , Navarro, H.A.f , Carroll, F.I.f , Bruchas, M.R.b c d e
Quantitative signaling and structure-activity analyses demonstrate functional selectivity at the nociceptin/orphanin FQ opioid receptor
(2015) Molecular Pharmacology, 88 (3), pp. 502-511. 

DOI: 10.1124/mol.115.099150


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anesthesiology, Basic Research Division, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
e Division of Biology and Biomedical Sciences Program in Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
f RTI International, Research Triangle Park, NC, United States
g Vanderbilt University, Nashville, TN, United States


Abstract
Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein-coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays, we identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G protein and arrestin pathways) to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands on the basis of NOPR antagonist J-113,397 [(±)-1-[(3R
,4R)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] to explore structure-activity relationships. Our study shows that NOPR is capable of biased signaling, and further, the NOPR selective ligands MCOPPB [1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-(3R)-3-piperidinyl-1H-benzimidazole trihydrochloride] and NNC 63-0532 [8-(1-naphthalenylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-3-acetic acid, methyl ester] are G protein-biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus




Tso, M.C.F., Herzog, E.D.
Was Cajal right about sleep?
(2015) BMC Biology, 13 (1), art. no. 67, . 

DOI: 10.1186/s12915-015-0178-5


Washington University in St. Louis, Department of Biology, St. Louis, MO, United States


Abstract
Cajal's careful observations of the anatomy of the nervous system led him to some lesser-known predictions about the function of glia as mediators of sleep. Reporting over 120 years later in BMC Biology, Bellesi et al. examine changes in gene expression and morphology of astrocytes with sleep. Their results provide support for and revisions to Cajal's predictions. See research article: doi: 10.1186/s12915-015-0176-7. © 2015 Tso and Herzog.


Document Type: Note
Source: Scopus




Suh, J., Abrams, R.A.
Reduced object-based perception in the near-hand space
(2015) Experimental Brain Research, 10 p. Article in Press. 

DOI: 10.1007/s00221-015-4414-6


Department of Psychology, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States


Abstract
Previous studies have shown that hand proximity changes visual perception (Abrams et al. in Cognition 107(3):1035–1047, 2008). The present study examined the effects of hand proximity on object-based perception. In three experiments, participants viewed stimuli that were either near to or far from their hands. The target stimulus appeared, after a cue, in one of two rectangular objects: either at the location that had been previously cued, at the uncued end of the cued object, or in the uncued object. We found a significantly reduced same-object benefit in reaction time for stimuli near the hands in one experiment. Interestingly, we observed a same-object cost in sensitivity for stimuli near the hands in another experiment. The results reveal that object-based perception is disrupted in the near-hand space. This is consistent with previous findings revealing altered visual processing near the hands. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
Embodied cognition;  Near-hand vision;  Object-based perception;  Visual attention


Document Type: Article in Press
Source: Scopus




Ackermann, M.A.a , Ward, C.W.b , Gurnett, C.c , Kontrogianni-Konstantopoulos, A.a
Myosin Binding Protein-C Slow Phosphorylation is Altered in Duchenne Dystrophy and Arthrogryposis Myopathy in Fast-Twitch Skeletal Muscles
(2015) Scientific Reports, 5, art. no. 13235, . 

DOI: 10.1038/srep13235


a University of Maryland, School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, MD, United States
b University of Maryland, School of Nursing, Baltimore, MD, United States
c Washington University, School of Medicine, Department of Neurology, St. Louis, MO, United States


Abstract
Myosin Binding Protein-C slow (sMyBP-C), encoded by MYBPC1, comprises a family of regulatory proteins of skeletal muscles that are phosphorylated by PKA and PKC. MYBPC1 missense mutations are linked to the development of Distal Arthrogryposis-1 (DA-1). Although structure-function details for this myopathy are evolving, function is undoubtedly driven by sequence variations and post-translational modifications in sMyBP-C. Herein, we examined the phosphorylation profile of sMyBP-C in mouse and human fast-twitch skeletal muscles. We used Flexor Digitorum Brevis (FDB) isolated from young (
2-months old) and old (14-months old) wild type and mdx mice, and human Abductor Hallucis (AH) and gastrocnemious muscles carrying the DA-1 mutations. Our results indicate both constitutive and differential phosphorylation of sMyBP-C in aged and diseased muscles. We report a 7-35% reduction in the phosphorylation levels of select sites in old wild type and young or old mdx FDB mouse muscles, compared to young wild type tissue. Similarly, we observe a 30-70% decrease in the phosphorylation levels of all PKA and PKC phospho-sites in the DA-1 AH, but not gastrocnemius, muscle. Overall, our studies show that the phosphorylation pattern of sMyBP-C is differentially regulated in response to age and disease, suggesting that phosphorylation plays important roles in these processes.


Document Type: Article
Source: Scopus




Kung, N.H.a , Bucelli, R.C.a , McClelland, C.M.b , Van Stavern, G.P.b
Ocular Neuromyotonia Associated with Chronic Inflammatory Demyelinating Polyneuropathy
(2015) Neuro-Ophthalmology, 3 p. Article in Press. 

DOI: 10.3109/01658107.2015.1059464


a Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA
b Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri, USA


Abstract
Ocular neuromyotonia (ONM) is a neuro-ophthalmic disorder characterized by episodic diplopia caused by contraction of one or more ocular muscles due to spontaneous excitation of the respective ocular motor nerve. We report a patient whose ocular neuromyotonia arose in the setting of a subacute demyelinating polyneuropathy consistent with chronic inflammatory demyelinating polyneuropathy (CIDP) and subsequently resolved following the initiation of intravenous immunoglobulin (IVIg) for her neuropathy. Our patient provides additional evidence towards the role of demyelination and ephaptic neurotransmission in ocular neuromyotonia and also represents the first reported case of ocular neuromyotonia associated with a systemic neurological condition. © 2015 Taylor & Francis, LLC


Author Keywords
Chronic inflammatory demyelinating polyneuropathy;  diplopia;  ocular motility;  ocular neuromyotonia


Document Type: Article in Press
Source: Scopus




Del-Aguila, J.L.a b , Koboldt, D.C.c , Black, K.a b , Chasse, R.a b , Norton, J.a b , Wilson, R.K.c , Cruchaga, C.a b
Alzheimer's disease: Rare variants with large effect sizes
(2015) Current Opinion in Genetics and Development, 33, pp. 49-55. 

DOI: 10.1016/j.gde.2015.07.008


a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, United States
b Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, United States
c The Genome Institute, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Recent advances in sequencing technology and novel genotyping arrays (focused on low-frequency and coding variants) have made it possible to identify novel coding variants with large effect sizes and also novel genes (TREM2, PLD3, UNC5C, and AKAP9) associated with Alzheimer's disease (AD) risk. The major advantages of these studies over the classic genome-wide association studies (GWAS) include the identification of the functional variant and the gene-driven association. In addition to the large effect size, these studies make it possible to model these variants and genes using cell and animal systems. On the other hand, the underlying population-variability of these very low allele frequency variants poses a great challenge to replicating results. Studies that include very large datasets (>10,000 cases and controls) and combine sequencing and genotyping approaches will lead to the identification of novel genes for Alzheimer's disease. © 2015 Elsevier Ltd.


Document Type: Review
Source: Scopus




Westbrook, A., Braver, T.S.
Cognitive effort: A neuroeconomic approach
(2015) Cognitive, Affective and Behavioral Neuroscience, 15 (2), art. no. 12, pp. 395-415. Cited 2 times.

DOI: 10.3758/s13415-015-0334-y


Department of Psychology, Washington University in Saint Louis, Saint Louis, MO, United States


Abstract
Cognitive effort has been implicated in numerous theories regarding normal and aberrant behavior and the physiological response to engagement with demanding tasks. Yet, despite broad interest, no unifying, operational definition of cognitive effort itself has been proposed. Here, we argue that the most intuitive and epistemologically valuable treatment is in terms of effort-based decision-making, and advocate a neuroeconomics-focused research strategy. We first outline psychological and neuroscientific theories of cognitive effort. Then we describe the benefits of a neuroeconomic research strategy, highlighting how it affords greater inferential traction than do traditional markers of cognitive effort, including self-reports and physiologic markers of autonomic arousal. Finally, we sketch a future series of studies that can leverage the full potential of the neuroeconomic approach toward understanding the cognitive and neural mechanisms that give rise to phenomenal, subjective cognitive effort. © 2015, Psychonomic Society, Inc.


Author Keywords
Cognitive control;  Decision-making;  Dopamine;  Motivation;  Working memory


Document Type: Review
Source: Scopus




Nelson, P.T.a b , Jicha, G.A.a c , Wang, W.-X.a , Ighodaro, E.a , Artiushin, S.a , Nichols, C.G.d , Fardo, D.W.a e
ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target
(2015) Ageing Research Reviews, . Article in Press. 

DOI: 10.1016/j.arr.2015.07.007


a University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA
b University of Kentucky, Department of Pathology, Lexington, KY 40536, USA
c University of Kentucky, Department of Neurology, Lexington, KY, 40536, USA
d Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110, USA
e Department of Biostatistics, Lexington, KY, 40536, USA


Abstract
The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium ("K<inf>ATP</inf>") channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K<inf>ATP</inf> channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a "druggable target", relevant perhaps to both HS-Aging and Alzheimer's disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions. © 2015 Elsevier B.V.


Author Keywords
ABCC8;  Arteriolosclerosis;  GWAS;  Hippocampus;  Neuropathology;  Oldest-old;  SUR1;  SUR2A;  SUR2Ab;  SUR2B


Document Type: Article in Press
Source: Scopus




Salt, A.N., Gill, R.M., Hartsock, J.J.
Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid
(2015) JARO - Journal of the Association for Research in Otolaryngology, 16 (3), pp. 357-371. 

DOI: 10.1007/s10162-015-0512-1


Department of Otolaryngology, Washington University School of Medicine, Box 8115, 660, South Euclid Avenue, St. Louis, MO, United States


Abstract
Understanding how drugs are distributed in perilymph following local applications is important as local drug therapies are increasingly used to treat disorders of the inner ear. The potential contribution of cerebrospinal fluid (CSF) entry to perilymph homeostasis has been controversial for over half a century, largely due to artifactual contamination of collected perilymph samples with CSF. Measures of perilymph flow and of drug distribution following round window niche applications have both suggested a slow, apically directed flow occurs along scala tympani (ST) in the normal, sealed cochlea. In the present study, we have used fluorescein isothiocyanate-dextran as a marker to study perilymph kinetics in guinea pigs. Dextran is lost from perilymph more slowly than other substances so far quantified. Dextran solutions were injected from pipettes sealed into the lateral semicircular canal (SCC), the cochlear apex, or the basal turn of ST. After varying delays, sequential perilymph samples were taken from the cochlear apex or lateral SCC, allowing dextran distribution along the perilymphatic spaces to be quantified. Variability was low and findings were consistent with the injection procedure driving volume flow towards the cochlear aqueduct, and with volume flow during perilymph sampling driven by CSF entry at the aqueduct. The decline of dextran with time in the period between injection and sampling was consistent with both a slow volume influx of CSF (
30 nL/min) entering the basal turn of ST at the cochlear aqueduct and a CSF-perilymph exchange driven by pressure-driven fluid oscillation across the cochlear aqueduct. Sample data also allowed contributions of other processes, such as communications with adjacent compartments, to be quantified. The study demonstrates that drug kinetics in the basal turn of ST is complex and is influenced by a considerable number of interacting processes. © 2015, Association for Research in Otolaryngology.


Author Keywords
blood-labyrinth barrier;  cochlea;  perilymph pharmacokinetics;  round window


Document Type: Article
Source: Scopus




Faughn, C.a g , Marrus, N.b , Shuman, J.c , Ross, S.R.d , Constantino, J.N.e , Pruett, J.R., Jr.b , Povinelli, D.J.f
Brief Report: Chimpanzee Social Responsiveness Scale (CSRS) Detects Individual Variation in Social Responsiveness for Captive Chimpanzees
(2015) Journal of Autism and Developmental Disorders, 45 (5), pp. 1483-1488. 

DOI: 10.1007/s10803-014-2273-9


a Institute of Cognitive Science, University of Louisiana at Lafayette, Lafayette, LA, United States
b Department of Psychiatry, Washington University School of Medicine, 660 So. Euclid Avenue, Campus Box 8134, St. Louis, MO, United States
c Clinical Psychology, Indiana State University, Terre Haute, IN, United States
d Lester E. Fisher Center for the Study and Conservation of Apes at Lincoln Park Zoo, Chicago, IL, United States
e Department of Psychiatry (Child Division) and Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Biology, University of Louisiana at Lafayette, Lafayette, LA, United States
g 143 Le Medecin Rd., Carencro, LA, United States


Abstract
Comparative studies of social responsiveness, a core impairment in autism spectrum disorder (ASD), will enhance our understanding of typical and atypical social behavior. We previously reported a quantitative, cross-species (human–chimpanzee) social responsiveness measure, which included the development of the Chimpanzee Social Responsiveness Scale (CSRS). Here, we augment our prior CSRS sample with 25 zoo chimpanzees at three sites: combined N = 54. The CSRS demonstrated strong interrater reliability, and low-ranked chimpanzees, on average, displayed higher CSRS scores. The CSRS continues to discriminate variation in chimpanzee social responsiveness, and the association of higher scores with lower chimpanzee social standing has implications for the relationship between autistic traits and human social status. Continued comparative investigations of social responsiveness will enhance our understanding of underlying impairments in ASD, improve early diagnosis, and inform future therapies. © 2014, Springer Science+Business Media New York.


Author Keywords
Autism;  Chimpanzee;  Comparative cognition;  Nonhuman primate;  Social Responsiveness Scale


Document Type: Article
Source: Scopus




Jellinger, K.A.a , Alafuzoff, I.b , Attems, J.c , Beach, T.G.d , Cairns, N.J.e , Crary, J.F.f , Dickson, D.W.g , Hof, P.R.h , Hyman, B.T.i , Jack, C.R., Jr.j , Jicha, G.A.k , Knopman, D.S.l , Kovacs, G.G.m , Mackenzie, I.R.n , Masliah, E.o p , Montine, T.J.q , Nelson, P.T.r , Schmitt, F.k , Schneider, J.A.s t , Serrano-Pozo, A.u , Thal, D.R.v , Toledo, J.B.w , Trojanowski, J.Q.w , Troncoso, J.C.x , Vonsattel, J.P.f , Wisniewski, T.y z aa
PART, a distinct tauopathy, different from classical sporadic Alzheimer disease
(2015) Acta Neuropathologica, 129 (5), pp. 757-762. 

DOI: 10.1007/s00401-015-1407-2


a Institute of Clinical Neurobiology, Vienna, Austria
b Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
c Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom
d Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, United States
e Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
f Department of Pathology and Cell Biology and The Taub Institute for Research on Alzheimer’s Disease and The Aging Brain, Columbia University Medical Center, New York, NY, United States
g Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States
h Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
i Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, United States
j Department of Radiology, Mayo Clinic, Rochester, MN, United States
k Department of Neurology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
l Department of Neurology, Mayo Clinic, Rochester, MN, United States
m Institute of Neurology, Medical University of Vienna, Vienna, Austria
n Department of Pathology, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, Canada
o Department of Neurosciences, University of California San Diego, La Jolla, CA, United States
p Department of Pathology, University of California San Diego, La Jolla, CA, United States
q Department of Pathology, University of Washington, Seattle, WA, United States
r Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
s Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, IL, United States
t Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
u Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
v Laboratory of Neuropathology, Institute of Pathology, Center for Biomedical Research, Ulm University, Helmholtzstrasse 8/1, Ulm, Germany
w Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, United States
x Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
y Department of Neurology, New York University School of Medicine, New York, NY, United States
z Department of Pathology, New York University School of Medicine, New York, NY, United States
aa Department of Psychiatry, New York University School of Medicine, New York, NY, United States


Document Type: Letter
Source: Scopus




Baker, L.M.a , Paul, R.H.a , Heaps-Woodruff, J.M.a , Chang, J.Y.b , Ortega, M.b , Margolin, Z.b , Usher, C.a , Basco, B.b , Cooley, S.a , Ances, B.M.b c d
The Effect of Central Nervous System Penetration Effectiveness of Highly Active Antiretroviral Therapy on Neuropsychological Performance and Neuroimaging in HIV Infected Individuals
(2015) Journal of Neuroimmune Pharmacology, 10 (3), pp. 487-492. 

DOI: 10.1007/s11481-015-9610-4


a Department of Psychology, University of Missouri- Saint Louis, Saint Louis, MO, United States
b Department of Neurology, Washington University in Saint Louis School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO, United States
c Department of Radiology, Washington University in Saint Louis, Saint Louis, MO, United States
d Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO, United States


Abstract
The incidence of HIV-associated dementia has been greatly reduced in the era of highly active antiretroviral therapy (HAART); however milder forms of cognitive impairment persist. It remains uncertain whether HAART regimens with a high degree of central nervous system penetration effectiveness (CPE) exert beneficial neurological outcomes in HIV-infected (HIV+) individuals on stable treatment. Sixty-four HIV-infected adults on HAART were assigned a CPE score using a published ranking system and divided into high (≥7; n = 35) and low (<7; n = 29) CPE groups. All participants completed neuropsychological testing in addition to structural neuroimaging. Neuropsychological tests included measures known to be sensitive to HIV with values converted into standardized scores (NPZ-4) based on published normative scores. A semi-automated methodology was utilized to assess brain volumetrics within cortical (grey and white matter) and subcortical (thalamus, caudate, putamen) regions of interest. Analyses assessed NPZ-4 and brain volumetric differences between HIV+ individuals with high and low CPE scores. No significant differences in brain integrity were observed between the two groups. Long-term HAART regimens with a high degree of CPE were not associated with significantly improved neuropsychological or neuroimaging outcomes in HIV+ adults. Results suggest that alternate mechanisms may potentially contribute to better neurological outcomes in the era of HAART. © 2015, Springer Science+Business Media New York.


Author Keywords
Brain volumetrics;  CPE;  HIV;  Magnetic resonance imaging;  Neuropsychological performance


Document Type: Article
Source: Scopus




Radmanesh, A.a b , Greenberg, J.K.c , Chatterjee, A.b , Smyth, M.D.c , Limbrick, D.D., Jr.c , Sharma, A.b
Tonsillar pulsatility before and after surgical decompression for children with Chiari malformation type 1: an application for true fast imaging with steady state precession
(2015) Neuroradiology, 57 (4), pp. 387-393. 

DOI: 10.1007/s00234-014-1481-5


a Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Ave, L-352, San Francisco, CA, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, United States


Abstract
Introduction: We hypothesize that surgical decompression for Chiari malformation type 1 (CM-1) is associated with statistically significant decrease in tonsillar pulsatility and that the degree of pulsatility can be reliably assessed regardless of the experience level of the reader.

Methods: An Institutional Review Board (IRB)-approved Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study was performed on 22 children with CM-1 (8 males; mean age 11.4 years) who had cardiac-gated true-FISP sequence and phase-contrast cerebrospinal fluid (CSF) flow imaging as parts of routine magnetic resonance (MR) imaging before and after surgical decompression. The surgical technique (decompression with or without duraplasty) was recorded for each patient. Three independent radiologists with different experience levels assessed tonsillar pulsatility qualitatively and quantitatively and assessed peritonsillar CSF flow qualitatively. Results were analyzed. To evaluate reliability, Fleiss kappa for multiple raters on categorical variables and intra-class correlation for agreement in pulsatility ratings were calculated.

Results: After surgical decompression, the degree of tonsillar pulsatility appreciably decreased, confirmed by t test, both qualitatively (p values <0.001, <0.001, and 0.045 for three readers) and quantitatively (amount of decrease/p value for three readers 0.7 mm/<0.001, 0.7 mm/<0.001, and 0.5 mm/0.022). There was a better agreement among the readers in quantitative assessment of tonsillar pulsatility (kappa 0.753–0.834), compared to qualitative assessment of pulsatility (kappa 0.472–0.496) and qualitative assessment of flow (kappa 0.056 to 0.203). Posterior fossa decompression with duraplasty led to a larger decrease in tonsillar pulsatility, compared to posterior fossa decompression alone.

Conclusion: Tonsillar pulsatility in CM-1 is significantly reduced after surgical decompression. Quantitative assessment of tonsillar pulsatility was more reliable across readers than qualitative assessments of tonsillar pulsatility or CSF flow. © 2015, Springer-Verlag Berlin Heidelberg.


Author Keywords
Cerebellar tonsil;  Chiari malformation;  Flow imaging;  Posterior fossa decompression;  TrueFISP


Document Type: Article
Source: Scopus




Ning, M.S.a , Perkins, S.M.b , Dewees, T.b , Shinohara, E.T.a
Evidence of high mortality in long term survivors of childhood medulloblastoma
(2015) Journal of Neuro-Oncology, 122 (2), pp. 321-327. 

DOI: 10.1007/s11060-014-1712-y


a Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave B1003, Nashville, TN, United States
b Department of Radiation Oncology, Washington University School of Medicine, 4921 Parkview Place, CAM LL, Saint Louis, MO, United States


Abstract
The diagnosis of pediatric medulloblastoma now carries a much improved overall survival; however as outcomes advance, late mortality, from causes such as disease recurrence and subsequent malignancies, are of increasing concern for these patients. Using the Surveillance, Epidemiology, and End Results database, the causes of late mortality in long term survivors of medulloblastoma were evaluated. Patients diagnosed with a medulloblastoma between the ages of 0–19 years who survived at least 5 years after diagnosis were included. Using U.S. population data, standardized mortality ratios (SMRs) were calculated. Cumulative incidence estimates and standardized incidence ratios (SIRs) of subsequent malignancies were calculated. A total of 455 patients were included in the analysis. All patients received radiation as part of therapy. Median age at diagnosis was 7 years, and mean follow-up was 16 years. By the time of last follow-up, 20.4 % of patients had died, representing an SMR of 24.0 (95 % CI 19.3–29.4). Overall survival at 30 years was 65.5 %. Primary recurrence accounted for 59 % of late deaths, while subsequent malignancy accounted for 11.8 %. SIR for subsequent malignancy in these patients was 10.4 (95 % CI 6.9–15.1). The most common secondary tumor was another brain tumor (32 %), followed by thyroid cancer (21 %). These data demonstrate that late mortality remains a significant problem in these patients. The causes of death are largely attributable to disease recurrence and secondary malignancies. Efforts to improve risk stratification and tailor therapy will help in reducing late mortality in this population. © 2015, Springer Science+Business Media New York.


Author Keywords
Locoregional;  Neoplasm recurrence;  Pediatrics;  Second Malignancy;  SEER program;  Side effect


Document Type: Article
Source: Scopus




Lilienthal, L.a , Rose, N.S.b , Tamez, E.a , Myerson, J.a , Hale, S.a
Individuals with low working memory spans show greater interference from irrelevant information because of poor source monitoring, not greater activation
(2015) Memory and Cognition, 43 (3), pp. 357-366. Cited 1 time.

DOI: 10.3758/s13421-014-0465-3


a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States


Abstract
Although individuals with high and low working memory (WM) span appear to differ in the extent to which irrelevant information interferes with their performance on WM tasks, the locus of this interference is not clear. The present study investigated whether, when performing a WM task, high- and low-span individuals differ in the activation of formerly relevant, but now irrelevant items, and/or in their ability to correctly identify such irrelevant items. This was done in two experiments, both of which used modified complex WM span tasks. In Experiment 1, the span task included an embedded lexical decision task designed to obtain an implicit measure of the activation of both currently and formerly relevant items. In Experiment 2, the span task included an embedded recognition judgment task designed to obtain an explicit measure of both item and source recognition ability. The results of these experiments indicate that low-span individuals do not hold irrelevant information in a more active state in memory than high-span individuals, but rather that low-span individuals are significantly poorer at identifying such information as irrelevant at the time of retrieval. These results suggest that differences in the ability to monitor the source of information, rather than differences in the activation of irrelevant information, are the more important determinant of performance on WM tasks. © 2014, Psychonomic Society, Inc.


Author Keywords
Individual differences;  Irrelevant information;  Source memory;  Working memory


Document Type: Article
Source: Scopus




Malanowski, S.b , Baima, N.a
On Treating Athletes with Banned Substances: The Relationship Between Mild Traumatic Brain Injury, Hypopituitarism, and Hormone Replacement Therapy
(2015) Neuroethics, 8 (1), pp. 27-38. 

DOI: 10.1007/s12152-014-9215-2


a The Department of Philosophy, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States
b The Department of Philosophy, Philosophy-Neuroscience-Psychology program, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States


Abstract
Until recently, the problem of traumatic brain injury in sports and the problem of performance enhancement via hormone replacement have not been seen as related issues. However, recent evidence suggests that these two problems may actually interact in complex and previously underappreciated ways. A body of recent research has shown that traumatic brain injuries (TBI), at all ranges of severity, have a negative effect upon pituitary function, which results in diminished levels of several endogenous hormones, such as growth hormone and gonadotropin. This is a cause for concern for many popular sports that have high rates of concussion, a mild form of TBI. Emerging research suggests that hormone replacement therapy is an effective treatment for TBI-related hormone deficiency. However, many athletic organizations ban or severely limit the use of hormone replacing substances because many athletes seek to use them solely for the purposes of performance enhancement. Nevertheless, in the light of the research linking traumatic brain injury to hypopituitarism, this paper argues that athletic organizations’ policies and attitudes towards hormone replacement therapy should change. We defend two claims. First, because of the connection between TBI and pituitary function, it is likely many more athletes than previously acknowledged suffer from hormone deficiency and thus could benefit from hormone replacement therapy. Second, athletes’ hormone levels should be tested more rigorously and frequently with an emphasis on monitoring TBI and TBI-related issues, rather than simply monitoring policy violations. © 2014, Springer Science+Business Media Dordrecht.


Author Keywords
Biomedical ethics;  Concussions;  Enhancement;  Hormones;  Sports;  Traumatic brain injury


Document Type: Article
Source: Scopus




Lee, A.J.a , Bosch, R.J.a , Evans, S.R.a , Wu, K.a , Harrison, T.b , Grant, P.c , Clifford, D.B.d
Patterns of peripheral neuropathy in ART-naïve patients initiating modern ART regimen
(2015) Journal of NeuroVirology, 21 (2), pp. 210-218. 

DOI: 10.1007/s13365-015-0327-1


a Center for Biostatistics in AIDS Research, Department of Biostatistics, FXB 604B, Harvard School of Public Health, 651 Huntington Avenue, Boston, MA, United States
b Department of Neurology, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, United States
c Department of Medicine-Infectious Disease, Stanford School of Medicine, Stanford, CA, United States
d Department of Neurology, Washington University, Saint Louis, Mo, United States


Abstract
The purpose of this study was to evaluate associations of pre-ART CD4 with peripheral neuropathy (PN) and estimate the prevalence of PN in HIV-positive patients starting modern combination antiretroviral therapy (cART) regimens. ART-naïve subjects initiating cART were followed longitudinally and screened for signs/symptoms of PN. Lower pre-ART CD4 count was associated with post-ART PN. After 7 years (n = 117), the prevalence (95 % CI) of PN and SPN were 31 % (23, 40 %) and 5 % (2, 11 %) with pre-ART CD4 count >250 copies/μL. PN continues to be identified in HIV-infected individuals on modern cART by targeted assessment but is generally without symptoms. © 2015, Journal of NeuroVirology, Inc.


Author Keywords
Higher pre-ART CD4 count;  HIV;  Modern non-neurotoxic ART;  Peripheral neuropathy;  Risk factors;  Symptomatic peripheral neuropathy


Document Type: Article
Source: Scopus




Reddy, L.V., Miller, T.M.
RNA-targeted Therapeutics for ALS
(2015) Neurotherapeutics, 12 (2), pp. 424-427. 

DOI: 10.1007/s13311-015-0344-z


Department of Neurology, Washington University, 660 S. Euclid, St. Louis, MO, United States


Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to cell death of predominantly motor neurons. Despite extensive research in this disease, finding a way to slow the progress of the disease has been challenging. RNA-targeted therapeutic approaches, including small interfering RNA and antisense oligonucleotides are being developed for genetic forms of ALS. ALS provides an unique opportunity for the use of RNA inhibition strategies given a well-defined animal model, extensive available information regarding the causative genes, and recent experience in phase 1 clinical trial. © 2015, The American Society for Experimental NeuroTherapeutics, Inc.


Author Keywords
Amyotrophic lateral sclerosis;  Antisense oligonucleotides;  RNA interference;  siRNA


Document Type: Review
Source: Scopus




Heaps, J.M.a , Sithinamsuwan, P.b , Paul, R.a , Lerdlum, S.e , Pothisri, M.d , Clifford, D.c , Tipsuk, S.k , Catella, S.f , Busovaca, E.g , Fletcher, J.L.K.k , Raudabaugh, B.h , Ratto-Kim, S.i j , Valcour, V.f , Ananworanich, J.i j
Association between brain volumes and HAND in cART-naïve HIV+ individuals from Thailand
(2015) Journal of NeuroVirology, 21 (2), pp. 105-112. 

DOI: 10.1007/s13365-014-0309-8


a Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, MO, United States
b Department of Medicine, Division of Neurology, Phramongkutklao Hospital, Bangkok, Thailand
c Department of Neurology, Washington University, St. Louis, MO, United States
d Chulalongkorn University Hospital, Bangkok, Thailand
e Chulalongkorn University, Bangkok, Thailand
f Memory and Aging Center, UCSF Department of Neurology, University of California, San Francisco, CA, United States
g Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
h Columbia University School of Nursing, New York, NY, United States
i U.S. Military HIV Research Program, Walter Reed Army Institute of Research Silver Spring, MD., Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
j SEARCH, The Thai Red Cross AIDS Research Center, Bangkok, Thailand
k Memory and Aging Center, UCSF Department of Neurology, University of California, San Francisco, CA, United States


Abstract
This study aimed to determine the effects of human immunodeficiency virus (HIV) on brain structure in HIV-infected individuals with and without HIV-associated neurocognitive disorders (HAND). Twenty-nine HIV-uninfected controls, 37 HIV+, treatment-naïve, individuals with HAND (HIV+HAND+; 16 asymptomatic neurocognitive impairment (ANI), 12 mild neurocognitive disorder (MND), and 9 HIV-associated dementia HAD), and 37 HIV+, treatment-naïve, individuals with normal cognitive function (HIV+HAND−) underwent magnetic resonance imaging (MRI) and neuropsychological assessment. The HIV-infected participants had a mean (SD) age of 35 (7) years, mean (interquartile range (IQR)) CD4 count of 221 (83–324), and mean (IQR) log<inf>10</inf> plasma viral load of 4.81 (4.39–5.48). Six regions of interest were selected for analyses including total and subcortical gray matter, total white matter, caudate, corpus callosum, and thalamus. The HIV+/HAND+ group exhibited significantly smaller brain volumes compared to the HIV-uninfected group in subcortical gray and total gray matter; however, there were no statistically significant differences in brain volumes between the HIV+HAND+ and HIV+HAND− groups or between HIV+/HAND− and controls. CD4 count at time of combination antiretroviral therapy (cART) initiation was associated with total and subcortical gray matter volumes but not with cognitive measures. Plasma viral load correlated with neuropsychological performance but not brain volumes. The lack of significant differences in brain volumes between HIV+HAND+ and HIV+HAND− suggests that brain atrophy is not a sensitive measure of HAND in subjects without advanced immunosuppression. Alternatively, current HAND diagnostic criteria may not sufficiently distinguish patients based on MRI measures of brain volumes. © 2015, Journal of NeuroVirology, Inc.


Author Keywords
Cognition;  HIV-associated neurocognitive disorder;  Neuroimaging;  Thailand


Document Type: Article
Source: Scopus




Patterson, B.W.a , Elbert, D.L.b , Mawuenyega, K.G.c , Kasten, T.c , Ovod, V.c , Ma, S.d , Xiong, C.d g , Chott, R.a , Yarasheski, K.a , Sigurdson, W.c g , Zhang, L.h , Goate, A.e h h , Benzinger, T.f g , Morris, J.C.c g , Holtzman, D.c g h , Bateman, R.J.c g h
Age and amyloid effects on human central nervous system amyloid-beta kinetics
(2015) Annals of Neurology, 78 (3), pp. 439-453. 

DOI: 10.1002/ana.24454


a Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States
d Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
g Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Hope Center for Neurological Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Objective: Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aβ) kinetics in the central nervous system (CNS) of humans. Methods: Aβ kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition. Results: We found a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate. Interpretation: These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aβ turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aβ kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies. © 2015 American Neurological Association.


Document Type: Article
Source: Scopus




De Maria, A., Bassnett, S.
Birc7: A late fiber gene of the crystalline lens
(2015) Investigative Ophthalmology and Visual Science, 56 (8), pp. 4823-4834. 

DOI: 10.1167/iovs.15-16968


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


Abstract
PURPOSE. A distinct subset of genes, so-called “late fiber genes,” is expressed in cells bordering the central, organelle-free zone (OFZ) of the lens. The purpose of this study was to identify additional members of this group. METHODS. Fiber cells were harvested from various layers of the lens by laser micro-dissection and subjected to microarray, in situ hybridization, and Western blot analysis. RESULTS. Expression of Livin, a member of the inhibitor of apoptosis protein (IAP) family encoded by Birc7, was strongly upregulated in deep cortical fiber cells. The depth-dependent distribution of Livin mRNA was confirmed by quantitative PCR and in situ hybridization. The onset of Livin expression coincided with loss of organelles from primary fiber cells. Livin expression peaked at 1 month but was sustained even in aged lenses. Antibodies raised against mouse Livin labeled multiple bands on immunoblots, reflecting progressive proteolysis of the parent molecule during differentiation. Mice harboring a floxed Birc7 allele were generated and used to conditionally delete Birc7 in lens. Lenses from knockout mice grew normally and retained their transparency, suggesting that Livin does not have an indispensable role in fiber cell differentiation. CONCLUSIONS. Birc7 is a late fiber gene of the mouse lens. In tumor cells, Livin acts as an antiapoptotic protein, but its function in the lens is enigmatic. Livin is a RING domain protein with putative E3 ubiquitin ligase activity. Its expression in cells bordering the OFZ is consistent with a role in organelle degradation, a process in which the ubiquitin proteasome pathway has been implicated previously. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
Apoptosis;  Fiber cell differentiation;  Hypoxia;  Livin;  Organelle degradation


Document Type: Article
Source: Scopus




Huff, M.J.a , Bodner, G.E.b , Fawcett, J.M.c
Effects of distinctive encoding on correct and false memory:A meta-analytic review of costs and benefits and their origins in the DRM paradigm
(2015) Psychonomic Bulletin and Review, 22 (2), pp. 349-365. 

DOI: 10.3758/s13423-014-0648-8


a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b University of Calgary, Calgary, AB, Canada
c MRC Cognition and Brain Sciences Unit, Cambridge, United Kingdom


Abstract
We review and meta-analyze how distinctive encoding alters encoding and retrieval processes and, thus, affects correct and false recognition in the Deese–Roediger–McDermott (DRM) paradigm. Reductions in false recognition following distinctive encoding (e.g., generation), relative to a nondistinctive read-only control condition, reflected both impoverished relational encoding and use of a retrieval-based distinctiveness heuristic. Additional analyses evaluated the costs and benefits of distinctive encoding in within-subjects designs relative to between-group designs. Correct recognition was design independent, but in a within design, distinctive encoding was less effective at reducing false recognition for distinctively encoded lists but more effective for nondistinctively encoded lists. Thus, distinctive encoding is not entirely “cost free” in a within design. In addition to delineating the conditions that modulate the effects of distinctive encoding on recognition accuracy, we discuss the utility of using signal detection indices of memory information and memory monitoring at test to separate encoding and retrieval processes. © 2014, The Author(s).


Author Keywords
Distinctiveness;  DRM paradigm;  Encoding;  Meta-analysis;  Recognition;  Retrieval


Document Type: Review
Source: Scopus




Wu, X.a , Eggebrecht, A.T.b , Ferradal, S.L.c , Culver, J.P.b d , Dehghani, H.a
Efficient method for near real-time diffuse optical tomography of the human brain
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9538, art. no. 953804, . 

DOI: 10.1117/12.2183723


a School of Computer Science, University of Birmingham, Birmingham, United Kingdom
b Department of Radiology, Washington University School of Medicine, 4525 Scott Avenue, St Louis, MO, United States
c Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, United States
d Department of Biomedical Engineering, Washington University, One Brookings Drive, St. Louis, MO, United States


Abstract
Previous studies have showed only regions with a sensitivity higher that 1% of the maximum value can affect the recovery result for diffuse optical tomography (DOT). Two methods of efficient sensitivity map generation based on Finite Element Models (FEM) are developed based on (1) reduced sensitivity matrix and (2) parallelisation process. Time and memory efficiency of these processes are evaluated and compared with conventional methods. It is shown that the computational time for a full head model containing 200k nodes is reduced from 3 hours to 48 minutes and the required memory is reduced from 5.5 GB to 0.5 GB. For a range of mesh densities up to 320k nodes, the required memory is improved by
1000% and computational time by 400% to allow near real-time image recovery. © 2015 SPIE.


Author Keywords
Diffuse optical tomography;  efficient sensitivity matrix generation;  reduced sensitivity matrix


Document Type: Conference Paper
Source: Scopus




Sheybani, A.a , Reitsamer, H.b c , Ahmed, I.I.K.d e f
Fluid dynamics of a novel micro-fistula implant for the surgical treatment of glaucoma
(2015) Investigative Ophthalmology and Visual Science, 56 (8), pp. 4789-4795. 

DOI: 10.1167/iovs.15-16625


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Ophthalmology, University Clinic Salzburg/SALK, Austria
c Paracelsus Medical University, Salzburg, Austria
d Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
e Credit Valley Eye Care, Mississauga, ON, Canada
f Trillium Health Partners, Mississauga, ON, Canada


Abstract
PURPOSE. The purpose of this study was to describe the fluidics of a novel non-valved glaucoma implant designed to prevent hypotony and compare the fluidics of this device with two commonly used non-valved glaucoma devices. METHODS. The XEN 45 micro-fistula implant was designed to limit hypotony by virtue of its length and width according to the Hagen-Poiseuille equation. Flow testing was performed using a syringe pump and pressure transducer at multiple flow rates. The pressure differentials across the XEN implant, the Ex-Press implant, and 10 mm of silicone tubing from a Baerveldt implant at a physiologic flow rate (2.5 µL/min) were extrapolated. RESULTS. The XEN 45 achieved a steady-state pressure calculated at 7.56 mm Hg at 2.5 µL/min. At the same flow rate, the Ex-Press device and Baerveldt tubing reached steady-state pressures of 0.09 and 0.01 mm Hg, respectively. CONCLUSIONS. Under flow testing, the XEN micro-fistula implant was able to maintain backpressure above numerical hypotony levels without the use of complex valve systems. This is due to the XEN implant’s design, derived from the principles that dictate Newtonian fluids. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
Fluidics;  Glaucoma surgery;  MIGS


Document Type: Article
Source: Scopus




Avetisyan, M.a b , Wang, H.a b , Schill, E.M.a b , Bery, S.d , Grider, J.R.e , Hassell, J.A.f , Stappenbeck, T.b c , Heuckeroth, R.O.a b d
Hepatocyte growth factor and MET support mouse enteric nervous system development, the peristaltic response, and intestinal epithelial proliferation in response to injury
(2015) Journal of Neuroscience, 35 (33), pp. 11543-11558. 

DOI: 10.1523/JNEUROSCI.5267-14.2015


a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Regenerative and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, United States
e Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
f Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada


Abstract
Factors providing trophic support to diverse enteric neuron subtypes remain poorly understood. We tested the hypothesis that hepatocyte growth factor (HGF) and the HGF receptor MET might support some types of enteric neurons. HGF and MET are expressed in fetal and adult enteric nervous system. In vitro, HGF increased enteric neuron differentiation and neurite length, but only if vanishingly small amounts (1 pg/ml) of glial cell line-derived neurotrophic factor were included in culture media. HGF effects were blocked by phosphatidylinositol-3 kinase inhibitor and by MET-blocking antibody. Both of these inhibitors and MEK inhibition reduced neurite length. In adult mice, MET was restricted to a subset of calcitonin gene-related peptide-immunoreactive (IR) myenteric plexus neurons thought to be intrinsic primary afferent neurons (IPANs). Conditional MET kinase domain inactivation (Metfl/fl; Wnt1Cre+) caused a dramatic loss of myenteric plexus MET-IR neurites and 1–1′-dioctodecyl-3,3,3′,3′-tetramethylindocarbocyamine perchlorate (DiI) labeling suggested reduced MET-IR neurite length. In vitro, Metfl/fl; Wnt1Cre+ mouse bowel had markedly reduced peristalsis in response to mucosal deformation, but normal response to radial muscle stretch. However, whole-bowel transit, small-bowel transit, and colonic-bead expulsion were normal in Metfl/fl; Wnt1Cre+ mice. Finally, Metfl/fl; Wnt1Cre+ mice had more bowel injury and reduced epithelial cell proliferation compared with WT animals after dextran sodium sulfate treatment. These results suggest that HGF/MET signaling is important for development and function of a subset IPANs and that these cells regulate intestinal motility and epithelial cell proliferation in response to bowel injury. © 2015 the authors.


Author Keywords
Calcitonin gene-related peptide;  Dextran sodium sulfate (DSS);  Enteric nervous system;  Hepatocyte growth factor;  Intrinsic primary afferent neurons;  MET


Document Type: Article
Source: Scopus




Doyle, S.L.a , López, F.J.b , Celkova, L.c , Brennan, K.a , Mulfaul, K.a , Ozaki, E.c , Kenna, P.F.c d , Kurali, E.e , Hudson, N.c , Doggett, T.f , Ferguson, T.A.f , Humphries, P.c , Adamson, P.g h , Campbell, M.c
IL-18 immunotherapy for neovascular AMD: Tolerability and efficacy in nonhuman primates
(2015) Investigative Ophthalmology and Visual Science, 56 (9), pp. 5424-5430. Cited 1 time.

DOI: 10.1167/iovs.15-17264


a Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland
b Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, United States
c Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
d The Research Foundation, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin, Ireland
e Statistics Consulting Group, Quantitative Science, PTS, GlaxoSmithKline, King of Prussia, PA, United States
f Department of Ophthalmology and Visual Science, Washington University School of Medicine, St. Louis, MO, United States
g Ophthalmology Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom
h Ocular Biology and Therapeutics, Institute of Ophthalmology, University College London, London, United Kingdom


Abstract
PURPOSE. Age-related macular degeneration is the most common form of central retinal blindness in the elderly. Of the two end stages of disease, neovascular AMD-although the minority form- is the most severe. Current therapies are highly successful at controlling progression of neovascular lesions; however, a significant number of patients remain refractory to treatment and the development of alternative and additive therapies to anti-VEGFs is essential. METHODS. In order to address the translational potential of interleukin (IL)-18 for use in neovascular AMD, we initiated a nonhuman primate tolerability and efficacy study for the use of intravitreally (IVT) administered clinical grade human IL-18 (SB-485232). Cynomolgus monkeys were injected IVT with increasing doses of human IL-18 (two each at 1000, 3000, and 10,000 ng per eye). In tandem, 21 monkeys were administered nine laser burns in each eye prior to receiving IL-18 as an IVT injection at a range of doses. Fundus fluorescein angiography (FFA) was performed on days 8, 15, and 22 post injection and the development of neovascular lesions was assessed. RESULTS. We show intravitreal, mature, recombinant human IL-18 is safe and can reduce choroidal neovascular lesion development in cynomolgus monkeys. CONCLUSIONS. Based on our data comparing human IL-18 to current anti-VEGF-based therapy, clinical deployment of IL-18 for neovascular AMD has the potential to lead to a new adjuvant immunotherapy-based treatment for this severe form of central blindness. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
Age-related macular degeneration;  Immunotherapy;  Interleukin-18


Document Type: Article
Source: Scopus




Cicero, T.J., Ellis, M.S.
In reply
(2015) JAMA Psychiatry, 72 (8), pp. 850-851. 

DOI: 10.1001/jamapsychiatry.2015.0674


Department of Psychiatry, Washington University in St Louis, Campus B. 8134, 660 S Euclid Ave, St Louis, MO, United States


Document Type: Letter
Source: Scopus




Meyer, J.C.a , Ahmad, B.U.a , Blinder, K.J.a b , Shah, G.K.a
Laser therapy versus observation for symptomatic retinal artery macroaneurysms
(2015) Graefe's Archive for Clinical and Experimental Ophthalmology, 253 (4), pp. 537-541. 

DOI: 10.1007/s00417-014-2730-3


a The Retina Institute, 1600 S. Brentwood Blvd., Suite 800, St. Louis, MO, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Purpose: The optimal management approach to retinal arterial macroaneurysms (RAM) is unknown. This paper compares long-term outcomes in RAM treated with laser therapy versus observation. Methods: This is an IRB-approved retrospective study of patients with symptomatic RAM. Charts of patients with a diagnosis of RAM causing symptomatic visual loss were reviewed. Patients with less than 6 months follow up, other confounding diagnoses, or additional therapy beyond thermal laser were excluded. Statistical analysis was done using χ2 or Student’s t test as appropriate. Results: Forty-eight patients with RAM were identified and 27 were included in the study (13 treated, 14 observed). Mean visual acuity in the observation group improved from 20/120 to 20/96 (p = 0.53) compared to 20/280 to 20/54 (p = 0.0003) in the treated group. Subgroup analysis showed that visual acuity in primarily hemorrhagic lesions treated with laser therapy improved by 1.21 logMAR compared to a loss of 0.11 logMAR (p = 0.002) in those that were observed. In primarily exudative lesions, both treated and observed lesions showed an improvement of 0.32 logMAR. No patients in the treatment group had a final visual acuity below 20/200 compared to four in the observation group. Conclusion: Treatment with direct laser photocoagulation was associated in this study with greater improvement in visual acuity and may decrease the risk of severe visual loss especially in primarily hemorrhagic RAM lesions. Compared to observation alone. © 2014, Springer-Verlag Berlin Heidelberg.


Author Keywords
Retinal artery macroaneurysm;  Retinal vascular abnormality;  Thermal laser therapy


Document Type: Article
Source: Scopus




Kaufman, D.M.a b , Crowder, C.M.a c
Mitochondrial proteostatic collapse leads to hypoxic injury
(2015) Current Biology, 25 (16), pp. 2171-2176. 

DOI: 10.1016/j.cub.2015.06.062


a Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 850 Republican Street, N110, Seattle, WA, United States
b Medical Scientist Training Program, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
c Department of Genome Sciences, University of Washington School of Medicine, 850 Republican Street, N110, Seattle, WA, United States


Abstract
Hypoxic injury is a key pathological event in a variety of diseases. Despite the clinical importance of hypoxia, modulation of hypoxic injury mechanisms for therapeutic benefit has not been achieved, suggesting that critical features of hypoxic injury have not been identified or fully understood. Because mitochondria are the main respiratory organelles of the cell, they have been the focus of much research into hypoxic injury. Previous research has focused on mitochondria as effectors of hypoxic injury, primarily in the context of apoptosis activation [1] and calcium regulation [2]; however, little is known about how mitochondria themselves are injured by hypoxia. Maintenance of protein folding is essential for normal mitochondrial function [3], whereas failure to maintain protein homeostasis (proteostasis) appears to be a component of aging [4, 5] and a variety of diseases [6, 7]. Previously, it has been demonstrated that mitochondria possess their own unfolded protein response [8-10] that is activated in response to mitochondrial protein folding stress, a response that is best understood in C. elegans. Because hypoxia has been shown to disrupt ATP production and translation of nuclear encoded proteins [11] - both of which are shown to disrupt mitochondrial proteostasis in other contexts [3, 12] - we hypothesized that failure to maintain mitochondrial proteostasis may play a role in hypoxic injury. Utilizing C. elegans models of global [13, 14], focal [15], and cell non-autonomous hypoxic injury, we have found evidence of mitochondrial protein misfolding post-hypoxia and have found that manipulation of the mitochondrial protein folding environment is an effective hypoxia protective strategy. © 2015 Elsevier Ltd All rights reserved.


Document Type: Article
Source: Scopus




Munn-Chernoff, M.A.a , Keel, P.K.b , Klump, K.L.c , Grant, J.D.a , Bucholz, K.K.a , Madden, P.A.F.a , Heath, A.C.a , Duncan, A.E.a d
Prevalence of and familial influences on purging disorder in a community sample of female twins
(2015) International Journal of Eating Disorders, 48 (6), pp. 601-606. 

DOI: 10.1002/eat.22378


a Department of Psychiatry, Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychology, Florida State University, Tallahassee, FL, United States
c Department of Psychology, Michigan State University, East Lansing, MI, United States
d George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States


Abstract
Objective Purging disorder (PD) was recently included as an otherwise specified feeding or eating disorder (OSFED) in the DSM-5; however, limited information is available on its prevalence, and its etiology is unknown. Method Data from 1,790 monozygotic and 1,440 dizygotic European American female twins (age range = 18-29 years) from the Missouri Adolescent Female Twin Study were used to investigate prevalence and familial influences for PD. A structured clinical interview assessed lifetime DSM-IV criteria for eating disorders and PD. After adjustment for age, twin correlations and biometrical twin models were used to estimate familial (i.e., genetic plus shared environmental) influences on PD. Results One hundred and twenty one (3.77%; 95% CI: 3.14, 4.49) women met criteria for lifetime PD. Twin correlations suggested that genetic, shared environmental, and nonshared environmental factors influenced liability to PD. Nonshared environmental factors accounted for 56% [35%, 79%] of the variance in PD. Although familial effects accounted for a significant proportion of variance (44% [21%, 65%]), it was not possible to disentangle the independent contributions of additive genetic effects (20% [0%, 65%]) and shared environmental effects (24% [0%, 57%]). Discussion PD is a prevalent form of eating pathology. Familial factors are relevant to the development of PD but do not demonstrate the magnitude of heritable factors found for other eating disorders. © 2015 Wiley Periodicals, Inc.


Author Keywords
eating disorders;  genetics;  purging disorder;  twins;  women


Document Type: Article
Source: Scopus




Palmer, R.H.C.a b , Mcgeary, J.E.a b c , Heath, A.C.d , Keller, M.C.e , Brick, L.A.a , Knopik, V.S.a b
Shared additive genetic influences on DSM-IV criteria for alcohol dependence in subjects of European ancestry
(2015) Addiction, . Article in Press. 

DOI: 10.1111/add.13070


a Division of Behavioral Genetics, Department of Psychiatry Rhode Island Hospital Providence, RI USA
b Department of Psychiatry and Human Behavior Brown University Providence, RI USA
c Providence Veterans Affairs Medical Center Providence, RI USA
d Midwest Alcoholism Research Center, Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
e Department of Psychology and Neuroscience and Institute for Behavioral Genetics University of Colorado at Boulder Boulder, CO USA


Abstract
Background and Aims: Genetic studies of alcohol dependence (AD) have identified several candidate loci and genes, but most observed effects are small and difficult to reproduce. A plausible explanation for inconsistent findings may be a violation of the assumption that genetic factors contributing to each of the seven DSM-IV criteria point to a single underlying dimension of risk. Given that recent twin studies suggest that the genetic architecture of AD is complex and probably involves multiple discrete genetic factors, the current study employed common single nucleotide polymorphisms in two multivariate genetic models to examine the assumption that the genetic risk underlying DSM-IV AD is unitary. Design, Setting, Participants, Measurements: AD symptoms and genome-wide single nucleotide polymorphism (SNP) data from 2596 individuals of European descent from the Study of Addiction: Genetics and Environment were analyzed using genomic-relatedness-matrix restricted maximum likelihood. DSM-IV AD symptom covariance was described using two multivariate genetic factor models. Findings: Common SNPs explained 30% (standard error = 0.136, P = 0.012) of the variance in AD diagnosis. Additive genetic effects varied across AD symptoms. The common pathway model approach suggested that symptoms could be described by a single latent variable that had a SNP heritability of 31% (0.130, P = 0.008). Similarly, the exploratory genetic factor model approach suggested that the genetic variance/covariance across symptoms could be represented by a single genetic factor that accounted for at least 60% of the genetic variance in any one symptom. Conclusion: Additive genetic effects on DSM-IV alcohol dependence criteria overlap. The assumption of common genetic effects across alcohol dependence symptoms appears to be a valid assumption. © 2015 Society for the Study of Addiction.


Author Keywords
Alcohol dependence;  Alcoholism;  Diagnostic criteria;  DSM-IV;  GCTA;  Genetics


Document Type: Article in Press
Source: Scopus




Knauert, M.P.a , Haspel, J.A.b , Pisani, M.A.a
Sleep Loss and Circadian Rhythm Disruption in the Intensive Care Unit
(2015) Clinics in Chest Medicine, 36 (3), pp. 419-429. 

DOI: 10.1016/j.ccm.2015.05.008


a Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC-441 South, PO Box208057, New Haven, CT, United States
b Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, United States


Author Keywords
Circadian misalignment;  Circadian rhythm;  Critical illness;  Delirium;  Intensive care unit;  Sleep deprivation;  Sleep loss


Document Type: Review
Source: Scopus




Christopher, M.a b , Abrámoff, M.D.a b c d e , Tang, L.d , Gordon, M.O.f g , Kass, M.A.g , Budenz, D.L.h , Fingert, J.H.a d , Scheetz, T.E.a b d
Stereo photo measured ONH shape predicts development of POAG in subjects with ocular hypertension
(2015) Investigative Ophthalmology and Visual Science, 56 (8), pp. 4470-4479. 

DOI: 10.1167/iovs.14-16142


a Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, United States
b Department of Biomedical Engineering, University of Iowa, Iowa City, IA, United States
c Department of Electrical and Computer Engineering, University of Iowa, Iowa City, IA, United States
d Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States
e Department of Veterans Affairs, Iowa City VA Medical Center, Iowa City, IA, United States
f Division of Biostatistics, Washington University, St. Louis, MO, United States
g Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States
h Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, United States


Abstract
PURPOSE. To identify objective, quantitative optic nerve head (ONH) structural features and model the contributions of glaucoma. METHODS. Baseline stereoscopic optic disc images of 1635 glaucoma-free participants at risk for developing primary open-angle glaucoma (POAG) were collected as part of the Ocular Hypertension Treatment Study. A stereo correspondence algorithm designed for fundus images was applied to extract the three-dimensional (3D) information about the ONH. Principal component analysis was used to identify ONH 3D structural features and the contributions of demographic features, clinical variables, and disease were modeled using linear regression and linear component analysis. The computationally identified features were evaluated based on associations with glaucoma and ability to predict which participants would develop POAG. RESULTS. The computationally identified features were significantly associated with future POAG, POAG-related demographics (age, ethnicity), and clinical measurements (horizontal and vertical cup-to-disc ratio, central corneal thickness, and refraction). Models predicting future POAG development using the OHTS baseline data and STEP features achieved an AUC of 0.722 in cross-validation testing. This was a significant improvement over using only demographics (age, sex, and ethnicity), which had an AUC of 0.599. CONCLUSIONS. Methods for identifying objective, quantitative measurements of 3D ONH structure were developed using a large dataset. The identified features were significantly associated with POAG and POAG-related variables. Further, these features increased predictive model accuracy in predicting future POAG. The results indicate that the computationally identified features might be useful in POAG early screening programs or as endophenotypes to investigate POAG genetics. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
Image analysis;  Optic nerve head;  Primary open-angle glaucoma;  Stereo fundus;  Structural modeling


Document Type: Article
Source: Scopus




Feibel, R.M.
Sympathectomy for glaucoma: Its rise and fall (1898-1910)
(2015) Survey of Ophthalmology, 60 (5), pp. 500-507. 

DOI: 10.1016/j.survophthal.2015.02.003


Department of Ophthalmology and Visual Sciences, The Center for History Of Medicine, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The influence of the sympathetic nervous system upon intraocular pressure (IOP) has been a subject of great interest since 1727, when the first experimental ocular sympathetic paralysis was produced in dogs. By the middle of the 19th century, it was known that excision of the superior cervical sympathetic ganglion lowered, and that electrical stimulation of the sympathetic nerve trunk raised IOP in various animals. From these observations, it was thought that excision of this ganglion could replace or supplement the available operations for glaucoma of which iridectomy was the most popular. Iridectomy was acknowledged to be of great value in acute and subacute glaucoma, but less useful in chronic glaucoma. Iridectomy, however, was associated with major surgical complications and long-term failure, so that there was considerable appeal of an extraocular operation that avoided the risks of intraocular surgery. Beginning in 1898, cervical sympathectomy became a widely performed operation around the world, with most surgeons enthusiastic about its results, at least initially, and many publications from 1898 to 1905 claimed excellent results for various types of glaucoma. Opponents of the procedure emphasized that the effect on IOP was transient, and that the published reports of successful results were poorly documented. The popularity of sympathectomy gradually diminished and by 1910 it was abandoned. I discuss the reasons why cervical sympathectomy received such initial enthusiasm but was then questioned and discarded. These included bias from the surgeons promoting this surgery; the placebo effect; short follow-up; inaccurate, subjective, and variable measures of the surgical results; and the development of more effective procedures such as filtering surgery and cyclodialysis. © 2015 Elsevier Inc.


Author Keywords
Cervical sympathetic ganglia;  Glaucoma;  Intraocular pressure;  Sympathectomy for glaucoma;  Sympathetic nervous system


Document Type: Review
Source: Scopus




Sobaco, A.a , Treiman, R.b , Peereman, R.c , Borchardt, G.d , Pacton, S.a
The influence of graphotactic knowledge on adults’ learning of spelling
(2015) Memory and Cognition, 43 (4), pp. 593-604. 

DOI: 10.3758/s13421-014-0494-y


a Institut de Psychologie, Université Paris Descartes, INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France
b Psychology Department, Washington University in St. Louis, St. Louis, MO, United States
c Psychology Department, Université Grenoble Alpes, Grenoble, France
d Psychology Department, Université de Nîmes, Montpellier, France


Abstract
Three experiments investigated whether and how the learning of spelling by French university students is influenced by the graphotactic legitimacy of the spellings. Participants were exposed to three types of novel spellings: AB, which do not contain doublets (e.g., guprane); AAB, with a doublet before a single consonant, which is legitimate in French (e.g., gupprane); and ABB, with a doublet after a single consonant, which is illegitimate (e.g., guprrane). In Experiment 1, the nonwords were embedded within texts that participants read for meaning. In Experiment 2, participants read the nonwords in isolation, with or without instruction to memorize their spellings; they copied the nonwords in Experiment 3. In all of these conditions, AB and AAB spellings were learned more readily than ABB spellings. Although participants were highly knowledgeable about the illegitimacy of ABB spellings, the orthographic distinctiveness of these spellings did not make them easier to recall than legitimate spellings. When recalling ABB spellings, participants sometimes made transposition errors, doubling the wrong consonant of a cluster (e.g., spelling gupprane instead of guprrane). Participants almost never transposed the doubling for AAB items. Transposition errors, biased in the direction of replacing illegitimate with legitimate orthographic patterns, show that graphotactic knowledge influences memory for specific items. An analysis of the spellings produced in the copy phase and final recall test of Experiment 3 further suggests that transposition errors resulted not so much from reconstructive processes at the time of recall but from reconstructive processes or inefficient encoding at earlier points. © 2014, Psychonomic Society, Inc.


Author Keywords
Graphotactic regularities;  Implicit learning;  Reading;  Recall;  Spelling;  Statistical learning


Document Type: Article
Source: Scopus




Anokhin, A.P., Golosheykin, S.
Neural correlates of error monitoring in adolescents prospectively predict initiation of tobacco use
(2015) Developmental Cognitive Neuroscience, . Article in Press. 

DOI: 10.1016/j.dcn.2015.08.001


Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, PO Box 8134, St. Louis, MO 63105, USA


Abstract
Deficits in self-regulation of behavior can play an important role in the initiation of substance use and progression to regular use and dependence. One of the distinct component processes of self-regulation is error monitoring, i.e. detection of a conflict between the intended and actually executed action. Here we examined whether a neural marker of error monitoring, Error-Related Negativity (ERN), predicts future initiation of tobacco use. ERN was assessed in a prospective longitudinal sample at ages 12, 14, and 16 using a flanker task. ERN amplitude showed a significant increase with age during adolescence. Reduced ERN amplitude at ages 14 and 16, as well as slower rate of its developmental changes significantly predicted initiation of tobacco use by age 18 but not transition to regular tobacco use or initiation of marijuana and alcohol use. The present results suggest that attenuated development of the neural mechanisms of error monitoring during adolescence can increase the risk for initiation of tobacco use. The present results also suggest that the role of distinct neurocognitive component processes involved in behavioral regulation may be limited to specific stages of addiction. © 2015 The Authors.


Author Keywords
Adolescence;  ERN;  Error monitoring;  Longitudinal;  Substance use;  Tobacco


Document Type: Article in Press
Source: Scopus




Siemers, E.a , Dean, R.A.a , DeMattos, R.B.a , Hutton, M.L.b , Blennow, K.c , Shaw, L.M.d , Holtzman, D.M.e
Anti-Aβ antibody target engagement: commentary regarding Watt et al. Acta Neuropathol 127:803–810 (2014)
(2014) Acta Neuropathologica, 128 (4), pp. 609-610. 

DOI: 10.1007/s00401-014-1332-9


a Eli Lilly and Company, Indianapolis, IN, United States
b Eli Lilly and Company, Erl Wood, Surrey, United Kingdom
c Clinical Neurochemistry Lab. Dept. of Neuroscience and Physiology, University of Gothenburg, Mölndal Campus, Gothenburg, Sweden
d Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Neurology, Washington University, St. Louis, MO, United States


Document Type: Letter
Source: Scopus




Filas, B.A.a , Shah, N.S.a , Zhang, Q.a b , Shui, Y.-B.a , Lake, S.P.c , Beebe, D.C.a d
Quantitative imaging of enzymatic vitreolysis-induced fiber remodeling
(2014) Investigative Ophthalmology and Visual Science, 55 (12), pp. 8626-8637. 

DOI: 10.1167/iovs.14-15225


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Eye Center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
c Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO, United States
d Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
PURPOSE. Collagen fiber remodeling in the vitreous body has been implicated in cases of vitreomacular traction, macular hole, and retinal detachment, and also may occur during pharmacologic vitreolysis. The purpose of this study was to evaluate quantitative polarized light imaging (QPLI) as a tool for studying fiber organization in the vitreous and near the vitreoretinal interface in control and enzymatically perturbed conditions. METHODS. Fiber alignment was measured in anterior-posterior sections of bovine and porcine vitreous. Additional tests were performed on bovine lenses and nasal-temporal vitreous sections. Effects of proteoglycan degradation on collagen fiber alignment using trypsin and plasmin were assessed at the microstructural level using electron microscopy and at the global level using QPLI. RESULTS. Control vitreous showed fiber organization patterns consistent with the literature across multiple-length scales, including the global anterior-posterior coursing of vitreous fibers, as well as local fibers parallel to the equatorial vitreoretinal interface and transverse to the posterior interface. Proteoglycan digestion with trypsin or plasmin significantly increased fiber alignment throughout the vitreous (P < 0.01). The largest changes (3×) occurred in the posterior vitreous where fibers are aligned transverse to the posterior vitreoretinal interface (P < 0.01). CONCLUSIONS. Proteoglycan loss due to enzymatic vitreolysis differentially increases fiber alignment at locations where tractions are most common. We hypothesize that a similar mechanism leads to retinal complications during age-related vitreous degeneration. Structural changes to the entire vitreous body (as opposed to the vitreoretinal interface alone) should be evaluated during preclinical testing of pharmacological vitreolysis candidates. © 2014, The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
Collagen;  Plasmin;  Polarized light imaging;  Proteoglycans;  Trypsin;  Vitreoretinal traction;  Vitreous;  Vitreous degeneration


Document Type: Article
Source: Scopus




Wahlheim, C.N.
Testing can counteract proactive interference by integrating competing information
(2014) Memory and Cognition, 43 (1), pp. 27-38. Cited 1 time.

DOI: 10.3758/s13421-014-0455-5


Department of Psychology, Washington University, One Brookings Drive, St. Louis, MO, United States


Abstract
Testing initially learned information before presenting new information has been shown to counteract the deleterious effects of proactive interference by segregating competing sources of information. The present experiments were conducted to demonstrate that testing can also have its effects in part by integrating competing information. Variations of classic A–B, A–D paired-associate learning paradigms were employed that included two lists of word pairs and a cued-recall test. Repeated pairs appeared in both lists (A–B, A–B), control pairs appeared in List 2 only (A–B, C–D), and changed pairs appeared with the same cue in both lists but with different responses (A–B, A–D). The critical manipulation was whether pairs were tested or restudied in an interpolated phase that occurred between Lists 1 and 2. On a final cued-recall test, participants recalled List 2 responses and then indicated when they recollected that responses had earlier changed between lists. The change recollection measure indexed the extent to which competing responses were integrated during List 2. Change was recollected more often for tested than for restudied pairs. Proactive facilitation was obtained in cued recall when change was recollected, whereas proactive interference was obtained when change was not recollected. These results provide evidence that testing counteracted proactive interference in part by making List 1 responses more accessible during List 2, thus promoting integration and increasing later recollection of change. These results have theoretical implications because they show that testing can counteract proactive interference by integrating or segregating competing information. © 2014, Psychonomic Society, Inc.


Author Keywords
Change recollection;  Integration;  Proactive interference;  Reminding;  Testing effects

 


Document Type: Article
Source: Scopus