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WUSTL Neuroscience Publications Archive - May 2015

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May 25, 2015

Harpole, J.K.a , Levinson, C.A.b , Woods, C.M.a , Rodebaugh, T.L.b , Weeks, J.W.c , Brown, P.J.b d , Heimberg, R.G.e , Menatti, A.R.c , Blanco, C.d f , Schneier, F.d f , Liebowitz, M.d
Assessing the Straightforwardly-Worded Brief Fear of Negative Evaluation Scale for Differential Item Functioning Across Gender and Ethnicity
(2015) Journal of Psychopathology and Behavioral Assessment, 37 (2), pp. 306-317. 

DOI: 10.1007/s10862-014-9455-9


a Department of Psychology, University of KansasLawrence, KS, United States
b Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
c Department of Psychology, Ohio UniversityAthens, OH, United States
d Department of Psychiatry, Columbia University College of Physicians and SurgeonsNew York, NY, United States
e Department of Psychology, Temple UniversityPhiladelphia, PA, United States
f Anxiety Disorders Clinic, New York State Psychiatric InstituteNew York, NY, United States


Abstract
The Brief Fear of Negative Evaluation Scale (BFNE; Leary Personality and Social Psychology Bulletin, 9, 371–375, 1983) assesses fear and worry about receiving negative evaluation from others. Rodebaugh et al. Psychological Assessment, 16, 169–181, (2004) found that the BFNE is composed of a reverse-worded factor (BFNE-R) and straightforwardly-worded factor (BFNE-S). Further, they found the BFNE-S to have better psychometric properties and provide more information than the BFNE-R. Currently there is a lack of research regarding the measurement invariance of the BFNE-S across gender and ethnicity with respect to item thresholds. The present study uses item response theory (IRT) to test the BFNE-S for differential item functioning (DIF) related to gender and ethnicity (White, Asian, and Black). Six data sets consisting of clinical, community, and undergraduate participants were utilized (N = 2,109). The factor structure of the BFNE-S was confirmed using categorical confirmatory factor analysis, IRT model assumptions were tested, and the BFNE-S was evaluated for DIF. Item nine demonstrated significant non-uniform DIF between White and Black participants. No other items showed significant uniform or non-uniform DIF across gender or ethnicity. Results suggest the BFNE-S can be used reliably with men and women and Asian and White participants. More research is needed to understand the implications of using the BFNE-S with Black participants. © 2014, Springer Science+Business Media New York.


Author Keywords
Differential item functioning;  Fear of negative evaluation;  Item response theory;  Measurement invariance;  Social anxiety disorder


Document Type: Article
Source: Scopus




Li, J.M.a , Bentley, W.J.a , Snyder, A.Z.b c , Raichle, M.E.a b c , Snyder, L.H.a
Functional connectivity arises from a slow rhythmic mechanism
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (19), pp. E2527-E2535. 

DOI: 10.1073/pnas.1419837112


a Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, United States
b Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
The mechanism underlying temporal correlations among blood oxygen level-dependent signals is unclear. We used oxygen polarography to better characterize oxygen fluctuations and their correlation and to gain insight into the driving mechanism. The power spectrum of local oxygen fluctuations is inversely proportional to frequency raised to a power (1/f) raised to the beta, with an additional positive band-limited component centered at 0.06 Hz. In contrast, the power of the correlated oxygen signal is band limited from
.01 Hz to 0.4 Hz with a peak at 0.06 Hz. These results suggest that there is a band-limited mechanism (or mechanisms) driving interregional oxygen correlation that is distinct from the mechanism(s) driving local (1/f) oxygen fluctuations. Candidates for driving interregional oxygen correlation include rhythmic or pseudo-oscillatory mechanisms.


Author Keywords
Band-limited;  Criticality;  Oscillation;  Oxygen polarography;  Resting-state functional connectivity


Document Type: Article
Source: Scopus




Saha, D., Li, C., Peterson, S., Padovano, W., Katta, N., Raman, B.
Behavioural correlates of combinatorial versus temporal features of odour codes
(2015) Nature Communications, 6, art. no. 6953, . 

DOI: 10.1038/ncomms7953


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


Abstract
Most sensory stimuli evoke spiking responses that are distributed across neurons and are temporally structured. Whether the temporal structure of ensemble activity is modulated to facilitate different neural computations is not known. Here, we investigated this issue in the insect olfactory system. We found that an odourant can generate synchronous or asynchronous spiking activity across a neural ensemble in the antennal lobe circuit depending on its relative novelty with respect to a preceding stimulus. Regardless of variations in temporal spiking patterns, the activated combinations of neurons robustly represented stimulus identity. Consistent with this interpretation, locusts reliably recognized both solitary and sequential introductions of trained odourants in a quantitative behavioural assay. However, predictable behavioural responses across locusts were observed only to novel stimuli that evoked synchronized spiking patterns across neural ensembles. Hence, our results indicate that the combinatorial ensemble response encodes for stimulus identity, whereas the temporal structure of the ensemble response selectively emphasizes novel stimuli. © 2015 Macmillan Publishers Limited. All rights reserved.


Document Type: Article
Source: Scopus




Huh, S.-H.a , Warchol, M.E.b , Ornitz, D.M.a
Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling
(2015) eLife, 2015 (4), pp. 1-27. 

DOI: 10.7554/eLife.05921


a Departments of developmental Biology, Washington University School of MedicineSt. Louis, MO, United States
b Departments of Otolaryngology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
The sensory and supporting cells of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and supporting cells, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea. © 2015, eLife Sciences Publications Ltd. All rights reserved.


Author Keywords
Cochlea;  FGF20;  FGF9;  Mesenchyme;  Organ of Corti;  Sensory progenitor


Document Type: Article
Source: Scopus




Rokem, A.a , Yeatman, J.D.a b , Pestilli, F.a c , Kay, K.N.a d , Mezer, A.a e , Van Der Walt, S.f , Wandell, B.A.a
Evaluating the accuracy of diffusion MRI models in white matter
(2015) PLoS ONE, 10 (4), art. no. e0123272, . 

DOI: 10.1371/journal.pone.0123272


a Department of Psychology, StanfordStanford, CA, United States
b Institute for Learning and Brain Sciences, University of WashingtonSeattle, WA, United States
c Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana UniversityBloomington, IN, United States
d Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
e Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew UniversityGivat Ram, Jerusalem, Israel
f Division of Applied Mathematics, Stellenbosch UniversityStellenbosch, South Africa


Abstract
Models of diffusion MRI within a voxel are useful for making inferences about the properties of the tissue and inferring fiber orientation distribution used by tractography algorithms. A useful model must fit the data accurately. However, evaluations of model-accuracy of commonly used models have not been published before. Here, we evaluate model-accuracy of the two main classes of diffusion MRI models. The diffusion tensor model (DTM) summarizes diffusion as a 3-dimensional Gaussian distribution. Sparse fascicle models (SFM) summarize the signal as a sum of signals originating from a collection of fascicles oriented in different directions. We use cross-validation to assess model-accuracy at different gradient amplitudes (b-values) throughout the white matter. Specifically, we fit each model to all the white matter voxels in one data set and then use the model to predict a second, independent data set. This is the first evaluation of model-accuracy of these models. In most of the white matter the DTM predicts the data more accurately than test-retest reliability; SFM model-accuracy is higher than test-retest reliability and also higher than the DTM model-accuracy, particularly for measurements with (a) a b-value above 1000 in locations containing fiber crossings, and (b) in the regions of the brain surrounding the optic radiations. The SFM also has better parameter-validity: it more accurately estimates the fiber orientation distribution function (fODF) in each voxel, which is useful for fiber tracking. © 2015 Rokem et al.


Document Type: Article
Source: Scopus




Fox, J.M.a , Fernandez, K.C.a , Rodebaugh, T.L.a , Menatti, A.R.b , Weeks, J.W.b
Investigating stereotypes of social anxiety
(2015) Anxiety, Stress and Coping, 14 p. Article in Press. 

DOI: 10.1080/10615806.2015.1035999


a Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA
b Department of Psychology, Ohio University, Athens, OH, USA


Abstract
Background and Objectives: This paper consists of two studies that test for the presence and content of stereotypes of highly socially anxious individuals. Design: The current studies examined traits that comprise social anxiety stereotypes, and then tested whether undergraduate students held part of this stereotype via an implicit-association test (IAT). Methods: In Study 1, a sample of undergraduate students (n = 635) was asked to generate descriptors of people who are highly socially anxious. These descriptors were utilized to create the Social Anxiety Stereotype Measure (SASM) and the underlying factor structure of the SASM was analyzed. In Study 2, a different sample of undergraduate students (n = 87) was given an IAT to further test for the presence of one of the factors obtained in Study 1. Results: Factor analyses indicated the presence of two social anxiety stereotypes: social inhibition and oddity (comparative fit index = .97, Tucker-Lewis Index = .95, root mean square error of approximation = .07, standardized root mean square residual = .06). Oddity as a stereotype of social anxiety was further supported via an IAT: Participants reacted more quickly when oddity (vs. normality) words were paired with social anxiety (vs. social confidence) words (D = −1.15, SD = .26; t(85) = −41.50, p < .001). Conclusions: Factor analyses revealed two social anxiety stereotypes: social inhibition and oddity. Further testing of the oddity stereotype was supported via an IAT. © 2015 Taylor & Francis


Author Keywords
implicit-association test (IAT);  oddity;  social anxiety;  social anxiety disorder;  social inhibition;  stereotype


Document Type: Article in Press
Source: Scopus




Jin, S.C.a , Carrasquillo, M.M.b , Benitez, B.A.a , Skorupa, T.a , Carrell, D.a , Patel, D.a , Lincoln, S.b , Krishnan, S.b , Kachadoorian, M.b , Reitz, C.c d , Mayeux, R.c d , Wingo, T.S.e f , Lah, J.J.e , Levey, A.I.e , Murrell, J.g , Hendrie, H.h i , Foroud, T.j , Graff-Radford, N.R.k , Goate, A.M.a l m n o , Cruchaga, C.a l , Ertekin-Taner, N.b k
TREM2 is associated with increased risk for Alzheimer's disease in African Americans
(2015) Molecular Neurodegeneration, 10 (1), art. no. 19, . 

DOI: 10.1186/s13024-015-0016-9


a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, B8134St. Louis, MO, United States
b Department of Neuroscience, Mayo Clinic, 4500 San Pablo RoadJacksonville, FL, United States
c Department of Neurology, Columbia UniversityNew York, NY, United States
d Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surg., Columbia UniversityNew York, NY, United States
e Department of Neurology, Emory University School of MedicineAtlanta, GA, United States
f Division of Neurology, Atlanta Veterans Administration Medical CenterAtlanta, GA, United States
g Department of Pathology and Laboratory Medicine, Indiana University School of MedicineIndianapolis, IN, United States
h Indiana University Center for Aging ResearchIndianapolis, IN, United States
i Regenstrief Institute, Inc, 410 West 10th StreetIndianapolis, IN, United States
j Department of Medical and Molecular Genetics, Indiana University School of MedicineIndianapolis, IN, United States
k Department of Neurology, Mayo Clinic, 4500 San Pablo RoadJacksonville, FL, United States
l Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, 660 S. Euclid Avenue B8111St. Louis, MO, United States
m Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue B8111St. Louis, MO, United States
n Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park AvenueSt. Louis, MO, United States
o Department of Genetics, Washington University School of Medicine, 660 S. Euclid AvenueSt. Louis, MO, United States


Abstract
Background: TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer's disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case-control analyses in a total of 906 LOAD cases vs. 2,487 controls. Results: We identified significant LOAD risk association with p.L211P (p = 0.01, OR = 1.27, 95%CI = 1.05-1.54) and suggestive association with p.W191X (p = 0.08, OR = 1.35, 95%CI = 0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk. Conclusions: Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action. © 2015 Jin et al.; licensee BioMed Central.


Author Keywords
African-American;  Case-control;  Coding variants;  LOAD;  TREM2


Document Type: Article
Source: Scopus




Daniels, B.P., Klein, R.S.
Viral sensing at the blood-brain barrier: new roles for innate immunity at the CNS vasculature
(2015) Clinical pharmacology and therapeutics, 97 (4), pp. 372-379. 

DOI: 10.1002/cpt.75


Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri, USA


Abstract
Neurotropic viral infections are a major source of disease worldwide and represent a growing burden to public health. While the central nervous system (CNS) is normally protected from viral infection by the blood-brain barrier (BBB), many viruses are able to cross the BBB and establish CNS infection through processes that largely remain poorly understood. A growing body of recent research has begun to shed light on the viral and host factors that modulate BBB function, contributing to both protective and pathological disease processes. Central to these studies have been the actions of host cytokines and chemokines, which have increasingly been shown to be key regulators of BBB physiology. This review summarizes recent advances in understanding how BBB function governs both viral pathogenesis and host immune responses during neurotropic viral infections. © 2015 American Society for Clinical Pharmacology and Therapeutics.


Document Type: Review
Source: Scopus




Grucza, R.A.a , Hur, M.a , Agrawal, A.a , Krauss, M.J.a , Plunk, A.D.b , Cavazos-Rehg, P.A.a , Chaloupka, F.J.c , Bierut, L.J.a d
A reexamination of medical marijuana policies in relation to suicide risk
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.04.014


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
b Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA
c Department of Economics and Health Policy Center, University of Illinois at Chicago, Chicago, IL, USA
d Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Objectives: Previous research has suggested that medical marijuana policies lead to reductions in suicide rates. In this study, we further investigate the association between these policies and within-state changes in suicide risk. Methods: Data on suicide deaths (n = 662,993) from the National Vital Statistics System Multiple Cause of Death files were combined with living population data. Fixed-effects regression methods were employed to control for state differences in suicide rates and national and state secular trends. Analyses extended prior research that suggested a protective effect of medical marijuana policies by incorporating newer data and additional covariates. Results: After adjustment for race/ethnicity, tobacco control policies, and other covariates, we found no association between medical marijuana policy and suicide risk in the population ages 15 and older (OR = 1.000; 95% CI: 0.956, 1.045; p = 0.98), among men overall (OR = 0.996; 95% CI: 0.951, 1.043; p = 0.87) or for any other age-by-sex groups. Conclusion: We find no statistically significant association between medical marijuana policy and suicide risk. These results contradict prior analyses which did not control for race/ethnicity and certain state characteristics such as tobacco control policies. Failure to control for these factors in future analyses would likely bias estimates of the associations between medical marijuana policy and health outcomes. © 2015 Elsevier Ireland Ltd.


Author Keywords
Epidemiology;  Marijuana;  Medical marijuana;  Policy;  Suicide


Document Type: Article in Press
Source: Scopus




Wong, M.a , Roper, S.N.b
Genetic animal models of malformations of cortical development and epilepsy
(2015) Journal of Neuroscience Methods, . Article in Press. 

DOI: 10.1016/j.jneumeth.2015.04.007


a Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Neurosurgery, University of Florida, Gainesville, FL 32610, USA


Abstract
Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal lesions, such as focal cortical dysplasia, heterotopias, and tubers of tuberous sclerosis complex, and diffuse malformations, such as lissencephaly. Although some cortical malformations result from environmental insults during cortical development in utero, genetic factors are increasingly recognized as primary pathogenic factors across the entire spectrum of malformations. Genes implicated in causing different cortical malformations are involved in a variety of physiological functions, but many are focused on regulation of cell proliferation, differentiation, and neuronal migration. Advances in molecular genetic methods have allowed the engineering of increasingly sophisticated animal models of cortical malformations and associated epilepsy. These animal models have identified some common mechanistic themes shared by a number of different cortical malformations, but also revealed the diversity and complexity of cellular and molecular mechanisms that lead to the development of the pathological lesions and resulting epileptogenesis. © 2015 Elsevier B.V.


Author Keywords
Focal cortical dysplasia;  Heterotopia;  Lissencephaly;  Mice;  Seizure;  Tuberous sclerosis


Document Type: Article in Press
Source: Scopus




Mrugala, M.M.a , Engelhard, H.H.b , Dinh Tran, D.c , Kew, Y.d , Cavaliere, R.e , Villano, J.L.f , Annenelie Bota, D.g , Rudnick, J.h , Love Sumrall, A.i , Zhu, J.-J.j , Butowski, N.k
Erratum: Clinical Practice Experience With NovoTTF-100A™ System for Glioblastoma: The Patient Registry Dataset (PRiDe) (Seminars in Oncology (2014) 41:5 (S4-S13))
(2015) Seminars in Oncology, 42 (3), p. e33. 

DOI: 10.1053/j.seminoncol.2015.02.024


a University of Washington, Fred Hutchinson Cancer Research Center, 1959 NE Pacific St.Seattle, WA, United States
b University of Illinois Hospital and Health Sciences SystemChicago, IL, United States
c Washington University, School of MedicineSt. Louis, MO, United States
d Houston Methodist HospitalHouston, TX, United States
e Ohio State UniversityColumbus, OH, United States
f University of IllinoisChicago, IL, United States
g University of California Irvine, Medical CenterOrange, CA, United States
h Neuro-Oncology Program, Cedars-Sinai Medical CenterLos Angeles, CA, United States
i Levine Cancer InstituteCharlotte, NC, United States
j University of Texas, Health Science Center at HoustonHouston, TX, United States
k University of California, San FranciscoSan Francisco, CA, United States


Document Type: Erratum
Source: Scopus




Altman, M.a , Wilfley, D.E.b
Evidence Update on the Treatment of Overweight and Obesity in Children and Adolescents
(2015) Journal of Clinical Child and Adolescent Psychology, 44 (4), pp. 521-537. Cited 1 time.

DOI: 10.1080/15374416.2014.963854


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


Abstract
Childhood obesity is associated with increased medical and psychosocial consequences and mortality and effective interventions are urgently needed. Effective interventions are urgently needed. This article reviews the evidence for psychological treatments of overweight and obesity in child and adolescent populations. Studies were identified through searches of online databases and reference sections of relevant review articles and meta-analyses. Treatment efficacy was assessed using established criteria, and treatments were categorized as well-established, probably efficacious, possibly efficacious, experimental, or of questionable efficacy. Well-established treatments included family-based behavioral treatment (FBT) and Parent-Only Behavioral Treatment for children. Possibly efficacious treatments include Parent-Only Behavioral Treatment for adolescents, FBT-Guided Self-Help for children, and Behavioral Weight Loss treatment with family involvement for toddlers, children, and adolescents. Appetite awareness training and regulation of cues treatments are considered experimental. No treatments are considered probably efficacious, or of questionable efficacy. All treatments considered efficacious are multicomponent interventions that include dietary and physical activity modifications and utilize behavioral strategies. Treatment is optimized if family members are specifically targeted in treatment. Research supports the use of multicomponent lifestyle interventions, with FBT and Parent-Only Behavioral Treatment being the most widely supported treatment types. Additional research is needed to test a stepped care model for treatment and to establish the ideal dosage (i.e., number and length of sessions), duration, and intensity of treatments for long-term sustainability of healthy weight management. To improve access to care, the optimal methods to enhance the scalability and implementability of treatments into community and clinical settings need to be established. Copyright © Taylor & Francis Group, LLC.


Document Type: Article
Source: Scopus




Cornelis, M.C.a b , Byrne, E.M.c , Esko, T.d e f g , Nalls, M.A.h , Ganna, A.i , Paynter, N.j , Monda, K.L.k , Amin, N.l , Fischer, K.d , Renstrom, F.m , Ngwa, J.S.n , Huikari, V.o , Cavadino, A.p , Nolte, I.M.q , Teumer, A.r , Yu, K.s , Marques-Vidal, P.t , Rawal, R.u , Manichaikul, A.v , Wojczynski, M.K.w , Vink, J.M.x , Zhao, J.H.y , Burlutsky, G.z , Lahti, J.aa ab , Mikkilä, V.ac ad , Lemaitre, R.N.ae , Eriksson, J.af , Musani, S.K.ag , Tanaka, T.ah , Geller, F.ai , Luan, J.y , Hui, J.aj ak al am , Mägi, R.d , Dimitriou, M.an , Garcia, M.E.ao , Ho, W.-K.ap , Wright, M.J.aq , Rose, L.M.j , Magnusson, P.K.E.i , Pedersen, N.L.i , Couper, D.ar , Oostra, B.A.as , Hofman, A.l , Ikram, M.A.l at au , Tiemeier, H.W.l av , Uitterlinden, A.G.l aw , Van Rooij, F.J.A.l , Barroso, I.ax ay , Johansson, I.az , Xue, L.n , Kaakinen, M.o ba bb , Milani, L.d , Power, C.p , Snieder, H.q , Stolk, R.P.q , Baumeister, S.E.bc , Biffar, R.bd , Gu, F.s , Bastardot, F.be , Kutalik, Z.bf bg bh , Jacobs Jr, D.R.bi , Forouhi, N.G.y , Mihailov, E.d , Lind, L.bj , Lindgren, C.bk , Michaëlsson, K.bl , Morris, A.bk , Jensen, M.b , Khaw, K.-T.ap , Luben, R.N.ap , Wang, J.J.z , Männistö, S.bm , Perälä, M.-M.bm , Kähönen, M.bn , Lehtimäki, T.bo , Viikari, J.bp , Mozaffarian, D.a b bq br , Mukamal, K.bs , Psaty, B.M.ae bt bu bv , Döring, A.bw , Heath, A.C.bx , Montgomery, G.W.aq , Dahmen, N.by , Carithers, T.bz , Tucker, K.L.ca , Ferrucci, L.ah , Boyd, H.A.ai , Melbye, M.ai , Treur, J.L.x , Mellström, D.af , Hottenga, J.J.x , Prokopenko, I.bk cb , Tönjes, A.cc cd , Deloukas, P.ax ce cf , Kanoni, S.ce , Lorentzon, M.af , Houston, D.K.cg , Liu, Y.ch , Danesh, J.ap , Rasheed, A.ci , Mason, M.A.cj , Zonderman, A.B.ck , Franke, L.cl , Kristal, B.S.cm cn , Karjalainen, J.cl , Reed, D.R.co , Westra, H.-J.cl , Evans, M.K.cj , Saleheen, D.ap ci , Harris, T.B.ao , Dedoussis, G.an , Curhan, G.a , Stumvoll, M.cc cd , Beilby, J.aj ak al , Pasquale, L.R.a cp , Feenstra, B.ai , Bandinelli, S.cq , Ordovas, J.M.cr , Chan, A.T.a cs , Peters, U.ct , Ohlsson, C.af , Gieger, C.u , Martin, N.G.aq , Waldenberger, M.cu , Siscovick, D.S.ae bt , Raitakari, O.ad cv , Eriksson, J.G.ab cw cx , Mitchell, P.z , Hunter, D.J.a cy , Kraft, P.cy , Rimm, E.B.a b bq , Boomsma, D.I.x , Borecki, I.B.w , Loos, R.J.F.y cz da , Wareham, N.J.y , Vollenweider, P.be , Caporaso, N.s , Grabe, H.J.db , Neuhouser, M.L.ct , Wolffenbuttel, B.H.R.dc , Hu, F.B.a b bq , Hyppönen, E.p dd de , Järvelin, M.-R.o ba bb df dg , Cupples, L.A.n dh , Franks, P.W.b m di , Ridker, P.M.j , Van Duijn, C.M.l dj , Heiss, G.k , Metspalu, A.d , North, K.E.k , Ingelsson, E.bj bk , Nettleton, J.A.dk , Van Dam, R.M.dl , Chasman, D.I.j
Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption
(2015) Molecular Psychiatry, 20 (5), pp. 647-656. Cited 3 times.

DOI: 10.1038/mp.2014.107


a Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 401, Park DriveBoston, MA, United States
b Department of Nutrition, Harvard School of Public HealthBoston, MA, United States
c Queensland Brain Institute, University of QueenslandQLD, Australia
d Estonian Genome Center, University of TartuTartu, Estonia
e Division of Endocrinology, Children's Hospital BostonBoston, MA, United States
f Department of Genetics, Harvard Medical SchoolBoston, MA, United States
g Program in Medical and Population Genetics, Broad InstituteCambridge, MA, United States
h Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health (NIH)Bethesda, MD, United States
i Department of Medical Epidemiology and Biostatistics, Karolinska InstitutetKarolinska, Sweden
j Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth AvenueBoston, MA, United States
k Department of Epidemiology, University of North Carolina at Chapel HillChapel Hill, NC, United States
l Department of Epidemiology, Erasmus Medical CenterRotterdam, Netherlands
m Department of Clinical Sciences, Lund UniversityMalmö, Sweden
n Department of Biostatistics, Boston University, School of Public HealthBoston, MA, United States
o Institute of Health Sciences, University of OuluOulu, Finland
p Centre for Paediatric Epidemiology and Biostatistics, Medical Research Council (MRC) Centre of Epidemiology for Child Health, University College LondonLondon, United Kingdom
q Department of Epidemiology, University of Groningen, University Medical Center Groningen, Netherlands
r Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany
s Division of Cancer Epidemiology and Genetics, National Cancer InstituteBethesda, MD, United States
t Institute of Social and Preventive Medicine, Lausanne University HospitalLausanne, Switzerland
u Institute of Genetic Epidemiology, Helmholtz Zentrum-MünchenMunich-Neuherberg, Germany
v Center for Public Health Genomics, University of VirginiaCharlottesville, VA, United States
w Washington University, School of Medicine, Department of GeneticsSt Louis, MO, United States
x Department of Biological Psychology/Netherlands Twin Register, VU UniversityAmsterdam, Netherlands
y Medical Research Council (MRC) Epidemiology Unit, University of CambridgeCambridge, United Kingdom
z Centre for Vision Research, Department of Ophthalmology, University of SydneySydney, NSW, Australia
aa Institute of Behavioural Sciences, University of HelsinkiHelsinki, Finland
ab Folkhälsan Research CentreHelsinki, Finland
ac Department of Food and Environmental Sciences, University of HelsinkiHelsinki, Finland
ad Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University HospitalTurku, Finland
ae Cardiovascular Health Research Unit, Department of Medicine, University of WashingtonSeattle, WA, United States
af Centre for Bone and Arthritis Research, Institute of Medicine, University of GothenburgGothenburg, Sweden
ag University of Mississippi Medical CenterJackson, MI, United States
ah Translational Gerontology Branch, National Institute on Aging, NIHBaltimore, MD, United States
ai Statens Serum Institut, Department of Epidemiology ResearchCopenhagen, Denmark
aj Busselton Population Medical Research Foundation Inc.Busselton, WA, Australia
ak PathWest Laboratory Medicine WANedlands, WA, Australia
al School of Pathology and Laboratory Medicine, University of Western AustraliaNedlands, WA, Australia
am School of Population Health, University of Western AustraliaNedlands, WA, Australia
an Harokopio UniversityAthens, Greece
ao Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIHBethesda, MD, United States
ap Department of Public Health and Primary Care, Institute of Public Health, University of CambridgeCambridge, United Kingdom
aq QIMR Berghofer Medical Research InstituteQLD, Australia
ar Department of Biostatistics, University of NC at Chapel HillChapel Hill, NC, United States
as Department of Clinical Genetics, Erasmus MCRotterdam, Netherlands
at Department of Radiology, Erasmus Medical CenterRotterdam, Netherlands
au Department of Neurology, Erasmus Medical CenterRotterdam, Netherlands
av Department of Psychiatry, Erasmus Medical CenterRotterdam, Netherlands
aw Department of Internal Medicine, Erasmus Medical CenterRotterdam, Netherlands
ax Wellcome Trust Sanger InstituteHinxton, Cambridge, United Kingdom
ay University of Cambridge, Metabolic Research Laboratories, NIHR Cambridge Biomedical Research CentreCambridge, United Kingdom
az Department of Odontology, Umea UniversityUmea, Sweden
ba Biocenter Oulu, University of OuluOulu, Finland
bb Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom
bc Institute for Community Medicine, University Medicine Greifswald, Germany
bd Department of Prosthodontics, Gerodontology and Biomaterials, Center of Oral Health, University Medicine Greifswald, Germany
be Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, University of LausanneLausanne, Switzerland
bf Department of Medical Genetics, University of LausanneLausanne, Switzerland
bg Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV)Lausanne, Switzerland
bh Swiss Institute of BioinformaticsLausanne, Switzerland
bi Division of Epidemiology and Community Health, School of Public Health, University of MinnesotaMinneapolis, MN, United States
bj Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala UniversityUppsala, Sweden
bk Wellcome Trust Centre for Human Genetics, University of OxfordOxford, United Kingdom
bl Department of Surgical Sciences, Uppsala UniversityUppsala, Sweden
bm Department of Chronic Disease Prevention, National Institute for Health and WelfareHelsinki, Finland
bn Department of Clinical Physiology, Tampere University Hospital, University of TampereTampere, Finland
bo Department of Clinical Chemistry, School of Medicine, University of TampereTampere, Finland
bp Department of Medicine, University of Turku, Turku University HospitalTurku, Finland
bq Department of Epidemiology, Harvard School of Public HealthBoston, MA, United States
br Friedman School of Nutrition Science and Policy, Tufts UniversityBoston, MA, United States
bs Beth Israel Deaconess Medical CenterBoston, MA, United States
bt Cardiovascular Health Research Unit, Department of Epidemiology, University of WashingtonSeattle, WA, United States
bu Department of Health Services, University of WashingtonSeattle, WA, United States
bv Group Health Research Institute, Group Health CooperativeSeattle, WA, United States
bw Institute of Epidemiology, Helmholtz Zentrum-MünchenMunich-Neuherberg, Germany
bx Department of Psychiatry, Washington UniversitySt Louis, MO, United States
by Department for Psychiatry, Johannes-Gutenberg-UniversityMainz, Germany
bz School of Applied Sciences, University of MississippiOxford, MS, United States
ca Clinical Laboratory and Nutritional Sciences, University of MA LowellLowell, MA, United States
cb Department of Genomics of Common Diseases, Imperial College LondonLondon, United Kingdom
cc Medical Department, University of LeipzigLeipzig, Germany
cd IFB Adiposity Diseases, University of LeipzigLeipzig, Germany
ce William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of LondonLondon, United Kingdom
cf King Abdulaziz UniversityJeddah, Saudi Arabia
cg Wake Forest School of MedicineWinston-Salem, NC, United States
ch Wake Forest University Health SciencesWinston-Salem, NC, United States
ci Center for Non-Communicable Diseases, Pakistan
cj Health Disparities Research Section, Clinical Research Branch, National Institute on AgingBaltimore, MD, United States
ck Laboratory of Personality and Cognition, National Institute on Aging, NIHBaltimore, MD, United States
cl Department of Genetics, University Medical Center Groningen, University of GroningenGroningen, Netherlands
cm Department of Neurosurgery, Brigham and Women's HospitalBoston, MA, United States
cn Department of Surgery, Harvard Medical SchoolBoston, MA, United States
co Monell Chemical Senses CenterPhiladelphia, PA, United States
cp Mass Eye and Ear InfirmaryBoston, MA, United States
cq Geriatric Unit, Azienda Sanitaria FirenzeFlorence, Italy
cr Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts UniversityBoston, MA, United States
cs Division of Gastroenterology, MA General HospitalBoston, MA, United States
ct Public Health Sciences Division, Fred Hutchinson Cancer Research CenterSeattle, WA, United States
cu Research Unit of Molecular Epidemiology, Helmholtz Zentrum-MünchenMunich-Neuherberg, Germany
cv Department of Clinical Physiology and Nuclear Medicine, Turku University HospitalTurku, Finland
cw Department of General Practice and Primary Health Care, University of HelsinkiHelsinki, Finland
cx Helsinki University Central Hospital, Unit of General PracticeHelsinki, Finland
cy Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public HealthBoston, MA, United States
cz Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount SinaiNew York, NY, United States
da Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount SinaiNew York, NY, United States
db Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS Hospital Stralsund, Germany
dc Department of Endocrinology, University of Groningen, University Medical Center GroningenGroningen, Netherlands
dd School of Population Health, University of South AustraliaAdelaide, SA, Australia
de South Australian Health and Medical Research InstituteAdelaide, SA, Australia
df Department of Children and Young People and Families, National Institute for Health and WelfareOulu, Finland
dg Unit of Primary Care, Oulu University HospitalOulu, Finland
dh Framingham Heart StudyFramingham, MA, United States
di Department of Public Health and Clinical Medicine, Section for Medicine, Umea UniversityUmea, Sweden
dj Netherlands Consortium for Healthy Ageing and National Genomics InitiativeLeiden, Netherlands
dk Division of Epidemiology,Human Genetics and Environmental Sciences, University of Texas, Health Science Center at HoustonHouston, TX, United States
dl Department of Medicine, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore


Abstract
Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in
30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log 10 Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10 -8).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. © 2015 Macmillan Publishers Limited.


Document Type: Note
Source: Scopus




Sico, J.J.a b , Chang, C.-C.H.c , So-Armah, K.b , Justice, A.C.a b , Hylek, E.d , Skanderson, M.a , McGinnis, K.a , Kuller, L.H.c , Kraemer, K.L.c , Rimland, D.e , Bidwell Goetz, M.f , Butt, A.A.c g , Rodriguez-Barradas, M.C.h , Gibert, C.i , Leaf, D.f , Brown, S.T.j k , Samet, J.l , Kazis, L.m , Bryant, K.n , Freiberg, M.S.o
HIV status and the risk of ischemic stroke among men
(2015) Neurology, 84 (19), pp. 1933-1940. 

DOI: 10.1212/WNL.0000000000001560


a VA Connecticut Health Care System, West Haven Veterans Administration Medical CenterWest Haven, United States
b Yale University, School of MedicineNew Haven, CT, United States
c University of Pittsburgh, School of Medicine, Graduate School of Public HealthPittsburgh, PA, United States
d Boston Medical CenterMA, United States
e Emory University, School of Medicine, Atlanta Veterans Administration Medical CenterAtlanta, GA, United States
f David Geffen School of Medicine, UCLA, VA Greater Los Angeles Health Care SystemLos Angeles, CA, United States
g VA Pittsburgh Health Care SystemPittsburgh, PA, United States
h Michael E. DeBakey Veterans Administration Medical Center, Baylor College of MedicineHouston, TX, United States
i Washington DC Veterans Administration Medical Center, George Washington University, School of MedicineWashington,, DC, United States
j James J. Peters VABronx, United States
k Mount Sinai School of MedicineNew York, NY, United States
l Boston University, School of MedicineMA, United States
m Center for the Assessment of Pharmaceutical Practices, Boston University School of Public Health, Center for Healthcare Organization and Implementation ResearchBedford, MA, United States
n National Institute on Alcohol Abuse and AlcoholismBethesda, MD, United States
o Vanderbilt University, School of Medicine, Nashville Veterans Affairs Medical CenterNashville, TN, United States


Abstract
Objective: Given conflicting data regarding the association of HIV infection and ischemic stroke risk, we sought to determine whether HIV infection conferred an increased ischemic stroke risk among male veterans. Methods: The Veterans Aging Cohort Study-Virtual Cohort consists of HIV-infected and uninfected veterans in care matched (1:2) for age, sex, race/ethnicity, and clinical site. We analyzed data on 76,835 male participants in the Veterans Aging Cohort Study-Virtual Cohort who were free of baseline cardiovascular disease. We assessed demographics, ischemic stroke risk factors, comorbid diseases, substance use, HIV biomarkers, and incidence of ischemic stroke from October 1, 2003, to December 31, 2009. Results: During a median follow-up period of 5.9 (interquartile range 3.5-6.6) years, there were 910 stroke events (37.4% HIV-infected). Ischemic stroke rates per 1,000 person-years were higher for HIV-infected (2.79, 95% confidence interval 2.51-3.10) than for uninfected veterans (2.24 [2.06-2.43]) (incidence rate ratio 1.25 [1.09-1.43]; p < 0.01). After adjusting for demographics, ischemic stroke risk factors, comorbid diseases, and substance use, the risk of ischemic stroke was higher among male veterans with HIV infection compared with uninfected veterans (hazard ratio 1.17 [1.01-1.36]; p 0.04). Conclusions: HIV infection is associated with an increased ischemic stroke risk among HIV-infected compared with demographically and behaviorally similar uninfected male veterans. © 2015 American Academy of Neurology.

 


Document Type: Article
Source: Scopus

 

May 18, 2015

Gockley, J.a , Willsey, A.J.a b , Dong, S.a c , Dougherty, J.D.d e , Constantino, J.N.d , Sanders, S.J.a b
The female protective effect in autism spectrum disorder is not mediated by a single genetic locus
(2015) Molecular Autism, . Article in Press. 

DOI: 10.1186/s13229-015-0014-3


a Yale University School of Medicine, Department of Genetics, 333 Cedar Street, New Haven, CT, 06520 USA
b University of California, San Francisco, Department of Psychiatry, 401 Parnassus Avenue, San Francisco, CA, 94143 USA
c Peking University, Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, No.5 Yiheyuan Road, Haidian District, Beijing, 100871 People's Republic of China
d Washington University, Department of Psychiatry, 660 South Euclid Avenue, St Louis, MO, 63110 USA
e Washington University, Department of Genetics, 4566 Scott Ave, St Louis, MO, 63110 USA


Abstract
Background: A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. Methods: To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide. Results: No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect. Conclusions: The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE. © 2015 Gockley et al.; licensee BioMed Central.


Author Keywords
Autism spectrum disorder;  Female protective effect;  GWAS;  Sex bias


Document Type: Article in Press
Source: Scopus




Wolf, T.J.a b , Dahl, A.a , Auen, C.a , Doherty, M.a
The reliability and validity of the Complex Task Performance Assessment: A performance-based assessment of executive function
(2015) Neuropsychological Rehabilitation, 15 p. Article in Press. 

DOI: 10.1080/09602011.2015.1037771


a Program in Occupational Therapy, Washington University in St. Louis, School of Medicine, St. Louis, USA
b Department of Neurology, Washington University in St. Louis, School of Medicine, St. Louis, USA


Abstract
The objective of this study was to evaluate the inter-rater reliability, test-retest reliability, concurrent validity, and discriminant validity of the Complex Task Performance Assessment (CTPA): an ecologically valid performance-based assessment of executive function. Community control participants (n = 20) and individuals with mild stroke (n = 14) participated in this study. All participants completed the CTPA and a battery of cognitive assessments at initial testing. The control participants completed the CTPA at two different times one week apart. The intra-class correlation coefficient (ICC) for inter-rater reliability for the total score on the CTPA was .991. The ICCs for all of the sub-scores of the CTPA were also high (.889–.977). The CTPA total score was significantly correlated to Condition 4 of the DKEFS Color-Word Interference Test (p = −.425), and the Wechsler Test of Adult Reading (p  = −.493). Finally, there were significant differences between control subjects and individuals with mild stroke on the total score of the CTPA (p = .007) and all sub-scores except interpretation failures and total items incorrect. These results are also consistent with other current executive function performance-based assessments and indicate that the CTPA is a reliable and valid performance-based measure of executive function. © 2015 Taylor & Francis


Author Keywords
Cognition;  Ecological validity;  Executive function;  Occupational therapy;  Rehabilitation


Document Type: Article in Press
Source: Scopus




Remy, K.E.
Sedation protocol for critically ill pediatric patients
(2015) JAMA, 313 (17), p. 1754. 

DOI: 10.1001/jama.2015.3459


Division of Pediatric Critical Care Medicine, Washington University, St Louis, Missouri


Document Type: Letter
Source: Scopus




Kubanek, J.a b , Li, J.M.a , Snyder, L.H.a b
Motor role of parietal cortex in a monkey model of hemispatial neglect
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (16), pp. E2067-E2072. 

DOI: 10.1073/pnas.1418324112


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


Abstract
Parietal cortex is central to spatial cognition. Lesions of parietal cortex often lead to hemispatial neglect, an impairment of choices of targets in space. It has been unclear whether parietal cortex implements target choice at the general cognitive level, or whether parietal cortex subserves the choice of targets of particular actions. To address this question, monkeys engaged in choice tasks in two distinct action contexts - eye movements and arm movements. We placed focused reversible lesions into specific parietal circuits using the GABA<inf>A</inf> receptor agonist muscimol and validated the lesion placement using MRI. We found that lesions on the lateral bank of the intraparietal sulcus [lateral intraparietal area (LIP)] specifically biased choices made using eye movements, whereas lesions on the medial bank of the intraparietal sulcus [parietal reach region (PRR)] specifically biased choices made using arm movements. This double dissociation suggests that target choice is implemented in dedicated parietal circuits in the context of specific actions. This finding emphasizes a motor role of parietal cortex in spatial choice making and contributes to our understanding of hemispatial neglect. © 2015, National Academy of Sciences. All rights reserved.


Author Keywords
Attention;  Choice;  Decision;  LIP;  Spatial cognition


Document Type: Article
Source: Scopus




Jin, S.C.a , Carrasquillo, M.M.b , Benitez, B.A.a , Skorupa, T.a , Carrell, D.a , Patel, D.a , Lincoln, S.b , Krishnan, S.b , Kachadoorian, M.b , Reitz, C.c d , Mayeux, R.c d , Wingo, T.S.e f , Lah, J.J.e , Levey, A.I.e , Murrell, J.g , Hendrie, H.h i , Foroud, T.j , Graff-Radford, N.R.k , Goate, A.M.a l m n o , Cruchaga, C.a l , Ertekin-Taner, N.b k
TREM2 is associated with increased risk for Alzheimer's disease in African Americans
(2015) Molecular Neurodegeneration, . Article in Press. 

DOI: 10.1186/s13024-015-0016-9


a Washington University School of Medicine, Department of Psychiatry, 660 South Euclid Avenue B8134, St. Louis, MO, 63110 USA
b Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL, 32224 USA
c Psychiatry and Epidemiology, Columbia University, Departments of Neurology, New York, NY, 10032 USA
d Columbia University, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, New York, NY, 10032 USA
e Emory University School of Medicine, Department of Neurology, Atlanta, GA, 30033 USA
f Atlanta Veterans Administration Medical Center, Division of Neurology, Atlanta, GA, 30033 USA
g Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, IN, 46202 USA
h Indiana University Center for Aging Research, Indianapolis, IN, 46202 USA
i Regenstrief Institute, Inc, 410 West 10th Street, Suite 2000, Indianapolis, IN, 46202 USA
j Indiana University School of Medicine, Department of Medical and Molecular Genetics, Indianapolis, IN, 46202 USA
k Mayo Clinic, Department of Neurology, 4500 San Pablo Road, Jacksonville, FL, 32224 USA
l Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, 660 S. Euclid Avenue B8111, St. Louis, MO, 63110 USA
m Washington University School of Medicine, Department of Neurology, 660 S. Euclid Avenue B8111, St. Louis, MO, 63110 USA
n Washington University School of Medicine, Joanne Knight Alzheimer's Disease Research Center, 4488 Forest Park Avenue, St. Louis, MO, 63108 USA
o Washington University School of Medicine, Department of Genetics, 660 S. Euclid Avenue, St. Louis, MO, 63110 USA


Abstract
Background: TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer's disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case-control analyses in a total of 906 LOAD cases vs. 2,487 controls. Results: We identified significant LOAD risk association with p.L211P (p = 0.01, OR = 1.27, 95%CI = 1.05-1.54) and suggestive association with p.W191X (p = 0.08, OR = 1.35, 95%CI = 0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk. Conclusions: Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action. © 2015 Jin et al.; licensee BioMed Central.


Author Keywords
African-American;  Case-control;  Coding variants;  LOAD;  TREM2


Document Type: Article in Press
Source: Scopus




Sakurai, K.d , Chen, J.b , Khani, S.C.c , Kefalov, V.J.a
Regulation of mammalian cone phototransduction by recoverin and rhodopsin kinase
(2015) Journal of Biological Chemistry, 290 (14), pp. 9239-9250. 

DOI: 10.1074/jbc.M115.639591


a Dept. of Ophthalmology and Visual Sciences, Washington University School of Medicine, Campus B. 8096, 660 S. Euclid Ave.St. Louis, MO, United States
b Department of Ophthalmology, Zilkha Neurogenetic Institute, University of Southern CaliforniaLos Angeles, CA, United States
c Department of Ophthalmology, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical SchoolBoston, MA, United States
d Faculty of Life and Environmental Sciences, University of TsukubaTsukuba, Ibaraki, Japan


Abstract
Background: Calcium-mediated feedback to phototransduction is critical for modulating cone responses under different lighting conditions. Results: The calcium-binding protein recoverin potentiates dim light sensitivity, whereas increasing expression of its target, GRK1, delays response shutoff in cones. Conclusion: Recoverin and GRK1 levels modulate cone phototransduction. Significance: Cone pigment inactivation regulates cone responses in dim light but not in bright light. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


Document Type: Article
Source: Scopus




Ouwenga, R.L.a , Dougherty, J.a b
Fmrp targets or not: Long, highly brain-expressed genes tend to be implicated in autism and brain disorders
(2015) Molecular Autism, pp. 1-7. Article in Press. 

DOI: 10.1186/s13229-015-0008-1


a Department of Genetics, 4566 Scott Ave, Campus Box 8232, St. Louis, MO, 63110-1093 USA
b Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA


Abstract
Background: Many studies have demonstrated a robust statistical overlap between genes whose transcripts are reported as Fragile X Mental Retardation Protein (Fmrp)-binding targets and genes implicated in various psychiatric disorders, including autism. However, it is not clear how to interpret this overlap as the Fmrp protein itself is not considered to be central to all instances of these conditions. Findings: We tested whether Fmrp binding may be a proxy for some other features of these transcripts. Reviewing recent literature on the cross-linking and immunoprecipitation (CLIP)-derived targets of Fmrp in the brain, and the literature on identifying genes thought to mediate autism and other psychiatric disorders, reveals that both appear to be disproportionately made up of highly brain-expressed genes. This suggests a parsimonious explanation-that the overlap between Fmrp targets and neuropsychiatric candidate genes might be secondary to simple features such as transcript length and robust expression in the brain. Indeed, reanalyzing Fmrp high-throughput sequencing of RNAs isolated by CLIP (HITS-CLIP) data suggests that approximately 60% of CLIP tag depth can be predicted by gene expression, coding sequence length, and transcript length. Furthermore, there is a statistically significant overlap between autism candidate genes and random samples of long, highly brain-expressed genes, whether they are Fmrp targets or not. Conclusions: Comparison of known Fmrp-binding targets to candidate gene lists should be informed by both of these features. © 2015 Ouwenga and Dougherty; licensee BioMed Central.


Author Keywords
Autism;  FMRP interactome;  Genome-wide association


Document Type: Article in Press
Source: Scopus




Lai, H.a b , Gardner, V.a , Vetter, J.a , Andriole, G.L.a
Correlation between psychological stress levels and the severity of overactive bladder symptoms
(2015) BMC Urology, pp. 1-7. Article in Press. 

DOI: 10.1186/s12894-015-0009-6


a Washington University School of Medicine, Division of Urologic Surgery, Department of Surgery, 4960 Children's Place, Campus Box 8242, St Louis, MO, 63110 USA
b Washington University School of Medicine, Department of Anesthesiology, 4960 Children's Place, Campus Box 8242, St Louis, MO, 63110 USA


Abstract
Background: The relationship between psychological stress and interstitial cystitis/bladder pain syndrome (IC/BPS) has been well described. Even though there is some overlapping of symptoms between overactive bladder (OAB) and IC/BPS, there have been very few studies that specifically investigated the relationship between psychological stress and urinary symptoms in OAB patients who do not have pelvic pain. Here we examined the relationship between psychological stress levels and the severity of overactive bladder (OAB) symptoms. Methods: Patients diagnosed with OAB (n=51), IC/BPS (n=27), and age-matched healthy controls (n=30) participated in a case control study that inquired about their psychological stress levels using the perceived stress scale (PSS). PSS reported by the three patient groups were compared. Among OAB patients, their responses on the PSS was correlated to OAB symptoms using the following questionnaires: 1) international consultation on incontinence - urinary incontinence (ICIQ-UI), 2) international consultation on incontinence - overactive bladder (ICIQ-OAB), 3) OAB-q short form, 4) urogenital distress inventory (UDI-6), 5) incontinence impact questionnaire (IIQ-7), 6) urgency severity scale (USS), 7) numeric rating scales of urgency symptom, and 8) frequency symptom. Spearman's correlation tests were performed to examine the relationship between psychological stress levels and the severity of OAB symptoms. Results: OAB patients reported psychological stress levels that were as high as IC/BPS patients (median 17.0 versus 18.0, p=0.818, Wilcoxon sum rank test), and significantly higher than healthy controls (17.0, versus 7.5, p=0.001). Among OAB patients, there was a positive correlation between perceived stress levels and urinary incontinence symptoms (ICIQ-UI, Spearman's correlation coefficient=0.39, p=0.007), and impacts on quality of life (UDI-6, IIQ-7, OAB-q quality of life subscale; Spearman's correlation coefficient=0.32, 0.31, 0.39, and p=0.028, 0.005, 0.029, respectively). No significant correlation was observed between perceived stress levels and urgency or frequency symptoms (ICIQ-OAB, USS, numeric ratings of urgency and frequency). Conclusions: OAB patients reported psychological stress levels that were as high as IC/BPS patients, and significantly higher than healthy controls. There was a positive correlation between perceived stress levels and urinary incontinence symptoms, and its impacts on quality of life among OAB patients. © 2015 Lai et al.; licensee BioMed Central.


Author Keywords
Interstitial cystitis;  Overactive bladder;  Psychological stress;  Urgency incontinence;  Urinary urgency


Document Type: Article in Press
Source: Scopus




Huang, J.a b , Ikeuchi, Y.a b d , Malumbres, M.c , Bonni, A.a b
A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain
(2015) Neuron, 86 (3), pp. 726-740. 

DOI: 10.1016/j.neuron.2015.03.049


a Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Neurobiology, Harvard Medical SchoolBoston, MA, United States
c Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3Madrid, Spain
d Institute of Industrial Science, The University of Tokyo, 4-6-1 KomabaMeguro, Tokyo, Japan


Abstract
Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligaseCdh1-anaphase-promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1-APC forms acomplex with endogenous FMRP, and knockout ofCdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin signaling pathway that regulates mGluR-LTD in the brain. Huang etal. identify a novel signaling link between the major ubiquitin ligase Cdh1-APC and the fragile X syndrome protein FMRP that regulates mGluR-dependent synaptic plasticity, with significant implications for our understanding of fragile X and related syndromes. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus




Xian, H.a b , Gonzalez, C.c , Deych, E.c , Farris, S.d , Ding, J.e , Shannon, W.c , McCall, W.V.f
Age-Related Effects on Circadian Phase in the Sleep of Patients with Depression and Insomnia
(2015) Behavioral Sleep Medicine, 13 (3), pp. 208-216. 

DOI: 10.1080/15402002.2013.855213


a College for Public Health & Social Justice, Saint Louis University, United States
b Biostatistics, Salus CenterSt. Louis, United States
c Washington University School of MedicineSt. Louis, United States
d Wake Forest University School of Medicine, United States
e Washington University in St. Louis, United States
f The Medical College of Georgia, Georgia Regents University, United States


Abstract
We examined whether an age-related phase advance was present in 60 patients with depression and insomnia (mean age 41.5 [12.5] years) using diaries and 5 weekdays of actigraphy. Actigraphy was analyzed with functional data analysis. The low point of activity (bathyphase) for each subject was fitted by cosine function with 24-hr cycle time. Linear regression analysis revealed that increasing age was associated with earlier bedtimes (p < 0.001), shorter sleep latencies (p < 0.05), and earlier bathyphase (p < 0.001). These findings are consistent with prior reports of age-dependent phase-advances in sleep behavior in self-reported good sleepers and reinforce the premise that individualized behavioral therapy of older persons with insomnia may require prescription of earlier bedtimes and earlier rise times than would be employed in younger persons with insomnia. Further, we demonstrate that aging of the sleep system, at least as reflected in actigraphy, occurs as early as the third decade. ©, Taylor & Francis.


Document Type: Article
Source: Scopus




Aschenbrenner, A.J.a , Balota, D.A.a , Tse, C.-S.b , Fagan, A.M.c , Holtzman, D.M.c , Benzinger, T.L.S.d , Morris, J.C.c
Alzheimer disease biomarkers, attentional control, and semantic memory retrieval: Synergistic and mediational effects of biomarkers on a sensitive cognitive measure in non-demented older adults
(2015) Neuropsychology, 29 (3), pp. 368-381. 

DOI: 10.1037/neu0000133


a Department of Psychology, Washington University in St. Louis, United States
b Department of Educational Psychology, The Chinese University of Hong Kong, Hong Kong
c Department of Neurology, The Knight Alzheimer's Disease Research Center, Washington University in St. Louis, United States
d The Knight Alzheimer's Disease Research Center, Department of Radiology, Washington University in St. Louis, United States


Abstract
Objective: Past studies have shown that measures of attentional control and semantic memory are sensitive markers of Alzheimer's disease (AD). The effects of established biomarkers of AD (cerebrospinal fluid tau and amyloid-beta42, positron emission tomography Pittsburgh compound-B, and apolipoprotein E [APOE] genotype) on concurrent cognitive performance in cognitively normal individuals have been mixed. The present study examined the utility of combining attentional control with semantic retrieval as a sensitive correlate of AD biomarkers and used mediation analyses to examine possible mechanisms by which the biomarkers influence cognition. Method: Three hundred sixty-three participants completed a category verification task (CVT), and 113 of them concurrently underwent biomarker assessments. On each trial, participants viewed a category (e.g., "unit of time") and verified whether a subsequent target item was an exemplar of the category ("hour") or not ("clock"). Importantly, the nonmembers of the category were associatively related to the category (e.g., "clock" is not "a unit of time," but is highly related), and demanded attentional control to reject. Results: Accuracy to the foil items was the strongest discriminator between healthy aging and very mild symptomatic AD. Cerebrospinal fluid biomarkers had independent yet synergistic influence on CVT performance in cognitively healthy older adults. Furthermore, the influence of the biomarkers and APOE genotype was mediated primarily through increased levels of PIB. Conclusion: The combined influence of attentional control with semantic retrieval is a marker of symptomatic AD and a sensitive correlate of established biomarkers for AD risk in cognitively healthy participants. The biomarkers influenced cognition primarily through increased levels of amyloid in the brain. © 2014 American Psychological Association.


Author Keywords
Alzheimer's disease;  Attention;  Biomarkers;  Semantic retrieval


Document Type: Article
Source: Scopus




Wu, X.a , Eggebrecht, A.T.b , Ferradal, S.L.c , Culver, J.P.d , Dehghani, H.a
Atlas-based high-density diffuse optical tomography for imaging the whole human cortex
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9319, art. no. 931907, . 

DOI: 10.1117/12.2075339


a School of Computer Science, University of BirminghamBirmingham, United Kingdom
b Department of Radiology, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States
c Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical SchoolBoston, MA, United States
d Department of Biomedical Engineering, Washington University, One Brookings DriveSt. Louis, MO, United States


Abstract
Diffuse optical tomography (DOT) for brain imaging has the potential to be an alternative human brain mapping technique when MRI imaging is not applicable. It recovers tissue chromophore concentrations of brain tissue through measures of light transmission to monitor for example the resting-state brain dynamics. This imaging technique relies on simulation of the light propagation which can be generated based on a subject-specific model. There has been some study on using rigid atlas models as alternatives for model based DOT when subject-specific anatomical data is not available; but there is still a lack of detailed analysis between geometrical accuracy and internal light propagation in tissue for atlas-based DOT. This work is focused on High-Density DOT (HD-DOT) of the whole cortex based on atlas models from 11 different rigid registration algorithms across 24 subjects, and the results are evaluated in 19 areas of the human head. The correlation between geometrical surface error and internal light propagation errors is strong in most area but varies in different regions from R2 = 0.74 in the region around top of the head to R2 = 0.98 in the region around the temples. In the 11 registration methods, basic-4-landmark registration with 4.2mm average surface error and 50% average internal light propagation errors is shown to be the least accurate registration method whereas full-head landmark with non-iterative point to point with 1.7mm average surface error and 32% average internal light propagation error is shown to be the most accurate registration method for atlas-based DOT. © 2015 SPIE.


Author Keywords
atlas-based DOT;  Diffuse Optical Tomography;  functional connectivity brain imaging;  registration.;  sensitivity analysis;  whole head imaging


Document Type: Conference Paper
Source: Scopus




Stewart, S.B.a b , Greene, D.J.b c , Lessov-Schlaggar, C.N.b , Church, J.A.d , Schlaggar, B.L.a b c e f
Clinical correlates of parenting stress in children with tourette syndrome and in typically developing children
(2015) Journal of Pediatrics, 166 (5), pp. 1297-1302.e3. 

DOI: 10.1016/j.jpeds.2015.01.041


a Department of Neurology, School of Medicine, Washington University in St Louis, 4525 Scott AveSt Louis, MO, United States
b Department of Psychiatry, School of Medicine, Washington University in St LouisSt Louis, MO, United States
c Department of Radiology, School of Medicine, Washington University in St LouisSt Louis, MO, United States
d Department of Psychology, University of Texas at AustinAustin, TX, United States
e Department of Pediatrics, School of Medicine, Washington University in St LouisSt Louis, MO, United States
f Departments of Anatomy and Neurobiology, School of Medicine, Washington University in St LouisSt Louis, MO, United States


Abstract
Objective To determine the impact of tic severity in children with Tourette syndrome on parenting stress and the impact of comorbid attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) symptomatology on parenting stress in both children with Tourette syndrome and typically developing children. Study design Children with diagnosed Tourette syndrome (n = 74) and tic-free typically developing control subjects (n = 48) were enrolled in a cross-sectional study. Results Parenting stress was greater in the group with Tourette syndrome than the typically developing group. Increased levels of parenting stress were related to increased ADHD symptomatology in both children with Tourette syndrome and typically developing children. Symptomatology of OCD was correlated with parenting stress in Tourette syndrome. Parenting stress was independent of tic severity in patients with Tourette syndrome. Conclusions For parents of children with Tourette syndrome, parenting stress appears to be related to the child's ADHD and OCD comorbidity and not to the severity of the child's tic. Subthreshold ADHD symptomatology also appears to be related to parenting stress in parents of typically developing children. These findings demonstrate that ADHD symptomatology impacts parental stress both in children with and without a chronic tic disorder. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus




Roediger, H.L., Abel, M.
Collective memory: A new arena of cognitive study
(2015) Trends in Cognitive Sciences, . Article in Press. 

DOI: 10.1016/j.tics.2015.04.003


Department of Psychology, Washington University in St. Louis, One Brookings Drive, Box 1125, St. Louis, MO 63130-4899, USA


Abstract
Collective memory refers to recollection of events shared by a group. The topic has been of central interest in the humanities, but recently researchers have begun empirical studies. Topics such as how people remember a war or how quickly Americans forget their presidents can be studied objectively. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus




Vilupuru, S.a , Lin, L.a , Pepose, J.S.b
Comparison of Contrast Sensitivity and Through Focus in Small-Aperture Inlay, Accommodating Intraocular Lens, or Multifocal Intraocular Lens Subjects
(2015) American Journal of Ophthalmology, . Article in Press. 

DOI: 10.1016/j.ajo.2015.04.023


a AcuFocus Inc, Irvine, California
b Pepose Vision Institute and the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Missouri


Abstract
Purpose: To compare monocular and binocular mesopic contrast sensitivity and through focus following monocular implantation with KAMRA small-aperture inlay (AcuFocus, Irvine, California, USA) vs binocular implantation with an accommodating or multifocal intraocular lens (IOL) implant. Design: Three-treatment randomized clinical trial of presbyopia-correcting IOLs with comparison to results from a previous nonrandomized multicenter clinical trial on the KAMRA corneal inlay. Methods: Study population of 507 subjects with KAMRA inlays; predetermined subgroups included 327 subjects that underwent contrast sensitivity testing and another 114 subjects for defocus curve testing, along with 78 subjects randomized between bilateral Crystalens Advanced Optics (AO) (Bausch+ Lomb Surgical, Aliso Viejo, California, USA), AcrySof IQ ReSTOR+3.0 D (Alcon Laboratories, Fort Worth, Texas, USA), or Tecnis+4D Multifocal (MF) (Abbott Medical Optics, Santa Ana, California, USA) IOL. Results: KAMRA inlay subjects demonstrated improved intermediate and near vision with minimal to no change to distance vision, better contrast sensitivity in the inlay eye when compared to the multifocals, and better binocular contrast sensitivity when compared to all 3 intraocular lenses. Crystalens AO was superior in uncorrected intermediate vision compared to the KAMRA inlay, but not in distance-corrected intermediate, and was worse in near vision. The multifocals were superior in near vision at their respective optimum near focus points, but worse in intermediate vision compared to both KAMRA inlay and Crystalens AO. Conclusions: The demonstrated performance of these devices should be considered, along with subjects' visual demands and expectations, degree of crystalline lens dysfunction, and other ocular characteristics, inguiding the selection of small-aperture corneal inlay or specific intraocular lens in the correction of presbyopia. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Hodge, M.R.a , Horton, W.a , Brown, T.a , Herrick, R.a , Olsen, T.b , Hileman, M.E.a , McKay, M.a , Archie, K.A.a , Cler, E.a , Harms, M.P.c , Burgess, G.C.c , Glasser, M.F.d , Elam, J.S.d , Curtiss, S.W.d , Barch, D.M.c , Oostenveld, R.e , Larson-Prior, L.J.a f , Ugurbil, K.g , Van Essen, D.C.d , Marcus, D.S.a
ConnectomeDB-Sharing human brain connectivity data
(2015) NeuroImage, . Article in Press. 

DOI: 10.1016/j.neuroimage.2015.04.046


a Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
b Deck5 Consulting, Normal, IL, USA
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
d Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA
e Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
g Center for Magnetic Resonance Imaging, University of Minnesota, Minneapolis, MN, USA


Abstract
ConnectomeDB is a database for housing and disseminating data about human brain structure, function, and connectivity, along with associated behavioral and demographic data. It is the main archive and dissemination platform for data collected under the WU-Minn consortium Human Connectome Project. Additional connectome-style study data is and will be made available in the database under current and future projects, including the Connectome Coordination Facility. The database currently includes multiple modalities of magnetic resonance imaging (MRI) and magnetoencephalograpy (MEG) data along with associated behavioral data. MRI modalities include structural, task, resting state and diffusion. MEG modalities include resting state and task. Imaging data includes unprocessed, minimally preprocessed and analysis data. Imaging data and much of the behavioral data are publicly available, subject to acceptance of data use terms, while access to some sensitive behavioral data is restricted to qualified investigators under a more stringent set of terms. ConnectomeDB is the public side of the WU-Minn HCP database platform. As such, it is geared towards public distribution, with a web-based user interface designed to guide users to the optimal set of data for their needs and a robust backend mechanism based on the commercial Aspera fasp service to enable high speed downloads. HCP data is also available via direct shipment of hard drives and Amazon S3. © 2015 Elsevier Inc.


Author Keywords
Connectome Coordination Facility;  Connectomics;  Data sharing;  Human Connectome Project;  Neuroinformatics databases;  Open access;  XNAT


Document Type: Article in Press
Source: Scopus




Bui, D.C., McDaniel, M.A.
Enhancing learning during lecture note-taking using outlines and illustrative diagrams
(2015) Journal of Applied Research in Memory and Cognition, 4 (2), pp. 129-135. 

DOI: 10.1016/j.jarmac.2015.03.002


Department of Psychology, Washington University in St. Louis, One Brookings Drive, Campus Box No. 1125St. Louis, MO, United States


Abstract
The current study examined the effects of providing learning aids during a lecture on later test performance, and its relationship to structure-building ability. Before taking notes on an audio lecture, participants were either given a skeletal outline, an illustrative diagram, or no learning aid at all. After the lecture, participants were given a free recall test and a short-answer test that probed understanding of target concepts (requiring explanation). For low-ability structure builders, outlines improved free recall but not short-answer performance compared to the no-aid control condition. By contrast, providing high-ability structure builders with outlines improved free recall and short-answer performance (relative to the control). An illustrative diagram improved free recall and short-answer performance compared to the control condition, regardless of structure-building ability. Thus, these aids are generally useful for improving learning while listening to a lecture. Implications for the more specific enhancement patterns for low-ability structure builders are discussed. © 2015 Society for Applied Research in Memory and Cognition.


Author Keywords
Illustrative diagrams;  Note-taking;  Outlines;  Structure-building


Document Type: Article
Source: Scopus




Yao, J.a , Wang, L.a , Yang, J.-M.a , Maslov, K.I.a , Wong, T.T.W.a , Li, L.a , Huang, C.-H.b , Zou, J.b , Wang, L.V.a
High-speed label-free functional photoacoustic microscopy of mouse brain in action
(2015) Nature Methods, 12 (5), pp. 407-410. 

DOI: 10.1038/nmeth.3336


a Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. LouisSt. Louis, MO, United States
b Department of Electrical and Computer Engineering, Texas AandM UniversityCollege Station, TX, United States


Abstract
We present fast functional photoacoustic microscopy (PAM) for three-dimensional high-resolution, high-speed imaging of the mouse brain, complementary to other imaging modalities. We implemented a single-wavelength pulse-width-based method with a one-dimensional imaging rate of 100 kHz to image blood oxygenation with capillary-level resolution. We applied PAM to image the vascular morphology, blood oxygenation, blood flow and oxygen metabolism in both resting and stimulated states in the mouse brain. © 2015 Nature America, Inc.


Document Type: Article
Source: Scopus




Hogan, R.E., Moseley, E.D., Maccotta, L.
Hippocampal Surface Deformation Accuracy in T1-Weighted Volumetric MRI Sequences in Subjects with Epilepsy
(2015) Journal of Neuroimaging, 25 (3), pp. 452-459. 

DOI: 10.1111/jon.12135


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


Abstract
BACKGROUND AND PURPOSE: To demonstrate the accuracy across different acquisition and analysis methods, we evaluated the variability in hippocampal volumetric and surface displacement measurements resulting from two different MRI (magnetic resonance imaging) acquisition protocols. METHODS: Nine epilepsy patients underwent two independent T1-weighted magnetization prepared spoiled gradient sequences during a single 3T MRI session. Using high-dimension mapping-large deformation (HDM-LD) segmentation, we calculated volumetric estimates and generated a vector-based 3-dimensional surface model of each subject's hippocampi, and evaluated volume and surface changes, the latter using a cluster-based noise estimation model. RESULTS: Mean hippocampal volumes and standard deviations for the left hippocampi were 2,750 (826) mm3 and 2,782 (859) mm3 (P = .13), and for the right hippocampi were 2,558 (750) mm3 and 2,547 (692) mm3 (P = .76), respectively for the MPR1 and MPR2 sequences. Average Dice coefficient comparing overlap for segmentations was 86%. There was no significant effect of MRI sequence on volume estimates and no significant hippocampal surface change between sequences. CONCLUSION: Statistical comparison of hippocampal volumes and statistically thresholded HDM-LD surfaces in TLE patients showed no differences between the segmentations obtained in the two MRI acquisition sequences. This validates the robustness across MRI sequences of the HDM-LD technique for estimating volume and surface changes in subjects with epilepsy. © 2014 by the American Society of Neuroimaging.


Author Keywords
Epilepsy;  Hippocampus;  MRI


Document Type: Article
Source: Scopus




Steinhorn, R.a , McPherson, C.b c , Anderson, P.J.d e , Neil, J.f , Doyle, L.W.d e g , Inder, T.c
Neonatal morphine exposure in very preterm infants - Cerebral development and outcomes
(2015) Journal of Pediatrics, 166 (5), pp. 1200-1207.e4. 

DOI: 10.1016/j.jpeds.2015.02.012


a Department of Pediatrics, Washington University in St. LouisSt. Louis, MO, United States
b Department of Pharmacy, Brigham and Women's HospitalBoston, MA, United States
c Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, 75 Francis StBoston, MA, United States
d Department of Pediatrics, Royal Women's Hospital, University of MelbourneCarlton, VIC, Australia
e Murdoch Children's Research InstituteParkville, VIC, Australia
f Department of Neurology, Boston Children's HospitalBoston, MA, United States
g Department of Obstetrics and Gynecology, Royal Women's Hospital, University of MelbourneCarlton, VIC, Australia


Abstract
Objective To investigate the association of morphine exposure in very preterm infants with cerebral volumes and neurodevelopmental outcome from birth through middle childhood. Study design Observational study of very preterm infants in the Victorian Infant Brain Study cohort. A total of 230 infants born <30 weeks' gestational age or <1250 g were recruited from all admissions to the neonatal intensive care unit of the Royal Women's Hospital. Fifty-seven (25%) infants received morphine analgesia during their neonatal intensive care unit stay at the attending physician's discretion. Primary outcomes were regional brain volumes at term and 7 years; neurobehavioral performance at term; and cognitive, motor, emotional, behavioral, communication, and executive function scores at age 2 and 7 years. Linear regressions were used to compare outcomes between participants who did and did not receive morphine. Results At term, preterm infants who received morphine had similar rates of gray matter injury to no-morphine infants, but a trend toward smaller cortical volumes in the orbitofrontal (Pleft =.002, Pright =.01) and subgenual (Pleft =.01) regions. At 7 years, cortical volumes did not differ between groups. At 2 years, morphine-exposed children were more likely to show behavioral dysregulation (P =.007) than no-morphine children, but at 7 years no detrimental impacts of morphine on neurobehavioral outcome were observed. Conclusions Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus




Spudich, S.S.a , Ances, B.M.b
Neurologic complications of HIV infection
(2015) Topics in Antiviral Medicine, 23 (1), pp. 47-55. 


a Yale University, School of MedicineNew Haven, CT, United States
b Washington UniversitySt Louis, MO, United States


Abstract
More than 30 years into the HIV epidemic, research efforts are focusing on better understanding how the central nervous system (CNS) is adversely affected by HIV and on improving the quality of life of HIV-infected individuals. At the 2015 Conference on Retroviruses and Opportunistic Infections, neurologic presentations concentrated on characterization of potential CNS reservoirs of HIV, the pathogenesis of HIV-associated neurocognitive disorders (HAND), diagnosis of cognitive dysfunction caused by HIV, neuroimaging biomarkers of HAND, and treatment of modifiable risk factors of HAND. Studies presented also highlighted research on CNS disorders in international, resource-limited settings, setting the stage for a growing collection of collaborative studies that will directly impact the largest concentrations of people living with HIV worldwide. © 2015, IAS–USA. All rights reserved.


Author Keywords
Central nervous system;  Cerebrospinal fluid;  CROI 2015;  HIV;  HIV-associated neurocognitive disorder;  Neuroimaging;  Neuropathogenesis


Document Type: Review
Source: Scopus




Poliani, P.L.a , Wang, Y.b , Fontana, E.a , Robinette, M.L.b , Yamanishi, Y.b , Gilfillan, S.b , Colonna, M.b
TREM2 sustains microglial expansion during aging and response to demyelination
(2015) Journal of Clinical Investigation, 125 (5), pp. 2161-2170. 

DOI: 10.1172/JCI77983


a Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia School of MedicineBrescia, Italy
b Washington University School of Medicine, Department of Pathology and Immunology, 660 S. Euclid Ave., Box 8118St. Louis, MO, United States


Abstract
Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2-/- mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2-/- mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2-/- microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2-/- mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter. © 2015, American Society for Clinical Investigation. All rights reserved.

 


Document Type: Article
Source: Scopus

 

 

May 11, 2015

 

Rosenberg, A.J., Liu, H., Tu, Z.
A practical process for the preparation of [32P]S1P and binding assay for S1P receptor ligands
(2015) Applied Radiation and Isotopes, 102, pp. 5-9. 

DOI: 10.1016/j.apradiso.2015.04.010


Department of Radiology, Washington University School of Medicine, 510 South Kingshighway BoulevardSt. Louis, MO, United States


Abstract
Sphingosine-1-phosphate receptors (S1PRs) are important regulators of vascular permeability, inflammation, angiogenesis and vascular maturation. Identifying a specific S1PR PET radioligand is imperative, but it is hindered by the complexity and variability of current for binding affinity measurement procedures. Herein, we report a streamlined protocol for radiosynthesis of [32P]S1P with good radiochemical yield (36-50%) and high radiochemical purity (>99%). We also report a reproducible procedure for determining the binding affinity for compounds targeting S1PRs in vitro. © 2015 Elsevier Ltd.


Author Keywords
Competitive binding assay;  Phosphorus-32;  Radioligand;  Sphingosine 1-phosphate;  Sphingosine 1-phosphate Receptors;  Sphingosine kinase 1


Document Type: Article
Source: Scopus


Norvin, D.a , Kim, G.a , Baker-Nigh, A.a b , Geula, C.a
Accumulation and age-related elevation of amyloid-β within basal forebrain cholinergic neurons in the rhesus monkey
(2015) Neuroscience, 298, pp. 102-111. 

DOI: 10.1016/j.neuroscience.2015.04.011


a Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of MedicineChicago, IL, United States
b Department of Neurology, Washington University School of Medicine, Campus Box 8111Saint Louis, MO, United States


Abstract
Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable to damage and loss in a number of neurodegenerative disorders that afflict the elderly, particularly Alzheimer's disease. The reasons for this selective vulnerability remain poorly understood. Given that intraneuronal accumulation of the amyloid-β peptide (Aβ) has been shown to exert deleterious effects on neurons, we tested potential accumulation of Aβ within BFCN in rhesus monkeys, which like the human display age-related accumulation of this peptide in plaques. The non-isoform-specific Aβ antibodies 1282 and 6E10 and the specific antibodies to 1-40 amino acid isoform of Aβ (Aβ<inf>1-40</inf>) and 1-42 amino acid isoform of Aβ (Aβ<inf>1-42</inf>) species were used in immunohistochemical experiments of basal forebrain in young and aged rhesus monkeys. All four antibodies visualized cortical plaques in the same sections in which BFCN were examined, in aged but not in young animals. The basal forebrain region within which the BFCN are localized was virtually free of plaques. Appreciable Aβ immunoreactivity was present within the nucleus basalis of Meynert-cholinergic cell group 4 (nbM-Ch4), the major component of BFCN, with all antibodies used. Quantitation of optical density indicated significant age-related increases in immunoreactivity in nbM-Ch4 neurons with the Aβ<inf>1-40</inf> (p<0.002) and 1282 (p<0.03) antibodies. Immunoreactivity for 6E10 displayed a small, non-significant age-related increase in nbM-Ch4 neurons (p>0.05). No age-related changes were detected in Aβ<inf>1-42</inf> immunoreactivity in these neurons. Unlike the BFCN, cortical neurons within the same sections were virtually devoid of Aβ immunoreactivity, particularly with isoform-specific antibodies. Both smooth and granular intraneuronal Aβ immunoreactivity, reminiscent of endosomal/lysosomal packaged peptide, were observed within nbM-Ch4 neurons. In some nbM-Ch4 neurons, 1282 immunoreactivity had the appearance of large peptide aggregates. Significant accumulation and age-related increase of Aβ in BFCN is likely to interfere with the normal functioning of these neurons. It remains to be determined if similar accumulation of Aβ occurs in human BFCN. © 2015 IBRO.


Author Keywords
Age-related increase;  Amyloid-β;  Amyloid-β isoform;  Basal forebrain cholinergic neurons;  Intraneuronal accumulation;  Selective accumulation


Document Type: Article
Source: Scopus


Armstrong, R.A.a , Cairns, N.J.b c
Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders
(2015) Journal of Neural Transmission, 13 p. Article in Press. 

DOI: 10.1007/s00702-015-1402-8


a Vision Sciences, Aston UniversityBirmingham, United Kingdom
b Department of Neurology, Washington University School of MedicineSaint Louis, MO, United States
c Department Pathology and Immunology, Washington University School of MedicineSaint Louis, MO, United States


Abstract
The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders. © 2015 Springer-Verlag Wien


Author Keywords
Cellular inclusions;  Dentate gyrus (DG);  Hippocampus (HC);  Neurodegenerative disease;  Synucleinopathies;  Tauopathies


Document Type: Article in Press
Source: Scopus


Stepp, S.D.a , Scott, L.N.a , Jones, N.P.a , Whalen, D.J.b , Hipwell, A.E.a
Negative emotional reactivity as a marker of vulnerability in the development of borderline personality disorder symptoms
(2015) Development and Psychopathology, 12 p. Article in Press. 

DOI: 10.1017/S0954579415000395


a University of Pittsburgh School of Medicine
b Washington University School of Medicine


Abstract
Negative emotionality is a distinguishing feature of borderline personality disorder (BPD). However, this person-level characteristic has not been examined as a marker of vulnerability in the development of this disorder. The current study utilized a multimethod approach to examine the interplay between negative emotional reactivity and cumulative exposure to family adversity on the development of BPD symptoms across 3 years (ages 16–18) in a diverse, at-risk sample of adolescent girls (N = 113). A latent variable of negative emotional reactivity was created from multiple assessments at age 16: self-report, emotion ratings to stressors from ecological assessments across 1 week, and observer-rated negative affectivity during a mother–daughter conflict discussion task. Exposure to family adversity was measured cumulatively between ages 5 and 16 from annual assessments of family poverty, single parent household, and difficult life circumstances. The results from latent growth curve models demonstrated a significant interaction between negative emotional reactivity and family adversity, such that exposure to adversity strengthened the association between negative emotional reactivity and BPD symptoms. In addition, family adversity predicted increasing BPD symptoms during late adolescence. These findings highlight negative emotional reactivity as a marker of vulnerability that ultimately increases risk for the development of BPD symptoms. Copyright © Cambridge University Press 2015


Document Type: Article in Press
Source: Scopus


Mitra, A.a , Snyder, A.Z.a b , Blazey, T.a , Raichle, M.E.a b
Lag threads organize the brain's intrinsic activity
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (17), pp. E2235-E2244. Cited 1 time.

DOI: 10.1073/pnas.1503960112


a Department of Radiology, Washington UniversitySt. Louis, MO, United States
b Department of Neurology, Washington UniversitySt. Louis, MO, United States


Abstract
It has been widely reported that intrinsic brain activity, in a variety of animals including humans, is spatiotemporally structured. Specifically, propagated slow activity has been repeatedly demonstrated in animals. In human resting-state fMRI, spontaneous activity has been understood predominantly in terms of zero-lag temporal synchrony within widely distributed functional systems (resting-state networks). Here, we use resting-state fMRI from 1,376 normal, young adults to demonstrate that multiple, highly reproducible, temporal sequences of propagated activity, which we term "lag threads," are present in the brain. Moreover, this propagated activity is largely unidirectional within conventionally understood resting-state networks. Modeling experiments show that resting-state networks naturally emerge as a consequence of shared patterns of propagation. An implication of these results is that common physiologic mechanisms may underlie spontaneous activity as imaged with fMRI in humans and slowly propagated activity as studied in animals. © 2015, National Academy of Sciences. All rights reserved.


Author Keywords
Dynamics;  fMRI;  Intrinsic activity;  Resting state


Document Type: Article
Source: Scopus


Linder, T.a , Wang, S.b , Zangerl-Plessl, E.-M.a , Nichols, C.G.b , Stary-Weinzinger, A.a
Molecular dynamics simulations of KirBac1.1 mutants reveal global gating changes of Kir channels
(2015) Journal of Chemical Information and Modeling, 55 (4), pp. 814-822. 

DOI: 10.1021/acs.jcim.5b00010


a Department of Pharmacology and Toxicology, University of ViennaVienna, Austria
b Center for Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Prokaryotic inwardly rectifying (KirBac) potassium channels are homologous to mammalian Kir channels. Their activity is controlled by dynamical conformational changes that regulate ion flow through a central pore. Understanding the dynamical rearrangements of Kir channels during gating requires high-resolution structure information from channels crystallized in different conformations and insight into the transition steps, which are difficult to access experimentally. In this study, we use MD simulations on wild type KirBac1.1 and an activatory mutant to investigate activation gating of KirBac channels. Full atomistic MD simulations revealed that introducing glutamate in position 143 causes significant widening at the helix bundle crossing gate, enabling water flux into the cavity. Further, global rearrangements including a twisting motion as well as local rearrangements at the subunit interface in the cytoplasmic domain were observed. These structural rearrangements are similar to recently reported KirBac3.1 crystal structures in closed and open conformation, suggesting that our simulations capture major conformational changes during KirBac1.1 opening. In addition, an important role of protein-lipid interactions during gating was observed. Slide-helix and C-linker interactions with lipids were strengthened during activation gating. © 2015 American Chemical Society.


Document Type: Article
Source: Scopus


Gerdts, J.a , Brace, E.J.b , Sasaki, Y.a , DiAntonio, A.b c , Milbrandt, J.a c
SARM1 activation triggers axon degeneration locally via NAD+ destruction
(2015) Science, 348 (6233), pp. 453-457. 

DOI: 10.1126/science.1258366


a Department of Genetics, Washington University Medical SchoolSaint Louis, MO, United States
b Department of Developmental Biology, Washington University Medical SchoolSaint Louis, MO, United States
c Hope Center for Neurological DisordersSaint Louis, MO, United States


Abstract
Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD+) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD+, whereas SARM1-induced axon destruction could be counteracted by increased NAD+ synthesis. SARM1-induced depletion of NAD+ may explain the potent axon protection in Wallerian degeneration slow (Wlds) mutant mice.


Document Type: Article
Source: Scopus


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, 12 p. Article in Press. 

DOI: 10.1007/s10896-015-9721-y


a College of Social Work, DeSaussure College, University of South CarolinaColumbia, SC, United States
b George Warren Brown School of Social Work, Washington University in St. LouisSt. 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 in Press
Source: Scopus


Waters, E.A.a , Janssen, E.b , Kaufman, A.R.c , Peterson, L.M.d , Muscanell, N.L.e , Guadagno, R.E.f , Stock, M.L.g
The Relationship Between Young Adult Smokers’ Beliefs About Nicotine Addiction and Smoking-Related Affect and Cognitions
(2015) Journal of Cancer Education, 10 p. Article in Press. 

DOI: 10.1007/s13187-015-0819-y


a Division of Public Health Sciences, Washington University School of Medicine, 660 S. Euclid Ave, Campus, Box 8100St. Louis, MO, United States
b Maastricht University School for Public Health and Primary Care (Caphri), Department of Health Promotion, Faculty of Health, Medicine and Life SciencesMaastricht, Netherlands
c Division of Cancer Control and Population Sciences, National Cancer InstituteRockville, MD, United States
d Department of Psychology, Bryn Mawr CollegeBryn Mawr, PA, United States
e Knowledge Media Research CenterTübingen, Germany
f Emerging Media and Communication; Department of Psychology, University of Texas at DallasRichardson, TX, United States
g Department of Psychology, George Washington UniversityWashington, DC, United States


Abstract
Risk beliefs and self-efficacy play important roles in explaining smoking-related outcomes and are important to target in tobacco control interventions. However, information is lacking about the underlying beliefs that drive these constructs. The present study investigated the interrelationships among young adult smokers’ beliefs about the nature of nicotine addiction and smoking-related affect and cognitions (i.e., feelings of risk, worry about experiencing the harms of smoking, self-efficacy of quitting, and intentions to quit). Smokers (n = 333) were recruited from two large universities. Results showed that quit intentions were associated with feelings of risk, but not with worry or self-efficacy. Furthermore, higher feelings of risk were associated with lower beliefs that addiction is an inevitable consequence of smoking and with lower beliefs that the harms of smoking are delayed. This suggests that it is important for health messages to counter the possible negative effects of messages that strongly emphasize the addictiveness of nicotine, possibly by emphasizing the importance of quitting earlier rather than later. The findings also add to the evidence base that feelings of risk are powerful predictors of behavioral intentions. Furthermore, our results suggest that in some circumstances, feelings of risk predict quit intentions beyond that predicted by worry and self-efficacy. Gaining additional understanding of the tobacco-related beliefs that can increase feelings of risk and incorporating those beliefs into educational campaigns may improve the quality of such campaigns and reduce tobacco use. © 2015 Springer Science+Business Media New York (outside the USA)


Author Keywords
Gene-environment interaction;  Health beliefs;  Risk perception;  Tobacco use


Document Type: Article in Press
Source: Scopus


Fourie, N.H.a , Jolly, C.J.b , Phillips-Conroy, J.E.c d , Brown, J.L.e , Bernstein, R.M.f
Variation of hair cortisol concentrations among wild populations of two baboon species (Papio anubis, P. hamadryas) and a population of their natural hybrids
(2015) Primates, 14 p. Article in Press. 

DOI: 10.1007/s10329-015-0469-z


a Biobehavioral Branch, Intramural Research Program, National Institute of Nursing Research, National Institutes of Health, Room 2N104, 10 Center DriveBethesda, MD, United States
b Department of Anthropology, New York UniversityNew York, NY, United States
c Department of Anatomy and Neurobiology, Washington University School of MedicineSaint Louis, MO, United States
d Department of Anthropology, Washington UniversitySt. Louis, MO, United States
e Smithsonian Conservation Biology Institute, Center for Species SurvivalFront Royal, VA, United States
f Department of Anthropology, University of Colorado BoulderBoulder, CO, United States


Abstract
Male olive (Papio anubis) and hamadryas (P. hamadryas) baboons have distinctive sociobehavioral and physical characteristics. In the Awash National Park, Ethiopia, a hybrid population at the contact zone between these two species, exhibits heterogeneous sociobehavioral and physical characteristics. The ambiguity of the hybrid social environment and disruption of parental stress genotypes may be sources of physiological stress for hybrids. We examined levels of chronic stress among males of the three populations and tested the prediction that chronic cortisol levels would be higher among the hybrids. Animals were captured, sampled, and released during the wet season, and a hair sample was taken for assay. Cortisol was extracted from 182 hair samples with methanol and quantified by ELISA. We included age, age class, rainfall variation, and species affiliation in models examining variation in hair cortisol levels. Species and age significantly contributed to models explaining variation in hair cortisol. Infant hypercortisolism was observed in all three groups, and a decline in cortisol through juvenile and adolescent stages, with a subsequent rise in adulthood. This rise occurred earliest in hamadryas, corroborating other evidence of the precocious development of hamadryas baboons. As expected, hybrids had significantly elevated hair cortisol compared with olive baboons and hamadryas, irrespective of age, except for very young animals. Infant hypercortisolism was also less pronounced among hybrids. Species differences and age-related differences in cortisol levels suggest a dysregulated cortisol phenotype in hybrids, and possibly reflect some form of hybrid disadvantage. More work will be required to disentangle the effects of genetic factors and the social environment. © 2015 Japan Monkey Centre and Springer Japan (outside the USA)


Author Keywords
Baboons;  Behavior;  Cortisol;  Hair;  Hybrids;  Stress


Document Type: Article in Press
Source: Scopus


Hung, C.-F.a b , Breen, G.a c , Czamara, D.d , Corre, T.e f , Wolf, C.d , Kloiber, S.d , Bergmann, S.e f , Craddock, N.g , Gill, M.h , Holsboer, F.d , Jones, L.i , Jones, I.g , Korszun, A.j , Kutalik, Z.e f , Lucae, S.d , Maier, W.k , Mors, O.l , Owen, M.J.m , Rice, J.n , Rietschel, M.o , Uher, R.a p , Vollenweider, P.q , Waeber, G.q , Craig, I.W.a , Farmer, A.E.a , Lewis, C.M.a r , Müller-Myhsok, B.d , Preisig, M.s , McGuffin, P.a , Rivera, M.a c t u
A genetic risk score combining 32 SNPs is associated with body mass index and improves obesity prediction in people with major depressive disorder
(2015) BMC Medicine, 13 (1), art. no. 86, . 

DOI: 10.1186/s12916-015-0334-3


a King's College London, MRC SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, Box PO82London, United Kingdom
b Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Department of PsychiatryKaohsiung, Taiwan
c King's College London, National Institute for Health Research Biomedical Research Centre for Mental Health, The Maudsley and Institute of PsychiatryLondon, United Kingdom
d Max-Planck-Institute of Psychiatry, Kraepelinstraße 2Munich, Germany
e Universitaire Vaudois (CHUV), 1010, Institute of Social and Preventive Medicine (IUMSP), Centre HospitalierLausanne, Switzerland
f Swiss Institute of BioinformaticsLausanne, Switzerland
g Cardiff University, Hadyn Ellis Building, MRC Centre for Neuropsychiatric Genetics and Genomics, Maindy RoadCardiff, United Kingdom
h Department of Psychiatry, Trinity Centre for Health SciencesDublin 8, Ireland
i University of Birmingham, Department of Psychiatry, School of Clinical and Experimental MedicineBirmingham, United Kingdom
j Queen Mary's University of London, Barts and The London School of Medicine and DentistryLondon, United Kingdom
k University of Bonn, Department of PsychiatryBonn, Germany
l Aarhus University Hospital, Research Department P, Skovagervej 2Risskov, Denmark
m School of Medicine, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Henry Wellcome Building, Heath ParkCardiff, United Kingdom
n Washington University School of Medicine, Department of PsychiatrySt Louis, MO, United States
o Central Institute of Mental HealthMannheim, Germany
p Dalhousie University, Halifax, Department of PsychiatryNova Scotia, NS, Canada
q Division of Internal Medicine, CHUV, Rue du Bugnon 21Lausanne, Switzerland
r School of Medicine, King's College London, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guys HospitalLondon, United Kingdom
s Lausanne University Hospital, Department of PsychiatryPrilly-Lausanne, Switzerland
t University of Granada, CIBERSAM-University of Granada and Institute of Neurosciences Federico Olóriz, Centro de Investigación Biomédica, Avda del Conocimiento s/n, 18100 ArmillaGranada, Spain
u Hospitales Universitarios de Granada/Universidad de Granada, Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, C/ Dr. Azpitarte, 4, 18012Granada, Spain


Abstract
Background: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD. Methods: Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity. Results: In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P <0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; Χ2=27.68; P <0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC=0.71; 95% CI, 0.68-0.73; Χ2=28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results. Conclusions: A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity. © Hung et al.; licensee BioMed Central.


Author Keywords
Body mass index;  Genetic risk score;  Major depressive disorder;  Obesity


Document Type: Article
Source: Scopus


Gidday, J.M.a b c , Zhang, L.a , Chiang, C.-W.d , Zhu, Y.a
Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset
(2015) Neurotherapeutics, 12 (2), pp. 502-514. 

DOI: 10.1007/s13311-014-0330-x


a Department of Neurosurgery, Washington University School of MedicineSt. Louis, MO, United States
b Department of Ophthalmology & Visual Sciences, Washington University School of MedicineSt. Louis, MO, United States
c Department of Cell Biology & Physiology, Washington University School of MedicineSt. Louis, MO, United States
d Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
The neuroprotective efficacy of adaptive epigenetics, wherein beneficial gene expression changes are induced by nonharmful “conditioning” stimuli, is now well established in several acute, preclinical central nervous system injury models. Recently, in a mouse model of glaucoma, we demonstrated retinal ganglion cell (RGC) protection by repetitively “preconditioning” with hypoxia prior to disease onset, indicating an epigenetic approach may also yield benefits in chronic neurodegenerative disease. Herein, we determined whether presenting the repetitive hypoxic stimulus after disease initiation [repetitive hypoxic “postconditioning” (RH-Post)] could afford similar functional and morphologic protection against glaucomatous RGC injury. Chronic elevations in intraocular pressure (IOP) were induced unilaterally in adult male C57BL/6 mice by episcleral vein ligation. Mice were randomized to an RH-Post [1 h of systemic hypoxia (11 % oxygen) every other day, starting 4 days after IOP elevation] or an untreated control group. After 3 weeks of experimental glaucoma, the 21–27 % reduction and 5–25 % prolongation in flash visual-evoked potential amplitudes and latencies, respectively, and the 30 % impairment in visual acuity were robustly improved in RH-Post–treated mice, as was the 17 % loss in RGC soma number and 20 % reduction in axon integrity. These protective effects were observed without RH-Post affecting IOP. The present findings demonstrate that functional and morphologic protection of RGCs can be realized by stimulating epigenetic responses during the early stages of disease, and thus constitute a new conceptual approach to glaucoma therapeutics. © 2014, The American Society for Experimental NeuroTherapeutics, Inc.


Author Keywords
epigenetics;  Glaucoma;  neuroprotection;  optic nerve;  retina


Document Type: Article
Source: Scopus


Irwin, D.J.a b , Cairns, N.J.d , Grossman, M.b , McMillan, C.T.b , Lee, E.B.c , Van Deerlin, V.M.a , Lee, V.M.-Y.a , Trojanowski, J.Q.a
Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine
(2015) Acta Neuropathologica, 129 (4), pp. 469-491. 

DOI: 10.1007/s00401-014-1380-1


a Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Ageing, University of Pennsylvania School of Medicine, HUP Maloney 3rd Floor, 36th and Spruce StreetsPhiladelphia, PA, United States
b Department of Neurology, Penn Frontotemporal Degeneration Center, University of PennsylvaniaPhiladelphia, PA, United States
c Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, PA, United States
d Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD. © 2014, Springer-Verlag Berlin Heidelberg.


Author Keywords
ALS;  C9orf72;  FTLD;  GRN;  MAPT;  Tau;  TDP-43


Document Type: Review
Source: Scopus


Shanks, A.M.a , Avidan, M.S.b , Kheterpal, S.a , Tremper, K.K.a , Vandervest, J.C.a , Cavanaugh, J.M.c , Mashour, G.A.a
Alerting thresholds for the prevention of intraoperative awareness with explicit recall
(2015) European Journal of Anaesthesiology, 32 (5), pp. 346-353. Cited 1 time.

DOI: 10.1097/EJA.0000000000000123


a Department of Anesthesiology, University of Michigan, 1500 East Medical Center DriveAnn Arbor, MI, United States
b Department of Anesthesiology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Biomedical Engineering, Wayne State UniversityDetroit, MI, United States


Abstract
BACKGROUND Intraoperative awareness with explicit recall is a potentially devastating complication of surgery that has been attributed to low anaesthetic concentrations in the vast majority of cases. Past studies have proposed the determination of an adequate dose for general anaesthetics that could be used to alert providers of potentially insufficient anaesthesia. However, there have been no systematic analyses of appropriate thresholds to develop population-based alerting algorithms for preventing intraoperative awareness. OBJECTIVE To identify a threshold for intraoperative alerting that could be applied for the prevention of awareness with explicit recall. DESIGN Secondary analysis of a randomised controlled trial (Michigan Awareness Control Study). SETTING Three hospitals at a tertiary care centre in the USA. PATIENTS Unselected patients presenting for surgery under general anaesthesia. INTERVENTIONS Alerts based on end-tidal anaesthetic concentration or bispectral index values. MAIN OUTCOME MEASURES Using case and outcomes data from the primary study, end-tidal anaesthetic concentration and bispectral index values were analysed using Youden's index and c-statistics derived from a receiver operating characteristic curve to determine a specific alerting threshold for the prevention of awareness. RESULTS No single population-based threshold that maximises sensitivity and specificity could be identified for the prevention of intraoperative awareness, using either anaesthetic concentration or bispectral index values. The c-statistic for anaesthetic concentration was 0.431 ± 0.046, and 0.491 ± 0.056 for bispectral index values. CONCLUSION We could not derive a single population-based alerting threshold for the prevention of intraoperative awareness using either anaesthetic concentration or bispectral index values. These data indicate a need to move towards individualised alerting strategies in the prevention of intraoperative awareness. TRIAL REGISTRATION Primary trial registration (Michigan Awareness Control Study) ClinicalTrials.gov identifier: NCT00689091. © © 2015 Copyright European Society of Anaesthesiology.


Document Type: Article
Source: Scopus


Lee, J.H.a , Ryan, J.b , Andreescu, C.b , Aizenstein, H.b , Lim, H.K.c
Brainstem morphological changes in Alzheimer's disease
(2015) NeuroReport, 26 (7), pp. 411-415. 

DOI: 10.1097/WNR.0000000000000362


a Washington UniversitySt Louis, MO, United States
b Department of Psychiatry, School of Medicine, University of PittsburghPittsburgh, PA, United States
c Department of Psychiatry, Saint Vincent Hospital, Catholic University of Korea, 93 Ji-Dong Paldal-guSeoul, South Korea


Abstract
As brainstem nuclei are interconnected with several cortical structures and regulate several autonomic, cognitive, and behavioral functions, it might be important to place the brainstem within an important pathologic core in the progression of Alzheimer's disease (AD). Although there have been several postmortem studies reporting neuropathological alterations of the brainstem in AD, there has been no in-vivo structural neuroimaging study of the brainstem in the patients with AD. The aim of this study was to investigate differences in the brainstem volume and shape between patients with AD and elderly normal controls. Fifty AD patients (the Clinical Dementia Rating Scale>1) and 50 normal controls were recruited, and the brainstem volumes and deformations were compared between the AD and the controls. Patients with AD showed significant total volume [(mean ± SD) 21007± 1640mm3] reduction in the brainstem compared with the controls [(mean ± SD) 22530 ± 1750mm3] (P<0.001). In addition, AD patients showed significant brainstem deformations in the upper posterior brainstem corresponding to the midbrain compared with the healthy individuals (false discovery rate corrected P<0.05). This study is the first to explore brainstem volume change and deformations in AD. These structural changes in the midbrain areas might be at the core of the underlying neurobiological mechanisms of brainstem dysfunction with relevance to their various cognitive and behavioral symptoms such as memory impairment, sleep, and emotional disturbance in AD. However, further longitudinal studies might be needed to confirm these findings. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Author Keywords
Alzheimer's disease;  brainstem;  MRI;  shape analysis


Document Type: Article
Source: Scopus


Mazuski, C., Herzog, E.D.
Circadian rhythms: To sync or not to sync
(2015) Current Biology, 25 (8), art. no. 11839, pp. R337-R339. 

DOI: 10.1016/j.cub.2015.02.032


Department of Biology, Washington UniversitySt. Louis, MO, United States


Abstract
Summary Using real-time imaging of circadian gene expression, a new study reveals how a light pulse briefly desynchronizes clock neurons in the fly brain before they settle into a new, synchronized daily rhythm. © 2015 Elsevier Ltd. All rights reserved.


Document Type: Article
Source: Scopus


Kapoor, M.a , Agrawal, A.b
Commentary: Sex Differences in the Pathways to Symptoms of Alcohol Use Disorder: A Study of Opposite-Sex Twin Pairs
(2015) Alcoholism: Clinical and Experimental Research, . Article in Press. 

DOI: 10.1111/acer.12736


a Department of Neuroscience Icahn School of Medicine at Mount Sinai New York City, New York
b Department of Psychiatry Washington University in St. Louis St. Louis, Missouri


Document Type: Article in Press
Source: Scopus


Lopez-Escamez, J.A.a k , Carey, J.b , Chung, W.-H.c , Goebel, J.A.d , Magnusson, M.e , Mandalà, M.f , Newman-Toker, D.E.g , Strupp, M.h , Suzuki, M.i , Trabalzini, F.f , Bisdorff, A.j
Diagnostic criteria for Menière's disease
(2015) Journal of Vestibular Research: Equilibrium and Orientation, 25 (1), pp. 1-7. 

DOI: 10.3233/VES-150549


a Otology and Neurotology Group CTS495, Universidad de Granada, Junta de Andalucía, Avda de la Ilustracion, 114Granada, Spain
b Department of Otolaryngology, Head and Neck Surgery, John Hopkins University School of MedicineBaltimore, MD, United States
c Department of Otolaryngology, Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan Univerisity School of MedicineSeoul, South Korea
d Department of Otolaryngology, Head and Neck Surgery, Washington University School of MedicineSaint Louis, MO, United States
e Department of Otolaryngology, University of LundLund, Sweden
f Otology and Skull Base Department, Azienda Ospedaliera Universitaria SeneseSiena, Italy
g Department of Neurology, John Hopkins University School of MedicineBaltimore, MD, United States
h Department of Neurology, German Center for Vertigo and Balance Disorders, Ludwig-Maximilians UniversityMunich, Germany
i Department of Otolaryngology, Tokyo Medical UniversityTokyo, Japan
j Department of Neurology, Centre Hospitalier Emile MayrischEsch-sur-Alzette, Luxembourg
k Department of Otolaryngology, Hospital de PonienteEl Ejido, Almeria, Spain


Abstract
This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 minutes and 12 hours. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 minutes to 24 hours. © 2015 - IOS Press and the authors. All rights reserved.


Author Keywords
Meniere disease;  sensorineural hearing loss;  tinnitus;  Vertigo;  vestibular disorders


Document Type: Article
Source: Scopus


Kung, N.H., Dhar, R., Keyrouz, S.G.
Diffuse leptomeningeal carcinomatosis mimicking brain death
(2015) Journal of the Neurological Sciences, 352 (1-2), art. no. 13724, pp. 132-134. 

DOI: 10.1016/j.jns.2015.03.045


Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8111Saint Louis, MO, United States


Author Keywords
Brain death;  Coma;  Metastatic tumor


Document Type: Article
Source: Scopus


Lee, K.H.a b , Warchol, M.E.c , Pawlowski, K.S.a , Shao, D.a , Koulich, E.a , Zhou, C.Q.a , Lee, J.d , Henkemeyer, M.J.e
Ephrins and Ephs in cochlear innervation and implications for advancing cochlear implant function
(2015) Laryngoscope, 125 (5), pp. 1189-1197. 

DOI: 10.1002/lary.25066


a Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.Dallas, TX, United States
b Department of Developmental Biology, University of Texas Southwestern Medical CenterDallas, TX, United States
c Division of Pediatric Otolaryngology, Children's Medical CenterDallas, TX, United States
d Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine in St. LouisSt. Louis, MO, United States
e Department of Pathology, Harbor University of California Los Angeles Medical Medical CenterLos Angeles, CA, United States


Abstract
Objectives/Hypothesis Determine if the neuronal pathfinding cues resulting from Eph/ephrin interaction in the inner ear play a role in establishing the tonotopic innervation of the cochlea. Study Design Protein expression of Ephs and ephrins was evaluated in the inner ear of mice and chicks. Subsequently, in vitro, in vivo, and functional electrophysiologic studies were performed to indicate that Ephs and ephrins play a role regulating the normal innervation patterns in the mouse inner ear. Methods Eph and ephrin protein expression was identified in the inner ear by western blotting and localized by fluorescence immunohistochemistry and X-gal staining. Eph/ephrin effects on neurite outgrowth was assessed via co-culture with EphB2 expressing COS-1 cells. Anatomic effects of disrupting Eph/ephrin signaling on cochlear innervation were determined with lipophilic dye tracing and functional effects with auditory brainstem response (ABR). Results Expression of several different Ephs and ephrins were found in the inner ear of chicks and mice. The changes in ephrin-A2 immunoreactivity after gentamicin ototoxicity coincide with the spatio-temporal pattern of hair cell loss and regeneration in the chick cochlea. EphB2 inhibited outgrowth of spiral ganglion cell neurites. Knockout mice with null function of EphB1, EphB2, and EphB3 demonstrated abnormal inner ear innervation and elevated ABR thresholds, indicating hearing loss. Conclusions Ephrin-A2 may be involved in the guidance of ganglion cells to hair cells in the chick. Disruption of Eph/ephrin signaling results in abnormal innervation and hearing loss, suggesting that these proteins play a role in establishing normal innervation patterns in the mouse cochlea. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.


Author Keywords
axon guidance;  cochlear implants;  cochlear innervation;  Eph;  ephrin


Document Type: Article
Source: Scopus


Patterson Silver Wolf (Adelv Unegv Waya), D.A.
Factors Influencing the Implementation of a Brief Alcohol Screening and Educational Intervention in Social Settings not Specializing in Addiction Services
(2015) Social Work in Health Care, 54 (4), pp. 345-364. 

DOI: 10.1080/00981389.2015.1005270


Brown School, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Although alcohol use continues to be a major problem, when high-risk users enter social services, they are not provided with empirically supported treatments (ESTs). This study investigates predictors of successful implementation in agencies not specializing in addiction services. Fifty-four frontline workers in six organizations were enrolled in the study. After completing self-administered surveys of organizational culture and climate and attitudes toward ESTs, workers were trained to implement a brief intervention. The results indicate that organizational factors and attitudes may not be related to implementation. Although high implementers had similar traits, further research is needed to characterize successful EST implementers. © , Copyright © Taylor & Francis Group, LLC.


Author Keywords
alcohol and drug use;  empirically supported treatments;  implementation;  organizational culture and climate;  worker characteristics


Document Type: Article
Source: Scopus


Mitsuhashi, K., Wang, L.V., Anastasio, M.A.
Image reconstruction in transcranial photoacoustic computed tomography of the brain
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9323, art. no. 93233B, . 

DOI: 10.1117/12.2081050


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


Abstract
Photoacoustic computed tomography (PACT) holds great promise for transcranial brain imaging. However, the strong reflection, scattering, attenuation, and mode-conversion of photoacoustic waves in the skull pose serious challenges to establishing the method. The lack of an appropriate model of solid media in conventional PACT imaging models, which are based on the canonical scalar wave equation, causes a significant model mismatch in the presence of the skull and thus results in deteriorated reconstructed images. The goal of this study was to develop an image reconstruction algorithm that accurately models the skull and thereby ameliorates the quality of reconstructed images. The propagation of photoacoustic waves through the skull was modeled by a viscoelastic stress tensor wave equation, which was subsequently discretized by use of a staggered grid fourth-order finite-difference time-domain (FDTD) method. The matched adjoint of the FDTD-based wave propagation operator was derived for implementing a backprojection operator. Systematic computer simulations were conducted to demonstrate the effectiveness of the backprojection operator for reconstructing images in a realistic three-dimensional PACT brain imaging system. The results suggest that the proposed algorithm can successfully reconstruct images from transcranially-measured pressure data and readily be translated to clinical PACT brain imaging applications. © 2015 SPIE.


Author Keywords
Brain imaging;  Image reconstruction;  Photoacoustic computed tomography


Document Type: Conference Paper
Source: Scopus


Lin, L.a , Xia, J.a b , Wong, T.T.W.a , Zhang, R.a , Wang, L.V.a
In vivo deep brain imaging of rats using oral-cavity illuminated photoacoustic computed tomography
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9323, art. no. 93230G, . 

DOI: 10.1117/12.2076482


a Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, One Brookings DriveSt. Louis, MO, United States
b Department of Biomedical Engineering, State University of New York, University at BuffaloBuffalo, NY, United States


Abstract
We demonstrate, by means of internal light delivery, photoacoustic imaging of the deep brain of rats in vivo. With fiber illumination via the oral cavity, we delivered light directly into the bottom of the brain, much more than can be delivered by external illumination. The study was performed using a photoacoustic computed tomography (PACT) system equipped with a 512-element full-ring transducer array, providing a full two-dimensional view aperture. Using internal illumination, the PACT system provided clear cross sectional photoacoustic images from the palate to the middle brain of live rats, revealing deep brain structures such as the hypothalamus, brain stem, and cerebral medulla. © 2015 SPIE.


Author Keywords
Deep brain imaging;  Internal illumination;  Optical fiber;  Oral-cavity illumination;  Photoacoustic computed tomography


Document Type: Conference Paper
Source: Scopus


Lazear, H.M.a , Daniels, B.P.b , Pinto, A.K.a , Huang, A.C.c , Vick, S.C.a g , Doyle, S.E.d , Gale, M., Jr.c , Klein, R.S.a b e , Diamond, M.S.a e f
Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier
(2015) Science Translational Medicine, 7 (284), p. 284ra57. Cited 1 time.

DOI: 10.1126/scitranslmed.aaa4304


a Department of Medicine, Washington University School of MedicineSt. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Immunology, University of Washington School of MedicineSeattle, WA, United States
d ZymoGenetics, Bristol-Myers Squibb CompanySeattle, WA, United States
e Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States
f Department of Molecular Microbiology, Washington University School of MedicineSt. Louis, MO, United States
g Department of Microbiology and Immunology, University of North CarolinaChapel Hill, NC, United States


Abstract
Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1-/- mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1-/- mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.


Document Type: Article
Source: Scopus


Li, L.a b , Xia, J.a , Li, G.a , Garcia-Uribe, A.a , Wang, L.V.a b
Label-free structural photoacoustic tomography of intact mouse brain
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9323, art. no. 93230M, . 

DOI: 10.1117/12.2077236


a Department of Electrical and System Engineering, Washington University in St. Louis, One Brookings Dr.St. Louis, MO, United States
b Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Dr.St. Louis, MO, United States


Abstract
Capitalizing on endogenous hemoglobin contrast, photoacoustic computed tomography (PACT), a deep-tissue highresolution imaging modality, has drawn increasing interest in neuro-imaging. However, most existing studies are limited to functional imaging on the cortical surface, and the deep-brain structural imaging capability of PACT has never been demonstrated. Here, we explicitly studied the limiting factors of deep-brain PACT imaging. We found that the skull distorted the acoustic signal and blood suppressed the structural contrast from other chromophores. When the two effects are mitigated, PACT can provide high-resolution label-free structural imaging through the entire mouse brain. With 100 μm in-plane resolution, we can clearly identify major structures of the brain, and the image quality is comparable to that of magnetic resonance microscopy. Spectral PACT studies indicate that structural contrasts mainly originate from cytochrome and lipid. The feasibility of imaging the structure of the brain in vivo has also been discussed. Our results demonstrate that PACT is a promising modality for both structural and functional brain imaging. © 2015 SPIE.


Author Keywords
Brain imaging;  Label-free imaging;  Photoacoustic computed tomography;  Structural photoacoustic tomography


Document Type: Conference Paper
Source: Scopus


Reynolds, M.R.a b , Crilly, S.M.b , Sweeney, K.J.b , Farrell, M.b c , Rawluk, D.b
Metastatic pancreatic neuroendocrine tumor to the central nervous system in a patient with von Hippel-Lindau disease: A case report and literature review
(2015) British Journal of Neurosurgery, 29 (2), pp. 291-293. 

DOI: 10.3109/02688697.2014.957650


a Department of Neurological Surgery, Washington University in St. Louis, Campus Bux 8057, 660 S. Euclid Ave.St. Louis, MO, United States
b Department of Neurological Surgery, Beaumont HospitalDubline, Ireland
c Department of Neuropathology, Beaumont HospitalDubline, Ireland


Abstract
Pancreatic neuroendocrine tumor (NET) is frequently encountered in patients with von Hippel-Lindau disease (VHL) and uncommonly metastasizes to the central nervous system. Here, we present the case of a VHL patient with symptomatic pancreatic NET metastases to both the cervical spinal cord and a preexisting brainstem hemangioblastoma (e.g., tumor- to-tumor metastasis). © 2015 The Neurosurgical Foundation.


Author Keywords
Pancreatic neuroendocrine tumor;  Tumor-to-tumor metastasis;  Von Hippel-Lindau


Document Type: Review
Source: Scopus


Zhou, Y.a , Yi, X.b , Xing, W.a , Hu, S.a , Maslov, K.I.a , Wang, L.V.a
Photoacoustic microscopy of complex regional pain syndrome type I (CRPS-1) after stellate ganglion blocks in vivo
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9323, art. no. 932338, . 

DOI: 10.1117/12.2076691


a Washington University in St. Louis, Department of Biomedical Engineering, Optical Imaging Laboratory, One Brookings DriveSt. Louis, MO, United States
b Washington University School of Medicine, Department of Anesthesiology/Pain Management, 660 South Euclid AvenueSt. Louis, MO, United States


Abstract
We used photoacoustic microscopy (PAM) to assist diagnoses and monitor the progress and treatment outcome of complex regional pain syndrome type 1 (CRPS-1). Blood vasculature and oxygen saturation (sO<inf>2</inf>) were imaged by PAM in eight adult patients with CRPS-1. Patients' hands and cuticles were imaged both before and after stellate ganglion block (SGB) for comparison. For all patients, both the vascular structure and sO<inf>2</inf> could be assessed by PAM. In addition, more vessels and stronger signals were observed after SGB. © 2015 SPIE.


Author Keywords
Complex regional pain syndrome;  Photoacoustic microscopy;  Stellate ganglion block


Document Type: Conference Paper
Source: Scopus


McDermott, K.B., Gilmore, A.W.
The Role of Context in Understanding Similarities and Differences in Remembering and Episodic Future Thinking
(2015) Psychology of Learning and Motivation - Advances in Research and Theory, . Article in Press. 

DOI: 10.1016/bs.plm.2015.03.004


Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA


Abstract
Remembering events from one's lifetime (autobiographical remembering) and envisioning events one might experience in the future (episodic future thought) call upon many similar cognitive processes, yet humans can routinely distinguish between the two. How can we understand their similarities and differences (in phenomenological and processing terms)? This chapter suggests that the greater accessibility of contextual associations for remembered events than imagined events plays a key role in understanding this puzzle, and we present behavioral and neuroimaging evidence that converges on this conclusion. © 2015 Elsevier Inc.


Author Keywords
Autobiographical memory;  Autonoetic consciousness;  Context;  Contextual associations;  Episodic future thought;  Imagery;  Prospection;  Remembering


Document Type: Article in Press
Source: Scopus


Kulminski, A.M.a , Arbeev, K.G.a , Culminskaya, I.a , Ukraintseva, S.V.a , Stallard, E.a , Province, M.A.b , Yashin, A.I.a
Trade-Offs in the Effects of the Apolipoprotein E Polymorphism on Risks of Diseases of the Heart, Cancer, and Neurodegenerative Disorders: Insights on Mechanisms from the Long Life Family Study
(2015) Rejuvenation Research, 18 (2), pp. 128-135. 

DOI: 10.1089/rej.2014.1616


a Center for Population Health and Aging, Duke University, Trent Hall, Room 002, Box 90408Durham, NC, United States
b Washington University School of Medicine, Division of Statistical GenomicsSt. Louis, MO, United States


Abstract
The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]<inf>>75</inf>=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR<inf>>76</inf>=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10-3). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span. © Copyright 2015, Mary Ann Liebert, Inc.


Document Type: Article
Source: Scopus


Diemer, E.W.a , Grant, J.D.a b , Munn-Chernoff, M.A.a b , Patterson, D.A.c , Duncan, A.E.a b c
Gender Identity, Sexual Orientation, and Eating-Related Pathology in a National Sample of College Students
(2015) Journal of Adolescent Health, . Article in Press. 

DOI: 10.1016/j.jadohealth.2015.03.003


a Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
b Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, Missouri
c George Warren Brown School of Social Work, Washington University, St. Louis, Missouri


Abstract
Purpose: This study examined associations of gender identity and sexual orientation with self-reported eating disorder (SR-ED) diagnosis and compensatory behaviors in transgender and cisgender college students. Methods: Data came from 289,024 students from 223 U.S. universities participating in the American College Health Association-National College Health Assessment II (median age, 20years). Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were compared among transgender students (n= 479) and cisgender sexual minority (SM) male (n= 5,977) and female (n= 9,445), unsure male (n= 1,662) and female (n= 3,395), and heterosexual male (n= 91,599) and female (n= 176,467) students using chi-square tests. Logistic regression models were used to estimate the odds of eating-related pathology outcomes after adjusting for covariates. Results: Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were highest among transgender students and lowest among cisgender heterosexual men. Compared to cisgender heterosexual women, transgender students had greater odds of past-year SR-ED diagnosis (odds ratio [OR], 4.62; 95% confidence interval [CI], 3.41-6.26) and past-month use of diet pills (OR, 2.05; 95% CI, 1.48-2.83) and vomiting or laxatives (OR, 2.46; 95% CI, 1.83-3.30). Although cisgender SM men and unsure men and women also had elevated rates of SR-ED diagnosis than heterosexual women, the magnitudes of these associations were lower than those for transgender individuals (ORs; 1.40-1.54). Conclusions: Transgender and cisgender SM young adults have elevated rates of compensatory behavior and SR-ED diagnosis. Appropriate interventions for these populations are urgently needed. © 2015 Society for Adolescent Health and Medicine.


Author Keywords
College students;  Compensatory behaviors;  Eating disorders;  Gender identity;  Sexual orientation


Document Type: Article in Press
Source: Scopus


Siuda, E.R.a b , Copits, B.A.a c , Schmidt, M.J.a , Baird, M.A.a f , Al-Hasani, R.a , Planer, W.J.a , Funderburk, S.C.a , McCall, J.G.a b , Gereau, R.W.a b c d , Bruchas, M.R.a b c d e
Spatiotemporal Control of Opioid Signaling and Behavior
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.03.066


a Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA
b Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
c Washington University Pain Center, Washington University in St. Louis, St. Louis, MO 63110, USA
d Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO 63110, USA
e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, USA
f University of Washington, Department of Pharmacology, Seattle, WA 98195-7280, USA


Abstract
Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches usebinary on/off control schemes. Here, we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically sensitive, mu-opioid-like receptor, which we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels and internalizes with kinetics similar to that of the mu-opioid receptor. To assess invivo utility, we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways. Siuda etal. develop a photosensitive mu-opioid-like receptor (opto-MOR) that triggers cAMP inhibition and MAP kinase activation, couples to GIRK currents, and internalizes like the mu-opioid receptor. Photostimulation of opto-MOR within discrete GABAergic nuclei induces real-time preference or aversion. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus


Corbetta, M.
Hemispatial neglect: Clinic, pathogenesis, and treatment
(2014) Seminars in Neurology, 34 (5), pp. 514-523. 

DOI: 10.1055/s-0034-1396005


Departments of Neurology, Radiology, Anatomy and Neurobiology, Biomedical Engineering Washington University, School of Medicine, 660 S.Euclid AveSt. Louis, MO, United States


Abstract
Hemispatial neglect is characterized by a failure of awareness on the side of space and body opposite the site of injury, has been extensively studied for its theoretical interest in revealing brain mechanisms of awareness and attention. More recently, it has become apparent that hemispatial neglect reflects not only damage of specific anatomical regions, but also the large-scale dysfunction of networks of brain regions specialized in attention, motor, and multimodal sensory processing. Finally, although previous studies showed that the symptoms of hemispatial neglect could be effectively, albeit transiently, improved by a variety of behavioral, pharmacological, and physical interventions, only recently have treatment studies begun to show long-lasting therapeutic effects. Future advances will require the integration of advanced brain imaging methods to identify abnormal brain circuitries and-in combination with sensory, cognitive, and neural stimulation-methods to modulate activity in those circuitries. © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York.


Author Keywords
attention;  networks;  rehabilitation;  stroke;  TMS


Document Type: Article
Source: Scopus


Yamamoto, K.a , Tanei, Z.-I.a b , Hashimoto, T.a , Wakabayashi, T.a , Okuno, H.c , Naka, Y.a , Yizhar, O.d , Fenno, L.E.d , Fukayama, M.b , Bito, H.c , Cirrito, J.R.e , Holtzman, D.M.e , Deisseroth, K.d , Iwatsubo, T.a
Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease
(2015) Cell Reports, . Article in Press. 

DOI: 10.1016/j.celrep.2015.04.017


a Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
b Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
c Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
d Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
e Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA


Abstract
Invivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects ofchronic synaptic activation on Aβ pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-lasting neuronal hyperexcitability, into the hippocampal perforant pathway of APP transgenic mice. Invivo microdialysis revealed a ~24% increase in the hippocampal interstitial fluid Aβ42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Aβ burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by ~2.5-fold compared with that in the contralateral side. Epileptic seizures were observed during the course of chronic stimulation, which might have partly contributed to the Aβ pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Aβ pathology and Alzheimer disease. Neuronal or synaptic activity has been implicated in the pathogenesis of Alzheimer disease. Yamamoto etal. show that chronic activation of the hippocampal perforant pathway in APP transgenic mice, using optogenetics, augments Aβ pathology within the presynaptic projection area in the dentate gyrus of the hippocampus. © 2015 The Authors.

 


Document Type: Article in Press
Source: Scopus

May 4, 2015

 Šikic, H.a b , Shi, Y.b , Lubura, S.a , Bassnett, S.b
A stochastic model of eye lens growth
(2015) Journal of Theoretical Biology, 376, pp. 15-31. 

DOI: 10.1016/j.jtbi.2015.03.021


a University of Zagreb, Faculty of Science, Department of Mathematics, Croatia
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, United States


Abstract
The size and shape of the ocular lens must be controlled with precision if light is to be focused sharply on the retina. The lifelong growth of the lens depends on the production of cells in the anterior epithelium. At the lens equator, epithelial cells differentiate into fiber cells, which are added to the surface of the existing fiber cell mass, increasing its volume and area. We developed a stochastic model relating the rates of cell proliferation and death in various regions of the lens epithelium to deposition of fiber cells and radial lens growth. Epithelial population dynamics were modeled as a branching process with emigration and immigration between proliferative zones. Numerical simulations were in agreement with empirical measurements and demonstrated that, operating within the strict confines of lens geometry, a stochastic growth engine can produce the smooth and precise growth necessary for lens function. © 2015 Elsevier Ltd.


Author Keywords
Branching process;  Emigration;  Epithelium;  Immigration;  Mitosis;  Proliferation


Document Type: Article
Source: Scopus




Cimino, P.J.a , Bredemeyer, A.b , Abel, H.J.c , Duncavage, E.J.b
A wide spectrum of EGFR mutations in glioblastoma is detected by a single clinical oncology targeted next-generation sequencing panel
(2015) Experimental and Molecular Pathology, 98 (3), pp. 568-573. 

DOI: 10.1016/j.yexmp.2015.04.006


a Department of Pathology and Immunology, Division of Neuropathology, Washington University School of MedicineSaint Louis, MO, United States
b Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of MedicineSaint Louis, MO, United States
c Division of Statistical Genomics, Washington University School of MedicineSaint Louis, MO, United States


Abstract
With the advent of large-scale genomic analysis, the genetic landscape of glioblastoma (GBM) has become more clear, including characteristic genetic alterations in EGFR. In routine clinical practice, genetic alterations in GBMs are identified using several disparate techniques that consume already limited amounts of tissue and add to overall testing costs. In this study, we sought to determine if the full spectrum of EGFR mutations in GBMs could be detected using a single next generation sequencing (NGS) based oncology assay in 34 consecutive cases. Using a battery of informatics tools to identify single nucleotide variants, insertions and deletions, and amplification (including variants EGFRvIII and EGFRvV), twenty-one of the 34 (62%) individuals had at least one alteration in EGFR by sequencing, consistent with published datasets. Mutations detected include several single nucleotide variants, amplification (confirmed by fluorescence in situ hybridization), and the variants EGFRvIII and EGFRvV (confirmed by multiplex ligation-dependent probe amplification). Here we show that a single NGS assay can identify the full spectrum of relevant EGFR mutations. Overall, sequencing based diagnostics have the potential to maximize the amount of genetic information obtained from GBMs and simultaneously reduce the total time, required specimen material, and costs associated with current multimodality studies. © 2015 Elsevier Inc.


Author Keywords
EGFR;  EGFRvIII;  Glioblastoma;  Glioma;  Next-generation sequencing


Document Type: Article
Source: Scopus




Akbari, S.H.A., Limbrick, D.D.
Response to letter to the editor for original manuscript, “Surgical management of complex multiloculated hydrocephalus in infants and children”
(2015) Child's Nervous System, 1 p. Article in Press. 

DOI: 10.1007/s00381-015-2711-9


Saint Louis School of Medicine, Washington UniversitySt. Louis, MO, United States


Document Type: Article in Press
Source: Scopus




Cradock, M.M.a , Gray, K.E.b , Kapp-Simon, K.A.c d , Collett, B.R.e f , Buono, L.A.g , Speltz, M.L.e f
Sex differences in the neurodevelopment of school-age children with and without single-suture craniosynostosis
(2015) Child's Nervous System, 9 p. Article in Press. 

DOI: 10.1007/s00381-015-2671-0


a Department of Psychology, St Louis Children’s Hospital; Department of Pediatrics, Washington University School of Medicine, One Children’s Place 3N-14St Louis, MO, United States
b Department of Health Services, University of WashingtonSeattle, WA, United States
c Department of Surgery, Feinberg School of Medicine, Northwestern UniversityChicago, IL, United States
d Departments of Plastic Surgery and Psychology, Shriners Hospitals for ChildrenChicago, IL, United States
e Center for Child Health, Behavior and Development, Seattle Children’s Research InstituteSeattle, WA, United States
f Department of Psychiatry and Behavioral Sciences, University of WashingtonSeattle, WA, United States
g Craniofacial Team, Children’s Healthcare of AtlantaAtlanta, GA, United States


Abstract
Purpose: Previous studies have indicated that infants and school-age children with single-suture craniosynostosis (SSC, cases) score modestly but consistently lower than unaffected children (controls) on neurodevelopmental tests. However, sex differences in these functions rarely have been examined, and it is unknown whether potential sex differences vary by case status (cases vs. controls) or location of suture fusion. Methods: We tested 182 cases and 183 demographically matched controls at a mean age of 7.4 years. We measured intellectual abilities with the Wechsler Scale of Intelligence for Children—Fourth Edition. We assessed reading, spelling, and math with a combination of the Wide Range Assessment Test—Fourth Edition, the Test of Word Reading Efficiency, and the Comprehensive Test of Phonological Processing. Results: Among both cases and controls, males scored lower on all measures than females with standard score differences ranging from −1.2 to −7.8 for controls (p values from <0.001 to 0.55) and −2.3 to −8.5 for cases (p values from <0.001 to 0.33). For all but one measure, sex differences were slightly larger for cases than controls. Among cases, males were more likely than females to have learning problems (50 vs. 30 %, respectively), with the highest level observed among males with unicoronal synostosis (86 %). Conclusions: Sex differences in neurodevelopmental abilities among children with SSC are substantial, but not a unique correlate of this disorder as similar differences were observed among controls. Girls and those with sagittal synostosis have the lowest risk for academic problems. Boys with unicoronal synostosis warrant close developmental surveillance. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
Achievement;  Cognition;  Craniosynostosis;  Gender;  Intelligence;  Sex


Document Type: Article in Press
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, 6 p. Article in Press. 

DOI: 10.1007/s11481-015-9610-4


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




Zhou, Y., Xia, X.-M., Lingle, C.J.
Cadmium-cysteine coordination in the BK inner pore region and its structural and functional implications
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (16), pp. 5237-5242. 

DOI: 10.1073/pnas.1500953112


Department of Anesthesiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
To probe structure and gating-associated conformational changes in BK-type potassium (BK) channels, we examined consequences of Cd2+ coordination with cysteines introduced at two positions in the BK inner pore. At V319C, the equivalent of valine in the conserved Kv proline-valine-proline (PVP) motif, Cd2+ forms intrasubunit coordination with a native glutamate E321, which would place the side chains of V319C and E321 much closer together than observed in voltage-dependent K+ (Kv) channel structures, requiring that the proline between V319C and E321 introduces a kink in the BK S6 inner helix sharper than that observed in Kv channel structures. At inner pore position A316C, Cd2+ binds with modest state dependence, suggesting the absence of an ion permeation gate at the cytosolic side of BK channel. These results highlight fundamental structural differences between BK and Kv channels in their inner pore region, which likely underlie differences in voltage-dependent gating between these channels. © 2015, National Academy of Sciences. All rights reserved.


Author Keywords
BK channels;  Cd2+ coordination;  K+ channels;  Slo1 channels;  State dependence


Document Type: Article
Source: Scopus




Luo, J.a , Feng, J.a , Liu, S.a , Walters, E.T.b , Hu, H.a
Molecular and cellular mechanisms that initiate pain and itch
(2015) Cellular and Molecular Life Sciences, 23 p. Article in Press. 

DOI: 10.1007/s00018-015-1904-4


a Department of Anesthesiology, The 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 StreetHouston, TX, United States


Abstract
Somatosensory neurons mediate our sense of touch. They are critically involved in transducing pain and itch sensations under physiological and pathological conditions, along with other skin-resident cells. Tissue damage and inflammation can produce a localized or systemic sensitization of our senses of pain and itch, which can facilitate our detection of threats in the environment. Although acute pain and itch protect us from further damage, persistent pain and itch are debilitating. Recent exciting discoveries have significantly advanced our knowledge of the roles of membrane-bound G protein-coupled receptors and ion channels in the encoding of information leading to pain and itch sensations. This review focuses on molecular and cellular events that are important in early stages of the biological processing that culminates in our senses of pain and itch. © 2015 Springer Basel


Author Keywords
Dorsal root ganglion;  Innate immune cells;  Keratinocytes;  Mas-related G-protein-coupled receptors;  Neuropeptides;  Transient receptor potential channels


Document Type: Article in Press
Source: Scopus




Wang, Y.a b , Ma, M.b , Tang, Q.a b , Zhu, L.a b , Koleini, M.c , Zou, D.c
The effects of different tensile parameters for the neurodynamic mobilization technique on tricipital muscle wet weight and MuRf-1 expression in rabbits with sciatic nerve injury
(2015) Journal of NeuroEngineering and Rehabilitation, 12 (1), . 

DOI: 10.1186/s12984-015-0034-4


a Rehabilitation Medicine Cente, Second Affiliated Hospital of Heilongjiang University of Chinese MedicineHarbin, China
b Rehabilitation Medicine College of Heilongjiang, University of Chinese MedicineHarbin, China
c Program in Physical Therapy, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Background: After peripheral nerve injury, muscles without innervation begin to undergo atrophy. Research has suggested that MuRf-1 may play a role in muscle atrophy. The neurodynamic mobilization technique (NMT) is a manual therapy method used to elongate a nerve along its long axis, resulting in improved blood flow to the nerve. However, the nerve can be damaged if elongated too much. The purpose of this study is to observe the effect of NMT on muscle wet weight and MuRf-1 expression in rabbits with sciatic nerve injury. Methods: Six adult rabbits were measured to determine the relationship between the joint angle of the lower limb and percent of sciatic nerve elongation to define the tensile parameters of NMT; Thirty adult rabbits were randomly assigned into a sham, model, NMT-A, NMT-B, or NMT-C groups. Four weeks post-treatment, the wet mass of the tricipital muscles and MuRf-1 expression were observed. Results: The wet mass of the tricipital muscles in the NMT-B group was significantly greater than the NMT-A, NMT-C, and model groups. In addition, MuRf-1 expression was significantly reduced in the NMT-B group compared with the NMT-A, NMT-C, and model groups. Conclusions: Elongating the nerve by NMT of 9% in rabbits decreased MuRf-1 expression and decelerated muscle atrophy in the subjects with sciatic nerve injury. © 2015 Wang et al.; licensee BioMed Central.


Author Keywords
MuRf-1;  Neurodynamic mobilization technique (NMT);  Peripheral nerve injury;  Tricipital muscle wet weight


Document Type: Article
Source: Scopus




McNeely, M.E.a c , Duncan, R.P.a c , Earhart, G.M.a b c
A comparison of dance interventions in people with Parkinson disease and older adults
(2015) Maturitas, 81 (1), pp. 10-16. 

DOI: 10.1016/j.maturitas.2015.02.007


a Program in Physical Therapy, Washington University School of Medicine in St. LouisSt. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine in St. LouisSt. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. Louis, Campus-Box 8502, 4444 Forest Park Blvd.St. Louis, MO, United States


Abstract
It is important for our aging population to remain active, particularly those with chronic diseases, like Parkinson disease (PD), which limit mobility. Recent studies in older adults and people with PD suggest dance interventions provide various motor benefits. The literature for dance in PD is growing, but many knowledge gaps remain, relative to what is known in older adults. The purpose of this review is to: (1) detail results of dance intervention studies in older adults and in PD, (2) describe limitations of dance research in these populations, and (3) identify directions for future study. Generally, a wide variety of dance styles have been investigated in older adults, while a more limited subset has been evaluated in PD. Measures vary widely across studies and a lack of standardized outcomes measures hinders cross-studies comparisons. Compared to the dance literature in older adults, there is a notable absence of evidence in the PD literature in outcome domains related to cardiovascular health, muscle strength, body composition, flexibility, and proprioception. As a whole, the dance literature supports substantial and wide-ranging benefits in both populations, but additional effort should be dedicated to well-designed comparative studies using standardized outcome measures to identify optimal treatment programs. © 2015 Elsevier Ireland Ltd. All rights reserved.


Author Keywords
Balance;  Dance;  Exercise;  Gait;  Parkinson disease;  Physical function


Document Type: Article
Source: Scopus




Renton, A.E.a , Pliner, H.A.a , Provenzano, C.b , Evoli, A.c , Ricciardi, R.d , Nalls, M.A.e , Marangi, G.a f , Abramzon, Y.a , Arepalli, S.g , Chong, S.g , Hernandez, D.G.g , Johnson, J.O.a , Bartoccioni, E.b , Scuderi, F.b , Maestri, M.d , Gibbs, J.R.h , Errichiello, E.a i , Chiò, A.i , Restagno, G.j , Sabatelli, M.c , Macek, M.k , Scholz, S.W.k , Corse, A.k , Chaudhry, V.k , Benatar, M.l , Barohn, R.J.m , McVey, A.m , Pasnoor, M.m , Dimachkie, M.M.m , Rowin, J.n , Kissel, J.o , Freimer, M.o , Kaminski, H.J.p , Sanders, D.B.q , Lipscomb, B.q , Massey, J.M.q , Chopra, M.r , Howard, J.F., Jr.r , Koopman, W.J.s , Nicolle, M.W.s , Pascuzzi, R.M.t , Pestronk, A.u , Wulf, C.u , Florence, J.u , Blackmore, D.v , Soloway, A.v , Siddiqi, Z.v , Muppidi, S.w , Wolfe, G.w , Richman, D.x , Mezei, M.M.y , Jiwa, T.y , Oger, J.y , Drachman, D.B.k , Traynor, B.J.a k
A genome-wide association study of myasthenia gravis
(2015) JAMA Neurology, 72 (4), pp. 396-404. Cited 1 time.

DOI: 10.1001/jamaneurol.2014.4103


a Neuromuscular Dise Ases Research Unit, Laboratory of Neurogenetics, Porter Neuroscience Research Center, 35 Convent DrBethesda, MD, United States
b Institute of General Pathology, Catholic UniversityRome, Italy
c Institute of Neurology, Catholic UniversityRome, Italy
d Department of Neuroscience, Cisanello Hospital, University of PisaPisa, Italy
e Molecular Genetics Section, National Institutes of Health, Porter Neuroscience Research CenterBethesda, MD, United States
f Institute of Medical Genetics, Catholic UniversityRome, Italy
g Genomics Technology Group, National Institutes of Health, Porter Neuroscience Research CenterBethesda, MD, United States
h Computational Biology Core, National Institutes of Health, Porter Neuroscience Research CenterBethesda, MD, United States
i Rita Levi Montalcini Department of Neuroscience, University of TurinTurin, Italy
j Molecular Genetics Unit, Department of Clinical Pathology, ASO OIRM-S AnnaTurin, Italy
k Department of Neurology, Johns Hopkins School of MedicineBaltimore, MD, United States
l Department of Neurology, University of MiamiMiami, FL, United States
m Department of Neurology, University of Kansas Medical CenterKansas City, United States
n Department of Neurology, University of Illinois College of MedicineChicago, United States
o Department of Neurology, Ohio State University Medical CenterColumbus, United States
p Department of Neurology, George Washington UniversityWashington, DC, United States
q Department of Neurology, Duke University Medical CenterDurham, NC, United States
r Department of Neurology, University of North CarolinaChapel Hill, United States
s Department of Clinical Neurosciences, London Health Sciences CentreLondon, ON, Canada
t Department of Neurology, Indiana University-Purdue UniversityIndianapolis, United States
u Department of Neurology, Washington University School of MedicineSt Louis, Missouri, United States
v Department of Medicine, University of Alberta HospitalEdmonton, AB, Canada
w Department of Neurology, University at Buffalo SMBS, State University of New YorkBuffalo, United States
x Department of Neurology, University of California, Davis Medical Center, United States
y Division of Neurology, University of British ColumbiaVancouver, BC, Canada


Abstract
IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10-8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10-8; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10-8; odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10-9; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10-12; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10-18; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10-11; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus




Urbin, M.A.a , Waddell, K.J.a , Lang, C.E.a b c
Acceleration metrics are responsive to change in upper extremity function of stroke survivors
(2015) Archives of Physical Medicine and Rehabilitation, 96 (5), art. no. 56051, pp. 854-861. 

DOI: 10.1016/j.apmr.2014.11.018


a Program in Physical Therapy, Washington University School of Medicine, Campus Box 8502, 4444 Forest ParkSt. Louis, MO, United States
b Program in Occupational Therapy, Washington University School of MedicineSt. Louis, MO, United States
c Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Abstract Objectives To (1) determine whether acceleration metrics derived from monitoring outside of treatment are responsive to change in upper extremity (UE) function; and secondarily to (2) compare metric values during task-specific training and while in the free-living environment, and (3) establish metric associations with an in-clinic measure of movement capabilities. Design Before-after observational study. Setting Inpatient hospital (primary purpose); outpatient hospital (secondary purpose). Participants Individuals (n=8) with UE hemiparesis <30 days poststroke (primary purpose); individuals (n=27) with UE hemiparesis ≥6 months poststroke (secondary purpose). Intervention The inpatient sample was evaluated for UE movement capabilities and monitored with wrist-worn accelerometers for 22 hours outside of treatment before and after multiple sessions of task-specific training. The outpatient sample was evaluated for UE movement capabilities and monitored during a single session of task-specific training and the subsequent 22 hours outside clinical settings. Main Outcome Measures Action Research Arm Test (ARAT) and acceleration metrics quantified from accelerometer recordings. Results Five metrics improved in the inpatient sample, along with UE function as measured on the ARAT: use ratio, magnitude ratio, variation ratio, median paretic UE acceleration magnitude, and paretic UE acceleration variability. Metric values were greater during task-specific training than in the free-living environment, and each metric was strongly associated with ARAT score. Conclusions Multiple metrics that characterize different aspects of UE movement are responsive to change in function. Metric values are different during training than in the free-living environment, providing further evidence that what the paretic UE does in the clinic may not generalize to what it does in everyday life. © 2015 by the American Congress of Rehabilitation Medicine.


Author Keywords
Accelerometry;  Neurology;  Paresis;  Rehabilitation;  Stroke


Document Type: Article
Source: Scopus




Jadvar, H.a , Subramaniam, R.M.b , Berman, C.G.c , Boada, F.d , Colletti, P.M.e , Guimaraes, A.R.f , McConathy, J.g , Meltzer, C.C.h , Noto, R.B.i , Packard, A.B.j , Rohren, E.M.k , Oates, M.E.l
American College of Radiology and Society of Nuclear Medicine and Molecular Imaging joint credentialing statement for PET/MR imaging: Brain
(2015) Journal of Nuclear Medicine, 56 (4), pp. 642-645. 

DOI: 10.2967/jnumed.115.155218


a University of Southern California, 2250 Alcazar St., CSC 102Los Angeles, CA, United States
b Johns Hopkins UniversityBaltimore, MD, United States
c Moffitt Cancer CenterTampa, FL, United States
d New York UniversityNY, NY, United States
e University of Southern CaliforniaLos Angeles, CA, United States
f Massachusetts General HospitalBoston, MA, United States
g Washington UniversitySt. Louis, MO, United States
h Emory UniversityAtlanta, GA, United States
i Brown UniversityProvidence, RI, United States
j Boston Children's HospitalBoston, MA, United States
k M.D. Anderson Cancer CenterHouston, TX, United States
l University of KentuckyLexington, KY, United States


Document Type: Article
Source: Scopus




Zazulia, A.
Antiplatelet and anticoagulant therapy after intracerebral hemorrhage
(2015) Neurologic Clinics, 33 (2), pp. 329-345. 

DOI: 10.1016/j.ncl.2014.12.005


Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box8111St Louis, MO, United States


Abstract
Management of patients with an indication for long-term oral antithrombotic therapy who have an intracerebral hemorrhage (ICH) presents a therapeutic dilemma. Should antithrombotic therapy be resumed, and if so, when, using what agent, and for whom? There is no consensus for answers to these questions. In the absence of randomized trials, management of antithrombotic therapy after ICH is based on a combination of observational data, pathophysiologic concepts, and decision analysis. At the heart of the decision is an assessment of the individual patient's risk of thromboembolism off antithrombotic therapy versus risk of ICH recurrence on antithrombotic therapy. © 2015 Elsevier Inc.


Author Keywords
Anticoagulation;  Antiplatelet therapy;  Atrial fibrillation;  Intracerebral hemorrhage;  Prosthetic heart valve;  Venous thromboembolism


Document Type: Review
Source: Scopus




Laske, C.a b c , Sohrabi, H.R.d e , Jasielec, M.S.f , Müller, S.c , Koehler, N.K.c , Gräber, S.a g , Förster, S.h , Drzezga, A.i , Mueller-Sarnowski, F.j k , Danek, A.j k , Jucker, M.a l , Bateman, R.J.m , Buckles, V.m , Saykin, A.J.n , Martins, R.N.d e , Morris, J.C.m
Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer's Disease: Results of the DIAN Study
(2015) BioMed Research International, 2015, art. no. 828120, . 

DOI: 10.1155/2015/828120


a German Center for Neurodegenerative Diseases (DZNE)Tübingen, Germany
b Section for Dementia Research, Department of Cellular Neurology, University of TübingenTübingen, Germany
c Department of Psychiatry and Psychotherapy, University of TübingenTübingen, Germany
d Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan UniversityPerth, WA, Australia
e School of Psychiatry and Clinical Neurosciences, University of Western AustraliaNedlands, WA, Australia
f Division of Biostatistics, Washington University School of MedicineSt. Louis, MO, United States
g Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany
h Department of Nuclear Medicine, TUM Neuroimaging Center (TUM-NIC), Klinikum Rechts der Isar, Technical University MunichMunich, Germany
i Department of Nuclear Medicine, University of CologneCologne, Germany
j Deutsches Zentrum für Neurodegenerative ErkrankungenMünchen, Germany
k Neurologische Klinik und Poliklinik, Ludwig-Maximilians-UniversitätMünchen, Germany
l Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany
m Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of MedicineSt. Louis, MO, United States
n Indiana Alzheimer Disease Center, Indiana University School of MedicineIndianapolis, IN, United States


Abstract
Objective. We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer's disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). Methods. The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. Results. At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. Conclusions. The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials. © 2015 Christoph Laske et al.


Document Type: Article
Source: Scopus




Oh, G.a , Wang, S.-C.a b , Pal, M.a , Chen, Z.F.c , Khare, T.a , Tochigi, M.a d , Ng, C.a , Yang, Y.A.a e , Kwan, A.a , Kaminsky, Z.A.a f , Mill, J.g r , Gunasinghe, C.g q , Tackett, J.L.h , Gottesman, I.I.i , Willemsen, G.j , De Geus, E.J.C.j , Vink, J.M.j , Slagboom, P.E.k , Wray, N.R.l m , Heath, A.C.n , Montgomery, G.W.l , Turecki, G.o p , Martin, N.G.l , Boomsma, D.I.j , McGuffin, P.g q , Kustra, R.c , Petronis, A.a
DNA modification study of major depressive disorder: Beyond locus-by-locus comparisons
(2015) Biological Psychiatry, 77 (3), pp. 246-255. 

DOI: 10.1016/j.biopsych.2014.06.016


a Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental HealthToronto, ON, Canada
b Institute of Systems Biology and Bioinformatics, National Central UniversityChungli, Taiwan
c Department of Public Health Sciences, Dalla Lana School of Public HealthToronto, ON, Canada
d Department of Neuropsychiatry, Graduate School of Medicine, University of TokyoTokyo, Japan
e Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern UniversityChicago, IL, United States
f Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins UniversityBaltimore, MD, United States
g Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's CollegeLondon, United Kingdom
h Department of Psychology, University of HoustonHouston, TX, United States
i Departments of Psychology and Psychiatry, University of Minnesota, MinneapolisMN, United States
j Department of Biological Psychology, VU University Amsterdam, Netherlands Twin Register, Netherlands
k Molecular Epidemiology, Leiden University Medical Center, Netherlands
l Queensland Institute of Medical Research, Herston, University of QueenslandSt Lucia, QLD, Australia
m Queensland Brain Institute, University of QueenslandSt. Lucia, QLD, Australia
n Department of Psychiatry, Washington University in St Louis, St. LouisMO, United States
o McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill UniversityMontreal, QC, Canada
p Department of Psychiatry, McGill University, MontrealQC, Canada
q National Institute for Health Research, Biomedical Research Centre for Mental Health at South London, Maudsley National Health Service Foundation TrustLondon, United Kingdom
r University of Exeter Medical School, Exeter UniversityExeter, United Kingdom


Abstract
Background: Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined. Methods: We performed DNA modification analysis in white blood cells from monozygotic twins discordant for MDD, in brain prefrontal cortex, and germline (sperm) samples from affected individuals and control subjects (total N = 304) using 8.1K CpG island microarrays and fine mapping. In addition to the traditional locus-by-locus comparisons, we explored the potential of new analytical approaches in epigenomic studies. Results: In the microarray experiment, we detected a number of nominally significant DNA modification differences in MDD and validated selected targets using bisulfite pyrosequencing. Some MDD epigenetic changes, however, overlapped across brain, blood, and sperm more often than expected by chance. We also demonstrated that stratification for disease severity and age may increase the statistical power of epimutation detection. Finally, a series of new analytical approaches, such as DNA modification networks and machine-learning algorithms using binary and quantitative depression phenotypes, provided additional insights on the epigenetic contributions to MDD. Conclusions: Mapping epigenetic differences in MDD (and other psychiatric diseases) is a complex task. However, combining traditional and innovative analytical strategies may lead to identification of disease-specific etiopathogenic epimutations. © 2015 Society of Biological Psychiatry.


Author Keywords
DNA modification;  Epigenetic outliers;  Epigenetics;  Heteroscedasticity;  Major depressive disorder;  Molecular networks


Document Type: Article
Source: Scopus




Galor, A.a b , Zlotcavitch, L.b , Walter, S.D.a b , Felix, E.R.a c , Feuer, W.b , Martin, E.R.d e , Margolis, T.P.f , Sarantopoulos, K.D.a g , Levitt, R.C.a d e g
Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain
(2015) British Journal of Ophthalmology, 99 (5), pp. 665-668. 

DOI: 10.1136/bjophthalmol-2014-306057


a Miami Veterans Administration Medical CenterMiami, FL, United States
b Bascom Palmer Eye Institute, University of MiamiMiami, FL, United States
c Department of Physical Medicine and Rehabilitation, University of Miami Miller School of MedicineMiami, FL, United States
d John P. Hussman Institute for Human Genomics, University of Miami Miller School of MedicineMiami, FL, United States
e John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of MedicineMiami, FL, United States
f Departement of Ophthalmology, Washington University School of MedicineSt Louis, MO, United States
g Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of MedicineMiami, FL, United States


Abstract
Objective: Studies of patients with non-ocular pain suggest that it is therapeutically useful to identify those with features of neuropathic pain. No data is available, however, on whether this approach has similar utility in dry eye. The purpose of this study was to determine whether severity and persistence of dry eye symptoms associate with self-reported symptoms of neuropathic ocular pain (NOP). Methods Design: Cohort study. Participants/setting: 102 men seen in the Miami Veterans Affairs eye clinic. A baseline evaluation was performed consisting of the dry eye questionnaire 5 (DEQ5) and ocular surface evaluation. Patients were contacted ≥2 years later to repeat the DEQ5 and complete questionnaires that further characterised their eye pain. Main outcome measure: The relationship between dry eye symptom severity and persistence (DEQ5) and additional measures of ocular pain (NOP). Results: Of 102 patients with variable dry eye symptoms, 70 reported at least mild symptoms on both encounters (DEQ5≥6). Fifty-four of 70 (77%) reported ≥1 NOP feature, and the number of NOP features correlated moderately with dry eye symptoms at both encounters (r=0.31-0.46, p<0.01). Patients with any symptom of NOP had higher dry eye symptom scores at both encounters (p<0.05), but similar ocular surface parameters. Hypersensitivity to wind and photoallodynia were associated with having mild or greater symptoms on both encounters (OR 3.4, 95% CI 1.2 to 10.0, p=0.02; OR 15.6, 95% CI 2.0 to 123, p=0.009, respectively). Conclusions: NOP features are common in patients with symptomatic dry eye and these features correlate with symptom severity and persistence. © 2015, BMJ Publishing Group. All rights reserved.


Document Type: Article
Source: Scopus




Davidson, L.S.a , Firszt, J.B.a , Brenner, C.a , Cadieux, J.H.b
Evaluation of hearing aid frequency response fittings in pediatric and young adult bimodal recipients
(2015) Journal of the American Academy of Audiology, 26 (4), pp. 393-407. 

DOI: 10.3766/jaaa.26.4.7


a Department of Otolaryngology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8115St. Louis, MO, United States
b St. Louis Children's HospitalSt. Louis, MO, United States


Abstract
Background: A coordinated fitting of a cochlear implant (CI) and contralateral hearing aid (HA) for bimodal device use should emphasize balanced audibility and loudness across devices. However, guidelines for allocating frequency information to the CI and HA are not well established for the growing population of bimodal recipients. Purpose: The study aim was to compare the effects of three different HA frequency responses, when fitting a CI and an HA for bimodal use, on speech recognition and localization in children/young adults. Specifically, the three frequency responses were wideband, restricted high frequency, and nonlinear frequency compression (NLFC), which were compared with measures of word recognition in quiet, sentence recognition in noise, talker discrimination, and sound localization. Research Design: The HA frequency responses were evaluated using an AB<inf>1</inf> AB<inf>2</inf> test design: wideband frequency response (baseline-A), restricted high-frequency response (experimental-B<inf>1</inf>), and NLFC-activated (experimental-B<inf>2</inf>). All participants were allowed 3-4 weeks between each test session for acclimatization to each new HA setting. Bimodal benefit was determined by comparing the bimodal score to the CI-alone score. Study Sample: Participants were 14 children and young adults (ages 7-21 yr) who were experienced users of bimodal devices. All had been unilaterally implanted with a Nucleus CI24 internal system and used either a Freedom or CP810 speech processor. All received a Phonak Naida IX UP behind-the-ear HA at the beginning of the study. Data Collection and Analysis: Group results for the three bimodal conditions (HA frequency response with wideband, restricted high frequency, and NLFC) on each outcome measure were analyzed using a repeated measures analysis of variance. Group results using the individual "best bimodal" score were analyzed and confirmed using a resampling procedure. Correlation analyses examined the effects of audibility (aided and unaided hearing) in each bimodal condition for each outcome measure. Individual data were analyzed for word recognition in quiet, sentence recognition in noise, and localization. Individual preference for the three bimodal conditions was also assessed. Results: Group data revealed no significant difference between the three bimodal conditions for word recognition in quiet, sentence recognition in noise, and talker discrimination. However, group data for the localization measure revealed that both wideband and NLFC resulted in significantly improved bimodal performance. The condition that yielded the "best bimodal" score varied across participants. Because of this individual variability, the "best bimodal" score was chosen for each participant to reassess group data within word recognition in quiet, sentence recognition in noise, and talker discrimination. This method revealed a bimodal benefit for word recognition in quiet after a randomization test was used to confirm significance. The majority of the participants preferred NLFC at the conclusion of the study, although a few preferred a restricted high-frequency response or reported no preference. Conclusions: These results support consideration of restricted high-frequency and NLFC HA responses in addition to traditional wideband response for bimodal device users.


Author Keywords
Bimodal fittings;  Pediatric;  Speech perception


Document Type: Conference Paper
Source: Scopus




Papadimitriou, C., Ferdoash, A., Snyder, L.H.
Ghosts in the machine: Memory interference from the previous trial
(2015) Journal of Neurophysiology, 113 (2), pp. 567-577. 

DOI: 10.1152/jn.00402.2014


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


Abstract
Previous memoranda can interfere with the memorization or storage of new information, a concept known as proactive interference. Studies of proactive interference typically use categorical memoranda and match-to-sample tasks with categorical measures such as the proportion of correct to incorrect responses. In this study we instead train five macaques in a spatial memory task with continuous memoranda and responses, allowing us to more finely probe working memory circuits. We first ask whether the memoranda from the previous trial result in proactive interference in an oculomotor delayed response task. We then characterize the spatial and temporal profile of this interference and ask whether this profile can be predicted by an attractor network model of working memory. We find that memory in the current trial shows a bias toward the location of the memorandum of the previous trial. The magnitude of this bias increases with the duration of the memory period within which it is measured. Our simulations using standard attractor network models of working memory show that these models easily replicate the spatial profile of the bias. However, unlike the behavioral findings, these attractor models show an increase in bias with the duration of the previous rather than the current memory period. To model a bias that increases with current trial duration we posit two separate memory stores, a rapidly decaying visual store that resists proactive interference effects and a sustained memory store that is susceptible to proactive interference. © 2015 the American Physiological Society.


Author Keywords
Attractor model;  Interference;  Spatial memory


Document Type: Article
Source: Scopus




Wilson, R.E.a , Harris, K.b , Vazire, S.a
Personality and friendship satisfaction in daily life: Do everyday social interactions account for individual differences in friendship satisfaction?
(2015) European Journal of Personality, 29 (2), pp. 173-186. Cited 4 times.

DOI: 10.1002/per.1996


a Department of Psychology, University of CaliforniaDavis, CA, United States
b Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Who are the people who maintain satisfying friendships? And, what are the behaviours that might explain why those people achieve high friendship satisfaction? We examined the associations between personality (self-reports and peer-reports) and friendship satisfaction (self-reports) among 434 students. We also examined whether role personality (how people act with their friends) and quantity and quality of social interactions using ecological momentary assessment mediate the associations between personality and friendship satisfaction. Extraversion, agreeableness, conscientiousness and (low) neuroticism were associated with higher levels of friendship satisfaction. These associations could not be accounted for by individual differences in role personality. In addition, our results suggest that quantity of time spent with friends and quality of friend interactions (depth of conversation, self-disclosure and lack of emotion suppression), although associated with friendship satisfaction, do not account for the associations between trait personality and friendship satisfaction. Future research should examine other potential interpersonal processes that explain why some people are more satisfied with their friendships than others and the consequences of friendship satisfaction (e.g. for well-being). © 2015 European Association of Personality Psychology.


Author Keywords
Social and personal relationships;  Social interaction;  Social support


Document Type: Article
Source: Scopus




Postuma, R.B.a b , Iranzo, A.c , Hogl, B.d , Arnulf, I.e , Ferini-Strambi, L.f , Manni, R.g , Miyamoto, T.h , Oertel, W.i , Dauvilliers, Y.j , Ju, Y.-E.k , Puligheddu, M.l , Sonka, K.m , Pelletier, A.a , Santamaria, J.c , Frauscher, B.d , Leu-Semenescu, S.e , Zucconi, M.f , Terzaghi, M.g , Miyamoto, M.n , Unger, M.M.i , Carlander, B.j , Fantini, M.-L.l o , Montplaisir, J.Y.b
Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: A multicenter study
(2015) Annals of Neurology, 77 (5), pp. 830-839. 

DOI: 10.1002/ana.24385


a Department of Neurology, L7-305 Montreal General Hospital, 1650 Cedar AvenueMontreal, QC, Canada
b Sleep Medicine Center for Advanced Studies, Sacred Heart Hospital of MontrealMontreal, QC, Canada
c Neurology Service, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research InstituteBarcelona, Spain
d Department of Neurology, Innsbruck Medical UniversityInnsbruck, Austria
e Institute of Brain and Spine Research Center, Pitié-Salpêtrière Hospital, Pierre and Marie Curie UniversityParis, France
f Sleep Disorders Center, Vita-Salute San Raffaele UniversityMilan, Italy
g C. Mondino National Neurological InstitutePavia, Italy
h Department of Neurology, Dokkyo Medical University, Koshigaya HospitalSaitama, Japan
i Department of Neurology, Philipps UniversityMarburg, Germany
j Department of Neurology, Gui de Chauliac Hospital, Montpellier, French National Institute for Health and Medical ResearchMontpellier, France
k Washington University, Multidisciplinary Sleep CenterSt Louis, MO, United States
l Sleep Center, Department of Cardiovascular and Neurological Sciences, University of CagliariCagliari, Italy
m Department of Neurology, Charles University, General University HospitalPrague, Czech Republic
n Department of Neurology, Dokkyo Medical University School of MedicineTochigi, Japan
o Department of Neurology, University of AuvergneClermont-Ferrand, France


Abstract
Objective To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD). Methods Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan-Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. Results Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio [OR] = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6). Interpretation Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences. Ann Neurol 2015;77:830-839 © 2015 American Neurological Association.


Document Type: Article
Source: Scopus




Kang, P., Dhand, A.
Teaching Video Neuro Images: Movement of a paralyzed arm with yawning
(2015) Neurology, 84 (16), p. e118. 

DOI: 10.1212/WNL.0000000000001489


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


Document Type: Note
Source: Scopus




Wingfield, A.a , Peelle, J.E.b
The effects of hearing loss on neural processing and plasticity
(2015) Frontiers in Systems Neuroscience, 9 (MAR), art. no. A035, 4 p. 

DOI: 10.3389/fnsys.2015.00035


a Volen National Center for Complex Systems, Brandeis UniversityWaltham, MA, United States
b Department of Otolaryngology, Washington UniversitySt. Louis, MO, United States


Author Keywords
Aging;  Auditory cortex;  Cognition;  Hearing loss;  Listening effort


Document Type: Editorial
Source: Scopus




Yoon, M.J.a , Yoshida, M.a , Johnson, S.a , Takikawa, A.b , Usui, I.b , Tobe, K.b , Nakagawa, T.c , Yoshino, J.d , Imai, S.-I.a
SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice
(2015) Cell Metabolism, . Article in Press. 

DOI: 10.1016/j.cmet.2015.04.002


a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
b The First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan
c Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan
d Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA


Abstract
Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD+ biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD+-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD+/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD+ production, and treating exvivo hypothalamic explants with purified eNAMPT enhances NAD+, SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD+ biosynthesis at a systemic level. Yoon etal. shed light on the two forms of the NAD+ biosynthetic enzyme, intra- and extracellular NAMPT. SIRT1-mediated deacetylation of iNAMPT promotes its extracellular secretion from adipocytes. eNAMPT, in turn, affects NAD+/SIRT1 signaling in the hypothalamus, with effects on physical activity, implicating adipose tissue as a systemic NAD+ modulator. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Dissel, S.a , Angadi, V.a , Kirszenblat, L.c , Suzuki, Y.a , Donlea, J.b , Klose, M.a , Koch, Z.a , English, D.a , Winsky-Sommerer, R.d , van Swinderen, B.c , Shaw, P.J.a
Sleep Restores Behavioral Plasticity to Drosophila Mutants
(2015) Current Biology, . Article in Press. 

DOI: 10.1016/j.cub.2015.03.027


a Department of Anatomy and Neurobiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110, USA
b Centre for Neural Circuits and Behaviour, University of Oxford, Oxford 1 3SR, UK
c Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
d Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey 2 7XH, UK


Abstract
Given the role that sleep plays in modulating plasticity, we hypothesized that increasing sleep would restore memory to canonical memory mutants without specifically rescuing the causal molecular lesion. Sleep was increased using three independent strategies: activating the dorsal fan-shaped body, increasing the expression of Fatty acid binding protein (dFabp), or by administering the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Short-term memory (STM) or long-term memory (LTM) was evaluated in rutabaga (rut) and dunce (dnc) mutants using aversive phototaxic suppression and courtship conditioning. Each of the three independent strategies increased sleep and restored memory to rut and dnc mutants. Importantly, inducing sleep also reverses memory defects in a Drosophila model of Alzheimer's disease. Together, these data demonstrate that sleep plays a more fundamental role in modulating behavioral plasticity than previously appreciated and suggest that increasing sleep may benefit patients with certain neurological disorders. Dissel etal. report the surprising result that sleep can cure two classic memory mutants without restoring the underlying genetic lesion. This extreme form of behavioral plasticity has not previously been recognized and is not accessible to the waking brain. Interestingly, sleep can also restore memory in a Drosophila model of Alzheimer's disease. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus




Huang, J.a b , Ikeuchi, Y.a b d , Malumbres, M.c , Bonni, A.a b
A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.03.049


a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
c Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
d Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8505, Japan


Abstract
Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligaseCdh1-anaphase-promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1-APC forms acomplex with endogenous FMRP, and knockout ofCdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin signaling pathway that regulates mGluR-LTD in the brain. Huang etal. identify a novel signaling link between the major ubiquitin ligase Cdh1-APC and the fragile X syndrome protein FMRP that regulates mGluR-dependent synaptic plasticity, with significant implications for our understanding of fragile X and related syndromes. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus