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WUSTL Neuroscience Publications Archive - April 2014

Scopus Weekly Reports:

 April 6, 2014

April 14, 2014

April 21, 2014

 

April 21, 2014

Waldron, M.a b , Vaughan, E.L.a , Bucholz, K.K.b , Lynskey, M.T.c , Sartor, C.E.b d , Duncan, A.E.b e , Madden, P.A.F.b ,
 

Heath, A.C.b Risks for early substance involvement associated with parental alcoholism and parental separation in an adolescent female cohort
(2014) Drug and Alcohol Dependence, 138 (1), pp. 130-136.

a School of Education, Indiana University, Bloomington, IN, United States
b Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Addictions Department, Institute of Psychiatry, King's College, London, United Kingdom
d Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
e George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States

Abstract

Background: We examined timing of substance involvement as a joint function of parental history of alcoholism and parental separation during childhood. Method: Data were drawn from a large cohort of female like-sex twins [n= 613 African Ancestry (AA), n= 3550 European or other ancestry (EA)]. Cox proportional hazards regression was conducted predicting age at first use of alcohol, first alcohol intoxication, first use and regular use of cigarettes, and first use of cannabis and other illicit drugs from dummy variables coding for parental alcoholism and parental separation. Propensity score analysis was also conducted comparing intact and separated families by predicted probability of parental separation. Results: In EA families, increased risk of substance involvement was found in both alcoholic and separated families, particularly through ages 10 or 14 years, with risk to offspring from alcoholic separated families further increased. In AA families, associations with parental alcoholism and parental separation were weak and with few exceptions statistically nonsignificant. While propensity score findings confirmed unique risks observed in EA families, intact and separated AA families were poorly matched on risk-factors presumed to predate parental separation, especially parental alcoholism, requiring cautious interpretation of AA survival-analytic findings. Conclusion: For offspring of European ancestry, parental separation predicts early substance involvement that is not explained by parental alcoholism nor associated family background characteristics. Additional research is needed to better characterize risks associated with parental separation in African American families. © 2014 Elsevier Ireland Ltd.

Author Keywords

Adolescent substance use;  Parental alcoholism;  Parental separation or divorce

Document Type: Article

Source: Scopus

Yoo, J.H.a b , Kreuter, M.W.b , Lai, C.b , Fu, Q.c

Understanding Narrative Effects: The Role of Discrete Negative Emotions on Message Processing and Attitudes Among Low-Income African American Women
(2014) Health Communication, 29 (5), pp. 494-504.

a Department of Communication, University of Missouri-St. Louis, United States
b Health Communication Research Lab, Washington University in St.Louis, United States
c Department of Biostatistics, College for Public Health and Social Justice, Saint Louis University, United States

Abstract

This study tests the processes through which breast cancer narrative messages are effective by taking a functional approach. We explore how discrete negative emotions (i.e., sadness, fear, and anger) induced by breast cancer survivor stories affect African American women's message processing, recall of message content, and attitudinal outcomes. Structural equation modeling was performed for narrative and informational versions of a breast cancer screening video shown to 489 low-income African American women ages 40 years and older. The model was well fitted. Sadness enhanced the persuasive process, while fear inhibited it. Sadness also helped participants recall more message-relevant content, while fear inhibited recall. Anger was not related to the persuasive process. Implications of these findings for narrative research and application are discussed. Copyright © Taylor & Francis Group, LLC.

Document Type: Article

Source: Scopus

Yuan, H.a , Wilson, C.M.b , Xia, J.c , Doyle, S.L.d e , Li, S.b , Fales, A.M.a , Liu, Y.f , Ozaki, E.d e , Mulfaul, K.d e , Hanna, G.g , Palmer, G.M.g , Wang, L.V.c , Grant, G.A.b , Vo-Dinh, T.a f

Plasmonics-enhanced and optically modulated delivery of gold nanostars into brain tumor
(2014) Nanoscale, 6 (8), pp. 4078-4082.

a Department of Biomedical Engineering, Fitzpatrick Institute for Photonics, Duke University, Durham, NC 27708, United States
b Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Clinical Medicine, School of Medicine, Trinity College Dublin, I-Dublin-2, Ireland
e National Children's Research Centre, Our Lady's Children's Hospital, Crumlin-Dublin-12, Ireland
f Department of Chemistry, Duke University, Durham, NC 27708, United States
g Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, United States

Abstract

Plasmonics-active gold nanostars exhibiting strong imaging contrast and efficient photothermal transduction were synthesized for a novel pulsed laser-modulated plasmonics-enhanced brain tumor microvascular permeabilization. We demonstrate a selective, optically modulated delivery of nanoprobes into the tumor parenchyma with minimal off-target distribution. © the Partner Organisations 2014.

Document Type: Article

Source: Scopus

Clifford, M.A.a b , Athar, W.a f , Leonard, C.E.a b , Russo, A.a g , Sampognaro, P.J.a h , Van Der Goes, M.-S.a c i , Burton, D.A.a , Zhao, X.a , Lalchandani, R.R.d , Sahin, M.e , Vicini, S.b c , Donoghue, M.J.a b

EphA7 signaling guides cortical dendriticdevelopment and spine maturation
(2014) Proceedings of the National Academy of Sciences of the United States of America, 111 (13), pp. 4994-4999.

 

a Departments of Biology, Georgetown University, Washington, DC 20057, United States
b Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20057, United States
c Departments of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, United States
d Program in Physiology and Biophysics, Georgetown University, Washington, DC 20057, United States
e F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital, Boston, MA 02115, United States
f Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
g Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
h Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
i McGovern Institute for Brain Research, Cambridge, MA 02139, United States

Abstract

The process by which excitatory neurons are generated and mature during the development of the cerebral cortex occurs in a stereotyped manner; coordinated neuronal birth, migration, and differentiation during embryonic and early postnatal life are prerequisites for selective synaptic connections that mediate meaningful neurotransmission in maturity. Normal cortical function depends upon the proper elaboration of neurons, including the initial extension of cellular processes that lead to the formation of axons and dendrites and the subsequent maturation of synapses. Here. we examine the role of cell-based signaling via the receptor tyrosine kinase EphA7 in guiding the extension and maturation of cortical dendrites. EphA7, localized to dendritic shafts and spines of pyramidal cells, is uniquely expressed during cortical neuronal development. On patterned substrates, EphA7 signaling restricts dendritic extent, with Src and Tsc1 serving as downstream mediators. Perturbation of EphA7 signaling in vitro and in vivo alters dendritic elaboration: Dendrites are longer and more complex when EphA7 is absent and are shorter and simpler when EphA7 is ectopically expressed. Later in neuronal maturation, EphA7 influences protrusions from dendritic shafts and the assembling of synaptic components. Indeed, synaptic function relies on EphA7; the electrophysiological maturation of pyramidal neurons is delayed in cultures lacking EphA7, indicating that EphA7 enhances synaptic function. These results provide evidence of roles for Eph signaling, first in limiting the elaboration of cortical neuronal dendrites and then in coordinating the maturation and function of synapses.

Author Keywords

Dendritic spine;  Neurogenesis;  Synaptogenesis

Document Type: Article

Source: Scopus

Gonzalez-Perez, V., Xia, X.-M., Lingle, C.J.

Functional regulation of BK potassium channels by γ1 auxiliary subunits
(2014) Proceedings of the National Academy of Sciences of the United States of America, 111 (13), pp. 4868-4873.

Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

Many K+ channels are oligomeric complexes with intrinsic structural symmetry arising from the homo-tetrameric core of their pore-forming subunits. Allosteric regulation of tetramerically symmetric proteins, whether by intrinsic sensing domains or associated auxiliary subunits, often mirrors the fourfold structural symmetry. Here, through patch-clamp recordings of channel population ensembles and also single channels, we examine regulation of the Ca2+- and voltage-activated large conductance Ca2+- activated K+ (BK) channel by associated γ1-subunits. Through expression of differing ratios of γ1:α-subunits, the results reveal an all-or-none functional regulation of BK channels by γ-subunits: channels either exhibit a full gating shift or no shift at all. Furthermore, the γ1- induced shift exhibits a state-dependent labile behavior that recapitulates the fully shifted or unshifted behavior. The γ1-induced shift contrasts markedly to the incremental shifts in BK gating produced by 1-4 β-subunits and adds a new layer of complexity to the mechanisms by which BK channel functional diversity is generated.

 

Author Keywords

Allostery;  Asymmetry;  Slo1 channels

Document Type: Article

Source: Scopus

Sadler, B.a b , Haller, G.b c , Agrawal, A.b , Culverhouse, R.d , Bucholz, K.b , Brooks, A.e , Tischfield, J.e , Johnson, E.O.f , Edenberg, H.g , Schuckit, M.h , Saccone, N.c , Bierut, L.b , Goate, A.b c

Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: Evidence for pleiotropy
(2014) Scientific Reports, 4, art. no. 4497, .

a School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, United States
b Department of Psychiatry, Washington University, St. Louis, MO, United States
c Department of Genetics, Washington University, St. Louis, MO, United States
d Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Genetics, Rutgers University, Piscataway, NJ, United States
f Division of Health Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC, United States
g Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
h Department of Psychiatry, University of California-San Diego, San Diego, CA, United States

Abstract

In the U.S.A., cocaine is the second most abused illicit drug. Variants within the CHRNB3-A6 gene cluster have been associated with cigarette consumption in several GWAS. These receptors represent intriguing candidates for the study of cocaine dependence because nicotinic receptors are thought to be involved in generalized addiction pathways. Using genotypic data from a GWAS of the Study of Addiction: Genetics and Environment (SAGE) dataset, we tested for association of CHRNB3-A6 SNPs with DSM-5 cocaine use disorder. Multiple SNPs in the region were significantly associated with increased risk of cocaine use disorder. Inclusion of the most significant SNP as a covariate in a linear regression model provided evidence for an additional independent signal within this locus for cocaine use disorder. These results suggest that the CHRNB3-A6 locus contains multiple variants affecting risk for vulnerability to cocaine and nicotine dependence as well as bipolar disorder, suggesting that they have pleiotropic effects.

Document Type: Article

Source: Scopus

Feczko, E.a b , Shulman, G.L.c , Petersen, S.E.d e , Pruett Jr., J.R.a

Interactions between concentric form-from-structure and face perception revealed by visual masking but not adaptation
(2014) Journal of Vision, 14 (2), pp. 1-21.

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental and Cognitive Neuroscience, Emory University, Atlanta, GA, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
e Departments of Psychology and Biomedical Engineering,, Washington University, St. Louis, MO, United States

Abstract

Findings from diverse subfields of vision research suggest a potential link between high-level aspects of face perception and concentric form-from-structure perception. To explore this relationship, typical adults performed two adaptation experiments and two masking experiments to test whether concentric, but not nonconcentric, Glass patterns (a type of form-fromstructure stimulus) utilize a processing mechanism shared by face perception. For the adaptation experiments, subjects were presented with an adaptor for 5 or 20 s, prior to discriminating a target. In the masking experiments, subjects saw a mask, then a target, and then a second mask. Measures of discriminability and bias were derived and repeated measures analysis of variance tested for pattern-specific masking and adaptation effects. Results from Experiment 1 show no Glass pattern-specific effect of adaptation to faces; results from Experiment 2 show concentric Glass pattern masking, but not adaptation, may impair upright/inverted face discrimination; results from Experiment 3 show concentric and radial Glass pattern masking impaired subsequent upright/inverted face discrimination more than translational Glass pattern masking; and results from Experiment 4 show concentric and radial Glass pattern masking impaired subsequent face gender discrimination more than translational Glass pattern masking. Taken together, these findings demonstrate interactions between concentric formfrom- structure and face processing, suggesting a possible common processing pathway. © 2014 ARVO.

Author Keywords

Face perception;  Glass patterns;  Holistic processing;  Moire perception;  Visual adaptation;  Visual masking

Document Type: Article

Source: Scopus

Rudokas, M.W., Varga, Z., Schubert, A.R., Asaro, A.B., Silva, J.R.

The Xenopus oocyte cut-open vaseline gap voltage-clamp technique with fluorometry
(2014) Journal of Visualized Experiments, (85), art. no. e51040, .

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

Abstract

The cut-open oocyte Vaseline gap (COVG) voltage clamp technique allows for analysis of electrophysiological and kinetic properties of heterologous ion channels in oocytes Recordings from the cut-open setup are particularly useful for resolving low magnitude gating currents, rapid ionic current activation, and deactivation. The main benefits over the two-electrode voltage clamp (TEVC) technique include increased clamp speed, improved signal-to-noise ratio, and the ability to modulate the intracellular and extracellular milieu. Here, we employ the human cardiac sodium channel (hNaV1.5), expressed in Xenopus oocytes, to demonstrate the cut-open setup and protocol as well as modifications that are required to add voltage clamp fluorometry capability. The properties of fast activating ion channels, such as hNaV1.5, cannot be fully resolved near room temperature using TEVC, in which the entirety of the oocyte membrane is clamped, making voltage control difficult. However, in the cut-open technique, isolation of only a small portion of the cell membrane allows for the rapid clamping required to accurately record fast kinetics while preventing channel run-down associated with patch clamp techniques. In conjunction with the COVG technique, ion channel kinetics and electrophysiological properties can be further assayed by using voltage clamp fluorometry, where protein motion is tracked via cysteine conjugation of extracellularly applied fluorophores, insertion of genetically encoded fluorescent proteins, or the incorporation of unnatural amino acids into the region of interest1. This additional data yields kinetic information about voltage-dependent conformational rearrangements of the protein via changes in the microenvironment surrounding the fluorescent molecule.

 

Author Keywords

Cut-open;  Developmental biology;  Ionic currents;  Issue 85;  Oocyte;  Sodium channels;  Voltage clamp;  Voltage clamp fluorometry;  Xenopus laevis

 

Document Type: Article

Source: Scopus

Fagan, A.M.a b , Xiong, C.b c , Jasielec, M.S.b c , Bateman, R.J.a b , Goate, A.M.a b d , Benzinger, T.L.S.b e , Ghetti, B.f , Martins, R.N.g , Masters, C.L.h , Mayeux, R.i , Ringman, J.M.j , Rossor, M.N.k , Salloway, S.l , Schofield, P.R.m n , Sperling, R.A.o , Marcus, D.b e , Cairns, N.J.a b p , Buckles, V.D.a b , Ladenson, J.H.p , Morris, J.C.a b p , Holtzman, D.M.a b

Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease
(2014) Science Translational Medicine, 6 (226), art. no. 226ra30, .

a Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Knight Alzheimer's Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63110, United States
c Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO 63110, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO 63110, United States
e Department of Radiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
f Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, United States
g WA Center for Alzheimer's Research and Care, Edith Cowan University, Perth, WA 6009, Australia
h Mental Health Research Institute, University of Melbourne, Melbourne, VIC 3052, Australia
i Department of Neurology, Taub Institute and the Sergievsky Center, Columbia University, New York, NY 10032, United States
j Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, United States
k Dementia Research Center, University College London, London WC1N 3BG, United Kingdom
l Department of Neurology and Psychiatry, Warren Alpert Medical School, Brown University, Providence, RI 02906, United States
m Neuroscience Research Australia, Sydney, NSW 2031, Australia
n School of Medical Sciences, University of New South Wales, Sydney, NSW 2031, Australia
o Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02129, United States
p Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1-42 (Aβ1-42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau 181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

 

Document Type: Article

Source: Scopus

 

McDermott, K.B., Agarwal, P.K., D'Antonio, L., Roediger III., H.L.I., McDaniel, M.A.

Both multiple-choice and short-answer quizzes enhance later exam performance in middle and high school classes
(2014) Journal of Experimental Psychology: Applied, 20 (1), pp. 3-21.

 

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

 

Abstract

Practicing retrieval of recently studied information enhances the likelihood of the learner retrieving that information in the future. We examined whether short-answer and multiple-choice classroom quizzing could enhance retention of information on classroom exams taken for a grade. In seventh-grade science and high school history classes, students took intermittent quizzes (short-answer or multiple-choice, both with correct-answer feedback) on some information, whereas other information was not initially quizzed but received equivalent coverage in all other classroom activities. On the unit exams and on an end-of-semester exam, students performed better for information that had been quizzed than that not quizzed. An unanticipated and key finding is that the format of the quiz (multiple-choice or short-answer) did not need to match the format of the criterial test (e.g., unit exam) for this benefit to emerge. Further, intermittent quizzing cannot be attributed to intermittent reexposure to the target facts: A restudy condition produced less enhancement of later test performance than did quizzing with feedback. Frequent classroom quizzing with feedback improves student learning and retention, and multiple-choice quizzing is as effective as short-answer quizzing for this purpose. © 2013 American Psychological Association.

 

Author Keywords

Classroom learning;  Education;  Quiz;  Retrieval practice;  Testing effect

Document Type: Article

Source: Scopus

 

Green, L., Myerson, J., Oliveira, L., Chang, S.E.

Discounting of delayed and probabilistic losses over a wide range of amounts
(2014) Journal of the Experimental Analysis of Behavior, 101 (2), pp. 186-200.

 

Washington University, St. Louis, United States

 Abstract

The present study examined delay and probability discounting of hypothetical monetary losses over a wide range of amounts (from $20 to $500,000) in order to determine how amount affects the parameters of the hyperboloid discounting function. In separate conditions, college students chose between immediate payments and larger, delayed payments and between certain payments and larger, probabilistic payments. The hyperboloid function accurately described both types of discounting, and amount of loss had little or no systematic effect on the degree of discounting. Importantly, the amount of loss also had little systematic effect on either the rate parameter or the exponent of the delay and probability discounting functions. The finding that the parameters of the hyperboloid function remain relatively constant across a wide range of amounts of delayed and probabilistic loss stands in contrast to the robust amount effects observed with delayed and probabilistic rewards. At the individual level, the degree to which delayed losses were discounted was uncorrelated with the degree to which probabilistic losses were discounted, and delay and probability loaded on two separate factors, similar to what is observed with delayed and probabilistic rewards. Taken together, these findings argue that although delay and probability discounting involve fundamentally different decision-making mechanisms, nevertheless the discounting of delayed and probabilistic losses share an insensitivity to amount that distinguishes it from the discounting of delayed and probabilistic gains.

 

Author Keywords

Amount;  Behavioral economics;  Delay discounting;  Humans;  Hyperboloid;  Losses;  Probability discounting

 

Document Type: Article

Source: Scopus

 

Thompson, J.P.a b , Riley, C.M.c , Eberlein, R.L.a b

Modelling for insight: The case of dementia in Singapore
(2014) Systems Research and Behavioral Science, 31 (2), pp. 227-235.

 

a Department of Social Science and Policy Studies, Worcester Polytechnic Institute, Worcester, MA, United States
b AstuteSD, Wayland Massachusetts USA and Farmington, Connecticut, United States
c Department of Anthropology, Washington University in St. Louis, St. Louis, Missouri, United States

 

Abstract

Many nations have rapidly ageing populations and consequently face important health care policy issues, including a need to address the care and treatment of individuals afflicted with ageing-related dementia. To help inform policymakers in Singapore concerned with dementia, we constructed a system dynamics model that represents changing population characteristics, incidence and prevalence of dementia, and a population-level natural history of this pernicious condition. In the model-building process, we encountered an unexpected simulation outcome that led to valuable insights. This article (i) describes how a difference between measured census data and the simulated population led to improvements in our population modelling, (ii) introduces a novel and generalizable means to simulate how the prevalence of mild, moderate, and severe dementia is likely to change over the next 20 years, and (iii) provides a comparison between two means of prevalence projection. © 2013 John Wiley & Sons, Ltd.

Author Keywords

Dementia;  Health care;  Natural history of disease;  Simulation;  Singapore

Document Type: Article

Source: Scopus

 

Jones, M.a , Lynch, K.T.b , Kass, A.E.c , Burrows, A.b , Williams, J.d , Wilfley, D.E.c , Taylor, C.B.a

Healthy weight regulation and eating disorder prevention in high school students: A universal and targeted web-based intervention
(2014) Journal of Medical Internet Research, 16 (2), art. no. e57, .

 

a Laboratory for the Study of Behavioral Medicine, Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, MC 5722, Stanford, CA, 94305-5722, United States
b PGSP-Stanford PsyD Consortium, Palo Alto University, Palo Alto, CA, United States
c Washington University in St Louis, St Louis, MO, United States
d Murdoch Children's Research Institute, Parkville, Australia

 

Abstract

Background: Given the rising rates of obesity in children and adolescents, developing evidence-based weight loss or weight maintenance interventions that can be widely disseminated, well implemented, and are highly scalable is a public health necessity. Such interventions should ensure that adolescents establish healthy weight regulation practices while also reducing eating disorder risk. Objective: This study describes an online program, StayingFit, which has two tracks for universal and targeted delivery and was designed to enhance healthy living skills, encourage healthy weight regulation, and improve weight/shape concerns among high school adolescents. Methods: Ninth grade students in two high schools in the San Francisco Bay area and in St Louis were invited to participate. Students who were overweight (body mass index [BMI]>85th percentile) were offered the weight management track of StayingFit; students who were normal weight were offered the healthy habits track. The 12-session program included a monitored discussion group and interactive self-monitoring logs. Measures completed pre- and post-intervention included self-report height and weight, used to calculate BMI percentile for age and sex and standardized BMI (zBMI), Youth Risk Behavior Survey (YRBS) nutrition data, the Weight Concerns Scale, and the Center for Epidemiological Studies Depression Scale. Results: A total of 336 students provided informed consent and were included in the analyses. The racial breakdown of the sample was as follows: 46.7% (157/336) multiracial/other, 31.0% (104/336) Caucasian, 16.7% (56/336) African American, and 5.7% (19/336) did not specify; 43.5% (146/336) of students identified as Hispanic/Latino. BMI percentile and zBMI significantly decreased among students in the weight management track. BMI percentile and zBMI did not significantly change among students in the healthy habits track, demonstrating that these students maintained their weight. Weight/shape concerns significantly decreased among participants in both tracks who had elevated weight/shape concerns at baseline. Fruit and vegetable consumption increased for both tracks. Physical activity increased among participants in the weight management track, while soda consumption and television time decreased. Conclusions: Results suggest that an Internet-based, universally delivered, targeted intervention may support healthy weight regulation, improve weight/shape concerns among participants with eating disorders risk, and increase physical activity in high school students. Tailored content and interactive features to encourage behavior change may lead to sustainable improvements in adolescent health.

Author Keywords

Adolescents;  Healthy weight regulation;  Prevention;  School-based intervention;  Universal and targeted delivery

Document Type: Article

Source: Scopus

 

Lo, W.-K.a , Biswas, S.K.a , Brako, L.a , Shiels, A.b , Gu, S.c , Jiang, J.X.c

Aquaporin-0 targets interlocking domains to control the integrity and transparency of the eye lens
(2014) Investigative Ophthalmology and Visual Science, 55 (3), pp. 1202-1212.

 

a Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, United States

 

Abstract

Purpose. Lens fiber cell membranes contain aquaporin-0 (AQP0), which constitutes approximately 50% of the total fiber cell membrane proteins and has a dual function as a water channel protein and an adhesion molecule. Fiber cell membranes also develop an elaborate interlocking system that is required for maintaining structural order, stability, and lens transparency. Herein, we used an AQP0-deficient mouse model to investigate an unconventional adhesion role of AQP0 in maintaining a normal structure of lens interlocking protrusions. Methods. The loss of AQP0 in AQP0-/- lens fibers was verified by Western blot and immunofluorescence analyses. Changes in membrane surface structures of wild-type and AQP0-/- lenses at age 3 to 12 weeks were examined with scanning electron microscopy. Preferential distribution of AQP0 in wild-type fiber cell membranes was analyzed with immunofluorescence and immunogold labeling using freeze-fracturing transmission electron microscopy. Results. Interlocking protrusions in young differentiating fiber cells developed normally but showed minor abnormalities at approximately 50 μm deep in the absence of AQP0 in all ages studied. Strikingly, protrusions in maturing fiber cells specifically underwent uncontrolled elongation, deformation, and fragmentation, while cells still retained their overall shape. Later in the process, these changes eventually resulted in fiber cell separation, breakdown, and cataract formation in the lens core. Immunolabeling at the light microscopy and transmission electron microscopy levels demonstrated that AQP0 was particularly enriched in interlocking protrusions in wild-type lenses. Conclusions. This study suggests that AQP0 exerts its primary adhesion or suppression role specifically to maintain the normal structure of interlocking protrusions that is critical to the integrity and transparency of the lens. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

 Author Keywords

Adhesion;  AQP0-deficient mice;  Aquaporin-0;  Interlocking domain;  Lens

 Document Type: Article

Source: Scopus

 

Edmiaston, J.a , Connor, L.T.b c d , Steger-May, K.e , Ford, A.L.d

A simple bedside stroke dysphagia screen, validated against videofluoroscopy, detects dysphagia and aspiration with high sensitivity
(2014) Journal of Stroke and Cerebrovascular Diseases, 23 (4), pp. 712-716.

 

a Department of Rehabilitation, Barnes-Jewish Hospital, St Louis, MO, United States
b Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
e Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States

 Abstract

Background Early identification of dysphagia is associated with lower rates of pneumonia after acute stroke. The Barnes-Jewish Hospital Stroke Dysphagia Screen (BJH-SDS) was previously developed as a simple bedside screen performed by nurses for sensitive detection of dysphagia and was previously validated against the speech pathologist's clinical assessment for dysphagia. In this study, acute stroke patients were prospectively enrolled to assess the accuracy of the BJH-SDS when tested against the gold standard test for dysphagia, the videofluoroscopic swallow study (VFSS). Methods Acute stroke patients were prospectively enrolled at a large tertiary care inpatient stroke unit. The nurse performed the BJH-SDS at the bedside. After providing consent, patients then underwent VFSS for determination of dysphagia and aspiration. The VFSS was performed by a speech pathologist who was blinded to the results of the BJH-SDS. Sensitivity and specificity were calculated. Pneumonia rates were assessed across the 5-year period over which the BJH-SDS was introduced into the stroke unit. Results A total of 225 acute stroke patients were enrolled. Sensitivity and specificity of the screen to detect dysphagia were 94% and 66%, respectively. Sensitivity and specificity of the screen to detect aspiration were 95% and 50%, respectively. No increase in pneumonia was identified during implementation of the screen (P =.33). Conclusion The BJH-SDS, validated against videofluoroscopy, is a simple bedside screen for sensitive identification of dysphagia and aspiration in the stroke population. © 2014 by National Stroke Association.

Author Keywords

aspiration;  dysphagia;  pneumonia;  screening test;  Stroke

Document Type: Article

Source: Scopus

 

Young, J.L.a , Lockhart, E.M.b , Baysinger, C.L.c

Anesthetic and obstetric management of the opioid-dependent parturient
(2014) International Anesthesiology Clinics, 52 (2), pp. 67-85.

a Department of Obstetrics and Gynecology, Vanderbilt University, School of Medicine, Nashville, TN, United States
b Department of Anesthesiology, Washington University, School of Medicine, St Louis, Missouri, United States
c Department of Anesthesiology, Vanderbilt University, School of Medicine, 1211 Medical Center Dr., Nashville, TN 37232-7580, United States

Document Type: Article

Source: Scopus

 

Peterson, D.S.a , Pickett, K.A.a b , Duncan, R.P.a , Perlmutter, J.S.a b c d e , Earhart, G.M.a b c

Brain activity during complex imagined gait tasks in Parkinson disease
(2014) Clinical Neurophysiology, 125 (5), pp. 995-1005.

 

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

 Abstract

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

Author Keywords

FMRI;  Gait;  Imagery;  Parkinson disease

Document Type: Article

Source: Scopus

 

Pepino, M.Y.a , Mennella, J.A.b

Cigarette smoking and obesity are associated with decreased fat perception in women
(2014) Obesity, 22 (4), pp. 1050-1055.

a Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, United States
b Monell Chemical Senses Center, Philadelphia, PA, United States 

 

Abstract

Objective Smoking and obesity are independently associated with high consumption of high-fat foods in women. We tested whether the co-occurrence of smoking and obesity associates with reduced oral fat perception. Methods Four groups of women (14 obese smokers, 11 obese never-smokers, 10 normal-weight smokers, 12 normal-weight never-smokers) rated vanilla puddings that varied in fat content for perceived intensity of creaminess and sweetness, using the general Labeled Magnitude Scale (gLMS), and degree of pleasantness, using the hedonic gLMS. To determine the role of retronasal smell, subjects rated puddings with and without noseclips. Results For all groups, perception of creaminess grew with increasing fat concentrations; puddings with any amount of fat were perceived as sweeter than fat-free pudding, and sweetness was enhanced when tasted without noseclips. Overall, obese smokers perceived less creaminess, sweetness, and pleasure while tasting the puddings than did the other three groups (all P values<0.02). Conclusion The ability to perceive fat and sweetness in and derive pleasure from foods is particularly compromised in obese women who smoke, which could contribute to excess calorie intake in this population already at high risk for cardiovascular and metabolic disease. Retronasal olfaction appears not to contribute to blunted flavor perception observed in obese smokers. Copyright © 2014 The Obesity Society.

 Document Type: Article

Source: Scopus

 

Sheffield, J.M.a , Gold, J.M.b , Strauss, M.E.c , Carter, C.S.d , MacDonald III, A.W.e , Ragland, J.D.d , Silverstein, S.M.f , Barch, D.M.a

Common and specific cognitive deficits in schizophrenia: Relationships to function
(2014) Cognitive, Affective and Behavioral Neuroscience, 14 (1), pp. 161-174.

 

a Department of Psychology, Washington University in St Louis, 1 Brookings Dr., St Louis, MO 63130, United States
b Maryland Psychiatric Research Center, Catonsville, MD, United States
c Case Western Reserve University, Cleveland, OH, United States
d University of California at Davis, Davis, CA, United States
e University of Minnesota, Minneapolis, MN, United States
f Rutgers-The State University of New Jersey, 57 U.S. Highway 1, New Brunswick, NJ 08901, United States 

 

Abstract

The goals of the present study were to assess the interrelationships among tasks from the MATRICS and CNTRACS batteries, to determine the degree to which tasks from each battery capture unique variance in cognitive dysfunction in schizophrenia, and to determine the ability of tasks from each battery to predict functional outcome. Subjects were 104 schizophrenia patients and 132 healthy control subjects recruited as part of the CNTRACS initiative. All subjects completed four CNTRACS tasks and two tasks from the MATRICS battery: Brief Assessment of Cognition in Schizophrenia Symbol Coding and the Hopkins Verbal Learning Test. Functional outcome was also assessed in the schizophrenia subjects. In both the patient and control groups, we found significant intercorrelations between all higher order cognitive tasks (episodic memory, goal maintenance, processing speed, verbal learning) but minimal relationships with the visual task. For almost all tasks, scores were significantly related to measures of functional outcome, with higher associations between CNTRACS tasks and performance-based measures of function and between one of the MATRICS tasks and self-reported functioning, relative to the other functioning measures. After regressing out variance shared by other tasks, we continued to observe group differences in performance among task residuals, particularly for measures of episodic memory from both batteries, although these residuals did not correlate as robustly with functional outcome as raw test scores. These findings suggest that there exists both shared and specific variance across cognitive tasks related to cognitive and functional impairments in schizophrenia and that measures derived from cognitive neuroscience can predict functional capacity and status in schizophrenia. © 2013 Psychonomic Society, Inc.

Author Keywords

Cognitive control;  Schizophrenia

Document Type: Article

Source: Scopus

 

Weidler, B.J., Abrams, R.A.

Enhanced cognitive control near the hands
(2014) Psychonomic Bulletin and Review, 21 (2), pp. 462-469.

 Department of Psychology, Washington University, One Brookings Drive, St, Louis, MO, 63130-4899, United States 

 Abstract

Recent research has shown that objects near the hands receive preferential visual processing. However, it is not known whether proximity to the hands can affect executive functions. Here we show, using two popular paradigms, that people exhibit enhanced cognitive control for stimuli that are near their hands: We observed reduced interference from incongruent flankers in a visual attention task, and reduced costs when switching to an alternative task in a task-switching paradigm. The results reveal a remarkable influence of posture on cognitive function and have implications for assessing the potential benefits of working on handheld devices. © 2013 Psychonomic Society, Inc.

Author Keywords
Cognitive control;  Embodied cognition;  Hand posture;  Task switching;  Visual attention 

Document Type: Article
Source: Scopus

 

April 14, 2014

Anticevic, A.a e f , Hu, S.a , Zhang, S.a , Savic, A.a h , Billingslea, E.a , Wasylink, S.a , Repovs, G.i , Cole, M.W.j , Bednarski, S.a , Krystal, J.H.a f , Bloch, M.H.a d , Li, C.-S.R.a c g , Pittenger, C.a b d e g
Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder
(2014) Biological Psychiatry, 75 (8), pp. 595-605. 


a Yale University, Department of Psychiatry, 34 Park Street, New Haven, CT 06519, United States
b Department of Psychology, Yale University, United States
c Department of Neurobiology, Yale University, United States
d Child Study Center, Yale University, United States
e Abraham Ribicoff Research Facilities, Yale University, United States
f NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University, United States
g Interdepartmental Neuroscience Program, Yale University, United States
h University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb, Croatia
i Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
j Washington University, St. Louis, MO, United States


Abstract
Background Obsessive-compulsive disorder (OCD) is associated with regional hyperactivity in cortico-striatal circuits. However, the large-scale patterns of abnormal neural connectivity remain uncharacterized. Resting-state functional connectivity studies have shown altered connectivity within the implicated circuitry, but they have used seed-driven approaches wherein a circuit of interest is defined a priori. This limits their ability to identify network abnormalities beyond the prevailing framework. This limitation is particularly problematic within the prefrontal cortex (PFC), which is large and heterogeneous and where a priori specification of seeds is therefore difficult. A hypothesis-neutral, data-driven approach to the analysis of connectivity is vital. Methods We analyzed resting-state functional connectivity data collected at 3T in 27 OCD patients and 66 matched control subjects with a recently developed data-driven global brain connectivity (GBC) method, both within the PFC and across the whole brain. Results We found clusters of decreased connectivity in the left lateral PFC in both whole-brain and PFC-restricted analyses. Increased GBC was found in the right putamen and left cerebellar cortex. Within regions of interest in the basal ganglia and thalamus, we identified increased GBC in dorsal striatum and anterior thalamus, which was reduced in patients on medication. The ventral striatum/nucleus accumbens exhibited decreased global connectivity but increased connectivity specifically with the ventral anterior cingulate cortex in subjects with OCD. Conclusions These findings identify previously uncharacterized PFC and basal ganglia dysconnectivity in OCD and reveal differentially altered GBC in dorsal and ventral striatum. Results highlight complex disturbances in PFC networks, which could contribute to disrupted cortical-striatal-cerebellar circuits in OCD. © 2014 Society of Biological Psychiatry.


Author Keywords
Basal ganglia;  functional connectivity;  global connectivity;  obsessive-compulsive disorder;  prefrontal cortex;  resting-state fMRI


Document Type: Article
Source: Scopus

Germany, R.a , Joseph, S.b , James, K.c , Kao, A.d e
A novel therapeutic approach for the treatment of central sleep apnea: The remede® system
(2014) Cardiovascular Revascularization Medicine, . Article in Press. 


a University of Oklahoma School of Medicine
b Washington University School of Medicine
c Respicardia, Inc.
d University of Missouri School of Medicine, Kansas City
e St. Luke's Mid-America Heart Institute


Abstract
Central sleep apnea (CSA) occurs primarily in cardiovascular patients and is associated with high morbidity and mortality. The disorder often is unrecognized due to the overlap of symptoms with those of the underlying cardiac disease. CSA can be easily diagnosed with a sleep study. Following optimization of all co-morbidities, the therapeutic approach available currently focuses on mask-based therapies which suffer from poor patient adherence. A new therapy, the remede® System, has been developed; it utilizes a transvenous, fully implantable system providing phrenic nerve stimulation intended to restore a more normal breathing pattern. The therapy demonstrated promising results based on an initial chronic study and a randomized trial is underway to further evaluate safety and efficacy of this novel system in patients with CSA. © 2014 Elsevier Inc. All rights reserved.


Author Keywords
Central sleep apnea;  Heart failure;  Phrenic nerve stimulation


Document Type: Article in Press
Source: Scopus

Norris, S.A.a , Derdeyn, C.P.a b c , Perlmutter, J.S.a c d e f
Levodopa-responsive hemiparkinsonism secondary to cystic expansion from a coiled cerebral aneurysm
(2014) Journal of Neuroimaging, . Article in Press. 


a Department of Neurology Washington University School of Medicine St. Louis, MO
b Department of Neurological Surgery Washington University School of Medicine St. Louis, MO
c Department of Radiology Washington University School of Medicine St. Louis, MO
d Department of Anatomy and Neurobiology Washington University School of Medicine St. Louis, MO
e Programs in Occupational Therapy Washington University School of Medicine St. Louis, MO
f Department of Physical Therapy Washington University School of Medicine St. Louis, MO


Abstract
An 80-year-old woman with longstanding hemifacial spasm had a 1 cm × 1.5 cm internal carotid artery terminus aneurysm treated with endovascularly delivered bare metal coils. Follow-up imaging revealed an expansile perianeurysmal cyst that coincided with development of contralateral dopa-responsive hemiparkinsonism. This is the first report of perianeurysmal cyst expansion causing levodopa-responsive hemiparkinsonism. © 2014 by the American Society of Neuroimaging.


Author Keywords
Aneurysm;  Cyst;  Hemifacial spasm;  Levodopa;  Parkinsonism


Document Type: Article in Press
Source: Scopus

Fowler, P.J.a , Henry, D.B.b , Schoeny, M.c , Gorman-Smith, D.c , Tolan, P.H.d
Effects of the SAFE Children preventive intervention on developmental trajectories of attention-deficit/hyperactivity disorder symptoms
(2014) Development and Psychopathology, . Article in Press. 


a Washington University in St. Louis
b University of Illinois at Chicago
c University of Chicago
d University of Virginia


Abstract
This study examined whether a family-based preventive intervention for inner-city children entering the first grade could alter the developmental course of attention-deficit/hyperactivity disorder (ADHD) symptoms. Participants were 424 families randomly selected and randomly assigned to a control condition (n = 192) or Schools and Families Educating Children (SAFE) Children (n = 232). SAFE Children combined family-focused prevention with academic tutoring to address multiple developmental-ecological needs. A booster intervention provided in the 4th grade to randomly assigned children in the initial intervention (n =101) evaluated the potential of increasing preventive effects. Follow-up occurred over 5 years with parents and teachers reporting on attention problems. Growth mixture models identified multiple developmental trajectories of ADHD symptoms. The initial phase of intervention placed children on more positive developmental trajectories for impulsivity and hyperactivity, demonstrating the potential for ADHD prevention in at-risk youth, but the SAFE Children booster had no additional effect on trajectory or change in ADHD indicators. Copyright © Cambridge University Press 2014.


Document Type: Article in Press
Source: Scopus

Wahlheim, C.N.
Proactive effects of memory in young and older adults: The role of change recollection
(2014) Memory & Cognition, . Article in Press. 


Department of Psychology, Washington University, One Brookings Drive, St. Louis, MO 63130, United States


Abstract
Age-related deficits in episodic memory are sometimes attributed to older adults being more susceptible to proactive interference. These deficits have been explained by impaired abilities to inhibit competing information and to recollect target information. In the present article, I propose that a change recollection deficit also contributes to age differences in proactive interference. Change recollection occurs when individuals can remember how information changed across episodes, and this counteracts proactive interference by preserving the temporal order of information. Three experiments were conducted to determine whether older adults are less likely to counteract proactive interference by recollecting change. Paired-associate learning paradigms with two lists of word pairs included pairs that repeated across lists, pairs that only appeared in List 2 (control items), and pairs with cues that repeated and responses that changed across lists. Young and older adults' abilities to detect changed pairs in List 2 and to later recollect those changes at test were measured, along with cued recall of the List 2 responses and confidence in recall performance. Change recollection produced proactive facilitation in the recall of changed pairs, whereas the failure to recollect change resulted in proactive interference. Confidence judgments were sensitive to these effects. The critical finding was that older adults recollected change less than did young adults, and this partially explained older adults' greater susceptibility to proactive interference. These findings have theoretical implications, showing that a change recollection deficit contributes to age-related deficits in episodic memory. © 2014 Psychonomic Society, Inc.


Author Keywords
Aging;  Change detection;  Change recollection;  Metacognition;  Proactive interference;  Reminding


Document Type: Article in Press
Source: Scopus

Fan, J.a , Zhang, X.a , Li, J.a , Jin, H.a , Padakanti, P.K.a , Jones, L.A.a , Flores, H.P.b , Su, Y.b , Perlmutter, J.S.a b , Tu, Z.a
Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate
(2014) Bioorganic and Medicinal Chemistry, . Article in Press. 


a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA
b Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA


Abstract
The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [11C]1-4 was achieved by alkylation of their corresponding desmethyl precursors with [11C]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [11C]1 and [11C]2 had high striatal accumulation (at peak time) for [11C]1 and [11C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [11C]1 and [11C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [11C]1 and [11C]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [11C]1 reached 1.8 at 30 min with a 3.5-fold striatum:cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [11C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [11C]1 is a promising candidate for quantification of PDE10A in vivo using PET. © 2014 Elsevier Ltd. All rights reserved.


Author Keywords
Carbon-11;  CNS;  MP-10;  PDE10A;  PET imaging


Document Type: Article in Press
Source: Scopus

Watson, C.P.N.a , Mackinnon, S.E.b , Dostrovsky, J.O.a , Bennett, G.J.c , Farran, R.P.d , Carlson, T.d
Nerve resection, crush and re-location relieve complex regional pain syndrome type II: A case report
(2014) Pain, . Article in Press. 


a Department of Medicine, University of Toronto, Toronto, Ontario, Canada
b Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
c Anesthesia Research Unit, McGill University, Montreal, Quebec, Canada
d Department of Anesthesia, University of Calgary, Alberta, Canada


Abstract
This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower-limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves. © 2014 International Association for the Study of Pain.


Author Keywords
Causalgia;  Complex regional pain syndrome;  Surgical treatment


Document Type: Article in Press
Source: Scopus

Fontebasso, A.M.a , Papillon-Cavanagh, S.b , Schwartzentruber, J.c , Nikbakht, H.d , Gerges, N.d , Fiset, P.-O.e , Bechet, D.d , Faury, D.b f , De Jay, N.d , Ramkissoon, L.A.g , Corcoran, A.g , Jones, D.T.W.h , Sturm, D.h , Johann, P.h , Tomita, T.i , Goldman, S.j , Nagib, M.k , Bendel, A.l , Goumnerova, L.m n , Bowers, D.C.o , Leonard, J.R.p , Rubin, J.B.q , Alden, T.i , Browd, S.r , Geyer, J.R.s , Leary, S.s , Jallo, G.t , Cohen, K.u , Gupta, N.v , Prados, M.D.v , Carret, A.-S.w , Ellezam, B.x , Crevier, L.y , Klekner, A.z , Bognar, L.z , Hauser, P.aa , Garami, M.aa , Myseros, J.ab , Dong, Z.ac , Siegel, P.M.ac , Malkin, H.ad , Ligon, A.H.n ae af , Albrecht, S.e , Pfister, S.M.h , Ligon, K.L.n ae af ag , Majewski, J.b , Jabado, N.a d f , Kieran, M.W.ad ah ai
Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma
(2014) Nature Genetics, . Article in Press. 


a 1] Division of Experimental Medicine, Montreal Childrens Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada
b 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada
c 1] Wellcome Trust Sanger Institute, Hinxton, UK
d Department of Human Genetics, McGill University, Montreal, Quebec, Canada
e Department of Pathology, Montreal Childrens Hospital, McGill University Health Centre, Montreal, Quebec, Canada
f Department of Pediatrics, McGill University, Montreal, Quebec, Canada
g Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
h Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
i Department of Neurological Surgery, Ann and Robert H. Lurie Childrens Hospital of Chicago, Northwestern University, Chicago, Illinois, USA
j Department of Pediatrics Hematology-Oncology, Ann and Robert H. Lurie Childrens Hospital of Chicago, Northwestern University, Chicago, Illinois, USA
k Clinical Pediatric Neurosurgical Oncology, Department of Surgery, Boston Childrens Hospital, Boston, Massachusetts, USA
l Department of Pediatric Hematology-Oncology, Childrens Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA
m 1] Department of Neurosurgery, Boston Childrens Hospital, Boston, Massachusetts, USA
n Harvard Medical School, Boston, Massachusetts, USA
o Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
p Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
q Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
r Department of Neurosurgery, Seattle Childrens Hospital, Seattle, Washington, USA
s Cancer and Blood Disorders Center, Seattle Childrens Hospital, Seattle, Washington, USA
t Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
u Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
v Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
w Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
x Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
y Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
z Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
aa 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
ab Department of Neurosurgery, Childrens National Medical Center, Washington, DC, USA
ac Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
ad Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
ae 1] Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
af Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, USA
ag Department of Pathology, Boston Childrens Hospital, Boston, Massachusetts, USA
ah 1] Harvard Medical School, Boston, Massachusetts, USA
ai Division of Pediatric Hematology/Oncology, Boston Childrens Hospital, Boston, Massachusetts, USA


Abstract
Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.


Document Type: Article in Press
Source: Scopus

Zolkowska, D.a , Dhir, A.a c , Krishnan, K.b , Covey, D.F.b , Rogawski, M.A.a d
Anticonvulsant potencies of the enantiomers of the neurosteroids androsterone and etiocholanolone exceed those of the natural forms
(2014) Psychopharmacology, . Article in Press. 


a Department of Neurology, University of California, Davis School of Medicine, Sacramento, CA 20817, United States
b Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
c Department of Biotechnology, Government of India, c/o Gujarat Forensic Sciences University, DFS Headquarters, Sector-18A, Near Police Bhavan, Gandhinagar, Gujarat 382007, India
d Department of Neurology, University of California, Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, United States


Abstract
Rationale Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms. Objectives The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models. Methods Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ). Results In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h). Conclusions The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics. © 2014 Springer-Verlag Berlin Heidelberg.


Author Keywords
Androsterone;  Enantiomer;  Etiocholanolone;  Maximal electroshock test;  Pentylenetetrazol test;  Six-Hertz test


Document Type: Article in Press
Source: Scopus

Beebe, D.C.a b , Shui, Y.-B.a , Siegfried, C.J.a , Holekamp, N.M.a c , Bai, F.a
Preserve the (intraocular) environment: the importance of maintaining normal oxygen gradients in the eye
(2014) Japanese Journal of Ophthalmology, . Article in Press. 


a Department of Ophthalmology and Visual Science, Washington University School of Medicine, 660 S. Euclid Ave.; Campus Box 8096, St. Louis, MO 63110, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
c Pepose Vision Institute, Chesterfield, MO, United States


Abstract
Oxygen levels in the eye are generally low and tightly regulated. Oxygen enters the eye largely by diffusion from retinal arterioles and through the cornea. In intact eyes, oxygen from the retinal arterioles diffuses into the vitreous body. There is a decreasing oxygen gradient from the retina to the lens, established by oxygen consumption by ascorbate in the vitreous fluid and lens metabolism. Age-related degeneration of the vitreous body or removal during vitrectomy exposes the posterior of the lens to increased oxygen, causing nuclear sclerotic cataracts. Lowering oxygen in the vitreous, as occurs in patients with ischemic diabetic retinopathy, protects against cataracts after vitrectomy. Vitrectomy and cataract surgery increase oxygen levels at the trabecular meshwork and with it the risk of open angle glaucoma. Two additional risk factors for glaucoma, African heritage and having a thinner cornea, are also associated with increased oxygen in the anterior chamber angle. Preservation of the vitreous body and the lens, two important oxygen consumers, would protect against nuclear sclerotic cataracts and open angle glaucoma. Delaying removal of the lens for as long as possible after vitrectomy would be an important step in delaying ocular hypertension and glaucoma progression. © 2014 Japanese Ophthalmological Society.


Author Keywords
Nuclear sclerotic cataract;  Open angle glaucoma;  Oxygen toxicity;  Phaco-vitrectomy;  Vitrectomy


Document Type: Article in Press
Source: Scopus

Kantrowitz, J.T.a b , Scaramello, N.a , Jakubovitz, A.a , Lehrfeld, J.M.a , Laukka, P.c , Elfenbein, H.A.d , Silipo, G.a , Javitt, D.C.a b
Amusia and protolanguage impairments in schizophrenia
(2014) Psychological Medicine, . Article in Press. 


a Schizophrenia Research Center, Nathan Kline Institute, Orangeburg, NY, USA
b Department of Psychiatry, Columbia University, New York, NY, USA
c Department of Psychology, Stockholm University, Sweden
d Olin Business School, Washington University, St Louis, MO, USA


Abstract
Background: Both language and music are thought to have evolved from a musical protolanguage that communicated social information, including emotion. Individuals with perceptual music disorders (amusia) show deficits in auditory emotion recognition (AER). Although auditory perceptual deficits have been studied in schizophrenia, their relationship with musical/protolinguistic competence has not previously been assessed. Method: Musical ability was assessed in 31 schizophrenia/schizo-affective patients and 44 healthy controls using the Montreal Battery for Evaluation of Amusia (MBEA). AER was assessed using a novel battery in which actors provided portrayals of five separate emotions. The Disorganization factor of the Positive and Negative Syndrome Scale (PANSS) was used as a proxy for language/thought disorder and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognition. Results: Highly significant deficits were seen between patients and controls across auditory tasks (p < 0.001). Moreover, significant differences were seen in AER between the amusia and intact music-perceiving groups, which remained significant after controlling for group status and education. Correlations with AER were specific to the melody domain, and correlations between protolanguage (melody domain) and language were independent of overall cognition. Discussion: This is the first study to document a specific relationship between amusia, AER and thought disorder, suggesting a shared linguistic/protolinguistic impairment. Once amusia was considered, other cognitive factors were no longer significant predictors of AER, suggesting that musical ability in general and melodic discrimination ability in particular may be crucial targets for treatment development and cognitive remediation in schizophrenia. Copyright © Cambridge University Press 2014.


Author Keywords
Amusia;  emotion;  language;  music;  schizophrenia;  social cognition


Document Type: Article in Press
Source: Scopus

Johnson, J.O.a , Pioro, E.P.b , Boehringer, A.c , Chia, R.d , Feit, H.e , Renton, A.E.f , Pliner, H.A.f , Abramzon, Y.f , Marangi, G.a g , Winborn, B.J.h , Gibbs, J.R.i j , Nalls, M.A.k , Morgan, S.j , Shoai, M.j , Hardy, J.j , Pittman, A.j , Orrell, R.W.l , Malaspina, A.m , Sidle, K.C.j , Fratta, P.n , Harms, M.B.o , Baloh, R.H.p , Pestronk, A.o , Weihl, C.C.o , Rogaeva, E.q , Zinman, L.r , Drory, V.E.s , Borghero, G.t , Mora, G.u , Calvo, A.v , Rothstein, J.D.w , Drepper, C.x y , Sendtner, M.z , Singleton, A.B.k , Taylor, J.P.h , Cookson, M.R.aa , Restagno, G.ab , Sabatelli, M.ac , Bowser, R.c , Chiò, A.ad , Traynor, B.J.a w
Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis
(2014) Nature Neuroscience, . Article in Press. 


a 1] Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
b 1] Department of Neurology, Neuromuscular Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
c 1] Division of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA
d 1] Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
e Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
f Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
g Institute of Medical Genetics, Catholic University of Sacred Heart, Rome, Italy
h Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
i 1] Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
j Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, UK
k Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
l Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK
m Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, North-East London and Essex Regional Motor Neuron Disease Care Centre, London, UK
n Department of Neurodegenerative Disease, University College London, London, UK
o Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
p Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA
q Tanz Centre for Research of Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
r Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
s Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
t Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy
u ALS Center, Salvatore Maugeri Foundation, Milan, Italy
v Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy
w Brain Science Institute, Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
x 1] Institute for Clinical Neurobiology, University of Würzburg, Würzburg, Germany
y Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
z Institute for Clinical Neurobiology, University of Würzburg, Würzburg, Germany
aa Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
ab 1] Molecular Genetics Unit, Department of Clinical Pathology, Azienda Sanitaria Ospedaliera Ospedale Infantile Regina Margherita-Santa Anna, Turin, Italy
ac 1] Neurological Institute, Catholic University and Insieme Contro le Malattie del Motoneurone Association for ALS Research, Rome, Italy
ad 1] 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy


Abstract
MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.


Document Type: Article in Press
Source: Scopus

Freudenburg, Z.V.a b , Gaona, C.M.c , Sharma, M.c , Bundy, D.T.c , Breshears, J.D.d , Pless, R.B.b , Leuthardt, E.C.c d
Fast-scale network dynamics in human cortex have specific spectral covariance patterns
(2014) Proceedings of the National Academy of Sciences of the United States of America, 111 (12), pp. 4602-4607. 


a Departments of Neurology and Neurosurgery, University Medical Center Utrecht, Rudolf Magnus Institute, 3584 CX, Utrecht, Netherlands
b Department of Computer Science, Washington University, St. Louis, MO, 63130, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO, 63130, United States
d Department of Neurological Surgery, Washington University, St. Louis, MO, 63130, United States


Abstract
Whether measured by MRI or direct cortical physiology, infraslow rhythms have defined state invariant cortical networks. The time scales of this functional architecture, however, are unlikely to be able to accommodate the more rapid cortical dynamics necessary for an active cognitive task. Using invasively monitored epileptic patients as a research model, we tested the hypothesis that faster frequencies would spectrally bind regions of cortex as a transient mechanism to enable fast network interactions during the performance of a simple hear-and-repeat speech task. We term these short-lived spectrally covariant networks functional spectral networks (FSNs). We evaluated whether spectrally covariant regions of cortex, which were unique in their spectral signatures, provided a higher degree of task-related information than any single site showing more classic physiologic responses (i.e., single-site amplitude modulation). Taken together, our results showing that FSNs are a more sensitive measure of task-related brain activation and are better able to discern phonemic content strongly support the concept of spectrally encoded interactions in cortex. Moreover, these findings that specific linguistic information is represented in FSNs that have broad anatomic topographies support a more distributed model of cortical processing.


Author Keywords
Covariant amplitude response;  Electrocorticography;  Oscillating electrical potential


Document Type: Article
Source: Scopus

Wang, H.a b , Han, M.a c d , Whetsell, W.e , Wang, J.f g , Rich, J.h , Hallahan, D.i , Han, Z.a b g
Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma
(2014) Oncogene, 33 (12), pp. 1558-1569. 


a Department of Radiation Oncology, Vanderbilt University School of Medicine, 1301 Medical Center Drive, Nashville, TN 37232, United States
b Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
c Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Science, Kunming, China
d Graduate School, Chinese Academy of Sciences, Beijing, China
e Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, United States
f Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, TN, United States
g Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States
h Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
i Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, United States


Abstract
PDZ domains represent one group of the major structural units that mediate protein interactions in intercellular contact, signal transduction and assembly of biological machineries. Tax-interacting protein (TIP)-1 protein is composed of a single PDZ domain that distinguishes TIP-1 from other PDZ domain proteins that more often contain multiple protein domains and function as scaffolds for protein complex assembly. However, the biological functions of TIP-1, especially in cell transformation and tumor progression, are still controversial as observed in a variety of cell types. In this study, we have identified ARHGEF7, a guanine nucleotide exchange factor for Rho GTPases, as one novel TIP-1-interacting protein in human glioblastoma cells. We found that the presence of TIP-1 protein is essential to the intracellular redistribution of ARHGEF7 and rhotekin, one Rho effector and the spatiotemporally coordinated activation of Rho GTPases (RhoA, Cdc42 and Rac1) in migrating glioblastoma cells. TIP-1 knockdown resulted in both aberrant localization of ARHGEF7 and rhotekin, as well as abnormal activation of Rho GTPases that was accompanied with impaired motility of glioblastoma cells. Furthermore, TIP-1 knockdown suppressed tumor cell dispersal in orthotopic glioblastoma murine models. We also observed high levels of TIP-1 expression in human glioblastoma specimens, and the elevated TIP-1 levels are associated with advanced staging and poor prognosis in glioma patients. Although more studies are needed to further dissect the mechanism(s) by which TIP-1 modulates the intracellular redistribution and activation of Rho GTPases, this study suggests that TIP-1 holds potential as both a prognostic biomarker and a therapeutic target of malignant gliomas. © 2014 Macmillan Publishers Limited.


Author Keywords
ARHGEF7;  Cell migration;  Glioblastoma;  Rho GTPases;  Rhotekin;  Tax-interacting protein-1


Document Type: Article
Source: Scopus

Vogel, A.C.a , Petersen, S.E.b c d e , Schlaggar, B.L.b c d f
The VWFA: It's not just for words anymore
(2014) Frontiers in Human Neuroscience, 8 (MAR), art. no. 88, . 


a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
f Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Reading is an important but phylogeny etically new skill. While neuro imaging studies have identified brain regions used in reading, it is unclear to what extent these regions become specialized for use predominantly in reading vs. other tasks. Over the past several years, our group has published three studies addressing this question, particularly focusing on whether the putative visual word form area (VWFA) is used predominantly in reading, or whether it is used more generally in a number of tasks. Our three studies utilize a range of neuro imaging techniques, including task based fMRI experiments, a seed based resting state functional connectivity (RSFC) experiment, and a network based RSFC experiment. Overall, our studies indicate that the VWFA is not used specifically or even predominantly for reading. Rather the VWFA is a general use region that has processing properties making it particularly useful for reading, though it continues to be used in any task that requires its general processing properties. Our network based RSFC analysis extends this finding to other regions typically thought to be used predominantly for reading. Here, we review these findings and describe how the three studies complement each other. Then, we argue that conceptualizing the VWFA as a brain region with specific processing characteristics rather than a brain region devoted to a specific stimulus class, allows us to better explain the activity seen in this region during a variety of tasks. Having this type of conceptualization not only provides a better understanding of the VWFA but also provides a framework for understanding other brain regions, as it affords an explanation of function that is in keeping with the long history of studying the brain in terms of the type of information processing performed (Posner, 1978). © 2014 Vogel, Petersen and Schlaggar.


Author Keywords
FMRI;  Occipito-temporal cortex;  Orthography;  Reading;  Resting-state FMRI;  Resting-state functional connectivity;  Resting-state networks;  Visual word form area


Document Type: Review
Source: Scopus

Gavilan, H.S.b , Kulikauskas, R.M.b d , Gutmann, D.H.c , Fehon, R.G.a
In vivo functional analysis of the human NF2 tumor suppressor gene in Drosophila
(2014) PLoS ONE, 9 (3), art. no. e90853, . 


a Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, United States
b Department of Biology, Duke University, Durham, NC, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, United States


Abstract
The proper control of tissue growth is essential during normal development and an important problem in human disease. Merlin, the product of the Neurofibromatosis 2 tumor suppressor gene, has been extensively studied to understand its functions in growth control. Here we describe experiments in which we used Drosophila as an in vivo system to test the functions of the normal human NF2 gene products and patient-derived mutant alleles. Although the predominant NF2 gene isoform, isoform 1, could functionally replace the Drosophila Merlin gene, a second isoform with a distinct C-terminal tail could not. Immunofluorescence studies show that the two isoforms have distinct subcellular localizations when expressed in the polarized imaginal epithelium, and function in genetic rescue assays correlates with apical localization of the NF2 protein. Interestingly, we found that a patient-derived missense allele, NF2L64P, appears to be temperature sensitive. These studies highlight the utility of Drosophila for in vivo functional analysis of highly conserved human disease genes. © 2014 Gavilan et al.


Document Type: Article
Source: Scopus

Peterson, D.S.a , Pickett, K.A.a b , Duncan, R.a , Perlmutter, J.a b c d , Earhart, G.M.a b c
Gait-related brain activity in people with Parkinson disease with freezing of gait
(2014) PLoS ONE, 9 (3), art. no. e90634, . 


a Program in Physical Therapy, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
d Radiology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Approximately 50% of people with Parkinson disease experience freezing of gait, described as a transient inability to produce effective stepping. Complex gait tasks such as turning typically elicit freezing more commonly than simple gait tasks, such as forward walking. Despite the frequency of this debilitating and dangerous symptom, the brain mechanisms underlying freezing remain unclear. Gait imagery during functional magnetic resonance imaging permits investigation of brain activity associated with locomotion. We used this approach to better understand neural function during gait-like tasks in people with Parkinson disease who experience freezing- "FoG +" and people who do not experience freezing- "FoG-". Nine FoG+ and nine FoG- imagined complex gait tasks (turning, backward walking), simple gait tasks (forward walking), and quiet standing during measurements of blood oxygen level dependent (BOLD) signal. Changes in BOLD signal (i.e. beta weights) during imagined walking and imagined standing were analyzed across FoG+ and FoG- groups in locomotor brain regions including supplementary motor area, globus pallidus, putamen, mesencephalic locomotor region, and cerebellar locomotor region. Beta weights in locomotor regions did not differ for complex tasks compared to simple tasks in either group. Across imagined gait tasks, FoG+ demonstrated significantly lower beta weights in the right globus pallidus with respect to FoG-. FoG+ also showed trends toward lower beta weights in other right-hemisphere locomotor regions (supplementary motor area, mesencephalic locomotor region). Finally, during imagined stand, FoG+ exhibited lower beta weights in the cerebellar locomotor region with respect to FoG-. These data support previous results suggesting FoG+ exhibit dysfunction in a number of cortical and subcortical regions, possibly with asymmetric dysfunction towards the right hemisphere. © 2014 Peterson et al.


Document Type: Article
Source: Scopus

Hung, Y.H.a , Faux, N.G.a , Killilea, D.W.b , Yanjanin, N.c , Firnkes, S.d , Volitakis, I.a , Ganio, G.a , Walterfang, M.e , Hastings, C.f , Porter, F.D.c , Ory, D.S.d , Bush, A.I.a
Altered transition metal homeostasis in Niemann-Pick disease, type C1
(2014) Metallomics, 6 (3), pp. 542-553. 


a Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia
b Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, United States
c Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20892, United States
d Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, United States
e Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, Melbourne, VIC 3050, Australia
f Children's Hospital, Research Center, Oakland, CA 94609, United States


Abstract
The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1-/- mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1-/- mouse model. NPC1 deficiency in the Npc1-/- mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1-/- mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C. © 2014 The Royal Society of Chemistry.


Document Type: Article
Source: Scopus

Yamada, K.a , Holth, J.K.a , Liao, F.a , Stewart, F.R.a , Mahan, T.E.a , Jiang, H.a , Cirrito, J.R.a , Patel, T.K.a , Hochgräfe, K.b c , Mandelkow, E.-M.b c , Holtzman, D.M.a
Neuronal activity regulates extracellular tau in vivo
(2014) Journal of Experimental Medicine, 211 (3), pp. 387-393. 


a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
b DZNE (German Center for Neurodegenerative Diseases), 53175 Bonn, Germany
c CAESAR Research Center, 53175 Bonn, Germany


Abstract
Tau is primarily a cytoplasmic protein that stabilizes microtubules. However, it is also found in the extracellular space of the brain at appreciable concentrations. Although its presence there may be relevant to the intercellular spread of tau pathology, the cellular mechanisms regulating tau release into the extracellular space are not well understood. To test this in the context of neuronal networks in vivo, we used in vivo microdialysis. Increasing neuronal activity rapidly increased the steady-state levels of extracellular tau in vivo. Importantly, presynaptic glutamate release is sufficient to drive tau release. Although tau release occurred within hours in response to neuronal activity, the elimination rate of tau from the extracellular compartment and the brain is slow (half-life of ~11 d). The in vivo results provide one mechanism underlying neuronal tau release and may link trans-synaptic spread of tau pathology with synaptic activity itself. © 2014 Yamada et al.


Document Type: Article
Source: Scopus

Nadelson, M.R.a , Sanders, R.D.c d , Avidan, M.S.b , Hardman, J.G.e
Perioperative cognitive trajectory in adults
(2014) British Journal of Anaesthesia, 112 (3), pp. 440-451. 


a Department of Anesthesiology, Washington University School of Medicine, Box 8054, 660 South Euclid Ave, St. Louis, MO 63110, United States
b Division of Cardiothoracic Anesthesiology and Surgery, Department of Anesthesiology, Washington University School of Medicine, Box 8054, 660 South Euclid Ave, St. Louis, MO 63110, United States
c Department of Anaesthesia, Surgical Outcomes Research Centre, University College London, London, United Kingdom
d Wellcome Department of Imaging Neuroscience, University College London, London, United Kingdom


Abstract
Approximately a quarter of a billion people undergo surgery every year hoping that the operation will alleviate symptoms, cure diseases, and improve quality-of-life. A concern has arisen that, despite the benefits of surgery, elderly patients might suffer neurological injury from surgery and general anaesthesia leading to persistent cognitive decline. However, many studies of postoperative cognition have had methodological weaknesses, including lack of suitable control groups, dissociation of cognitive outcomes from surgical outcomes, sub-optimal statistical techniques, and absence of longitudinal preoperative cognitive assessments. Emerging evidence suggests that after early cognitive decline, most patients return to their preoperative cognitive trajectories within 3 months of surgery; some even experience subsequent cognitive improvement. In this review, we summarize the scientific literature on perioperative cognition. We propose that the most important determinants of the postoperative cognitive trajectory are the preoperative cognitive trajectory, the success of the surgery, and events in the perioperative period. Postoperative complications, ongoing inflammation, and chronic pain are probably modifiable risk factors for persistent postoperative cognitive decline. When surgery is successful with minimal perioperative physiological perturbations, elderly patients can expect cognition to follow its preoperative course. Furthermore, when surgery alleviates symptoms and enhances quality-of-life, postoperative cognitive improvement is a possible and desirable outcome. © 2014 © The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Author Keywords
anesthesia recovery period;  postoperative period, cognition;  preoperative period

 

Document Type: Review
Source: Scopus

 

April 6, 2014

Agrawal, A.a , Madden, P.A.F.a , Bucholz, K.K.a , Heath, A.C.a , Lynskey, M.T.a b
Initial reactions to tobacco and cannabis smoking: A twin study
(2014) Addiction, 109 (4), pp. 663-671. 


a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
b Addictions Department, Institute of Psychiatry, King's College London, London, United Kingdom


Abstract
Background and Aims: Initial subjective reactions to cannabis and tobacco, broadly classified as positive or negative, have previously been explored for their associations with onset and maintenance of subsequent abuse/dependence. We examine (i) the factorial architecture of self-reported initial reactions to cannabis and tobacco; (ii) whether these factors associate with concurrently reported age at onset of DSM-IV diagnosis of nicotine dependence and cannabis abuse/dependence; and (iii) estimate heritable variation in and covariation between the factors. Design: Factorial and exploratory structural equation modeling was conducted to examine the factor structure of initial reactions. Cox proportional hazards modeling was employed to examine their association with time to onset of diagnosis of DSM-IV nicotine dependence and cannabis abuse/dependence. Classical twin modeling, using univariate and multivariate models, was used to parse variance in each factor (and the covariance between factors) to their additive genetic, shared environmental and non-shared environmental sources. Setting and Participants: General population sample of Caucasian female twins aged 18-32 years, with a life-time history of tobacco [n=2393] and cannabis [n=1445] use. Measurement: Self-report of initial subjective reactions to tobacco (cigarettes) and cannabis the first time they were used and time to onset of life-time history of DSM-IV diagnosis of abuse (cannabis) and dependence (cannabis or nicotine). Findings: Factors representing putatively positive and negative reactions to cannabis and tobacco emerged. Initial reactions to tobacco were associated with onset of DSM-IV diagnosis of nicotine dependence and cannabis abuse/dependence while initial reactions to cannabis were associated with onset of DSM-IV diagnosis of cannabis abuse/dependence alone. Genetic factors played a moderate role in each factor (heritability of 27-35%, P<0.05), with the remaining variance attributed to individual-specific environment. Covariation across the factors indexing positive and negative initial reactions was attributable to genetic sources (0.18-0.58, P<0.05) and to overlapping individual-specific environmental factors (-0.16 to 0.36, P<0.05). Conclusions: Initial subjective reactions to tobacco are associated with onset of DSM-IV diagnosis of nicotine dependence and cannabis abuse/dependence while initial subjective reactions to cannabis are only associated with onset of diagnosis of DSM-IV cannabis abuse/dependence. Genetic and environmental factors underpin the overlap across the factors representing initial reactions, both positive and negative. © 2013 Society for the Study of Addiction.


Author Keywords
Cannabis;  Genetic;  Heritability;  Initial reaction;  Tobacco;  Twin


Document Type: Article
Source: Scopus

Chandrasekar, I.a b , Goeckeler, Z.M.c , Turney, S.G.d , Wang, P.a , Wysolmerski, R.B.c , Adelstein, R.S.e , Bridgman, P.C.a
Nonmuscle myosin II is a critical regulator of clathrin-mediated endocytosis
(2014) Traffic, 15 (4), pp. 418-432. 


a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, United States
c Department of Neurobiology and Anatomy, Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV 26506, United States
d Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, United States
e Laboratory of Molecular Cardiology, NHLBI, NIH, Bethesda, MD 20892, United States


Abstract
Variable requirements for actin during clathrin-mediated endocytosis (CME) may be related to regional or cellular differences in membrane tension. To compensate, local regulation of force generation may be needed to facilitate membrane curving and vesicle budding. Force generation is assumed to occur primarily through actin polymerization. Here we examine the role of myosin II using loss of function experiments. Our results indicate that myosin II acts on cortical actin scaffolds primarily in the plane of the plasma membrane (bottom arrow) to generate changes that are critical for enhancing CME progression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Author Keywords
Actin;  Clathrin;  Endocytosis;  Myosin II


Document Type: Article
Source: Scopus

Shannon, B.a , Soto-Ortolaza, A.a , Rayaprolu, S.a , Cannon, H.D.a , Labbé, C.a , Benitez, B.A.b c , Choi, J.b c , Lynch, T.d , Boczarska-Jedynak, M.e , Opala, G.e , Krygowska-Wajs, A.f , Barcikowska, M.g , Van Gerpen, J.A.h , Uitti, R.J.h , Springer, W.a i , Cruchaga, C.b c , Wszolek, Z.K.h , Ross, O.A.a i
Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease
(2014) Neurobiology of Aging, . Article in Press. 


a Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
b Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
c Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
d Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland
e Department of Neurology, Medical University of Silesia, Katowice, Poland
f Department of Neurology, Jagiellonian University, Krakow, Poland
g Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
h Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
i Neurobiology of Disease Track, Mayo Graduate School, Mayo Clinic, Rochester, MN, USA


Abstract
We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson's disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson's disease patient-control series for the VPS29 and VPS26A/B genes. We identified only 2 rare nonsynonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson's disease. © 2014 Elsevier Inc. All rights reserved.


Author Keywords
Genetics;  Parkinson's disease and/or Parkinsonism;  Retromer;  VPS35


Document Type: Article in Press
Source: Scopus

Kumar, M.G.a , Emnett, R.J.b , Bayliss, S.J.a , Gutmann, D.H.b
Glomus tumors in individuals with neurofibromatosis type 1
(2014) Journal of the American Academy of Dermatology, . Article in Press. 


a Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine
b Department of Neurology, Washington University School of Medicine


Abstract
Background: Glomus tumors have recently been reported in individuals with the neurofibromatosis type 1 (NF1) cancer disposition syndrome. We compare the clinical and molecular features of these painful hamartomas in a series of sporadic and NF1-associated cases. Objective: We sought to evaluate the association of NF1 with glomus tumors and to compare NF1-associated glomus tumors with sporadic glomus tumors. Methods: We conducted a retrospective cohort study of all individuals with a histopathologic diagnosis of glomus tumor at a large tertiary care center from January 1998 to January 2013. Charts were reviewed for a coexisting diagnosis of NF1. Results: A total of 42 glomus tumors were identified in 34 individuals. Twelve (28.6%) were found in 6 patients with NF1. In 28 individuals with 30 sporadic tumors, there was no coexisting medical condition. Although multifocal tumors (16.7%) and tumor recurrence (33.3%) were more common in association with NF1, these trends did not reach statistical significance. NF1-associated glomus tumors exhibited no neurofibromin immunoreactivity, whereas their sporadic counterparts retained neurofibromin expression. Limitations: The retrospective design resulted in incomplete data capture. Conclusions: Detection of glomus tumors should raise suspicion for a concurrent diagnosis of NF1. © 2014 American Academy of Dermatology, Inc.


Author Keywords
glomus tumor;  neurofibromatosis;  neurofibromatosis type 1;  neurofibromin;  tumor disposition syndrome


Document Type: Article in Press
Source: Scopus

Holland, J.C.a , Kolko, R.P.a , Stein, R.I.b , Welch, R.R.a , Perri, M.G.c , Schechtman, K.B.d , Saelens, B.E.e , Epstein, L.H.f , Wilfley, D.E.a
Modifications in parent feeding practices and child diet during family-based behavioral treatment improve child zBMI
(2014) Obesity, . Article in Press. 


a Department of Psychiatry Washington University School of Medicine St. Louis, Missouri USA
b Department of Internal Medicine Washington University School of Medicine St. Louis, Missouri USA
c Department of Clinical and Health Psychology University of Florida Gainesville, Florida USA
d Department of Biostatistics Washington University School of Medicine St. Louis, Missouri USA
e Seattle Children's Research Institute University of Washington Seattle, Washington USA
f Department of Pediatrics University at Buffalo School of Medicine and Biomedical Sciences Buffalo, New York USA


Abstract
Objective: To examine associations between modifications in parent feeding practices, child diet, and child weight status after treatment and to evaluate dietary mediators. Methods: Children classified as overweight or obese and 7-11 years old (N=170) completed a 16-session family-based behavioral weight loss treatment (FBT) program. Anthropometrics (standardized body mass index (zBMI)), Child Feeding Questionnaire, and 24-hr dietary recalls were collected at baseline and post-FBT. Linear regression predicted child zBMI change. Single and multiple mediation tested child dietary modifications as mediators between change in parent feeding practices and child zBMI. Results: Restrictive parent feeding practices significantly decreased during FBT. Reductions in parent restriction, child weight concern, child's total energy intake, and percent energy from fat, and increases in parent perceived responsibility, and child percent energy from protein, predicted reductions in child zBMI. Change in child total energy intake mediated the relation between parent restriction and child zBMI change after accounting for covariates and additional dietary mediators. Conclusions: FBT is associated with a decrease in parental restriction, which is associated with reductions in child relative weight, which was mediated by a decrease in child energy intake. Teaching parents to reduce children's energy intake without being overly restrictive may improve child weight. © 2014 The Obesity Society.


Document Type: Article in Press
Source: Scopus

Lavonas, E.J.a , Severtson, S.G.a , Martinez, E.M.a , Bucher-Bartelson, B.a , Le Lait, M.-C.a , Green, J.L.a , Murrelle, L.E.b , Cicero, T.J.c , Kurtz, S.P.d , Rosenblum, A.e , Surratt, H.L.d , Dart, R.C.a
Abuse and diversion of buprenorphine sublingual tablets and film
(2014) Journal of Substance Abuse Treatment, . Article in Press. 


a Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, 777 Bannock Street, MC 0180, Denver, CO, 80204, USA
b Venebio Group, LLC, 7400 Beaufont Springs Drive, Suite 300, Richmond, VA 23225, USA
c Department of Psychiatry, Washington University in St. Louis, One Brookings Drive, Campus Box 8134, St. Louis, MO 63130 USA
d Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, 2 NE 40th Street, Suite 404, Miami, FL 33137 USA
e Institute for Treatment and Services Research, National Development and Research Institutes, 71 West 23rd Street, 4th floor, New York, NY 10010 USA


Abstract
Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned. © 2014 The Authors.


Author Keywords
Buprenorphine;  Drug abuse;  Drug formulations;  Substance-related disorders


Document Type: Article in Press
Source: Scopus

Hoag, J.a , Kupst, M.J.a , Briere, M.-E.b , Mabbott, D.c d , Elkin, T.D.e , Trask, C.L.f g , Isenberg, J.h i , Holm, S.j , Ambler, C.k , Strother, D.R.b
Feasibility of Conducting Long-Term Follow-Up of Children and Infants Treated for CNS Tumors on the Same Cooperative Group Clinical Trial Protocol
(2014) Journal of Clinical Psychology in Medical Settings, . Article in Press. 


a Department of Pediatrics, Hematology/Oncology/Bone Marrow Transplant, Medical College of Wisconsin, 8701 Watertown Plank Road, MFRC 3018, Milwaukee, WI 53226, United States
b Departments of Oncology and Pediatrics, University of Calgary, Calgary, AB, Canada
c Program in Neuroscience and Mental Health, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
d Department of Psychology, University of Toronto, Toronto, ON, Canada
e Department of Psychiatry, University of Mississippi Medical Center, Jackson, MS, United States
f Department of Psychiatry, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, United States
g Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, RI, United States
h Department of Psychology, St. Louis Children's Hospital, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
i Department of Neurology, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
j Psychology Service, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
k Division of Child Neurology, Stanford University, Stanford, CA, United States


Abstract
Given the barriers to conducting long-term assessment of neurocognitive and psychosocial functioning of those treated in infancy for central nervous system (CNS) tumors, a multi-site feasibility study was conducted. The primary objective was to demonstrate that it is feasible to identify, locate and assess the functioning of children treated on the same protocol 10-years post-treatment. Six sites obtained institutional approval, identified and recruited subjects, and obtained comprehensive neurocognitive and psychosocial data. All feasibility objectives were met. Barriers to participation included length of time for Institutional Review Board submission and review, clinical demands, limited eligible participants at individual institutions, difficulty locating long-term subjects and stipend/reimbursement concerns. Results indicate that long-term studies are feasible and essential given the need to address long-term issues of children treated at a young age for CNS tumors, especially as they relate to later academic and vocational planning, but require significant coordination and commitment of cooperative group and institutional resources. © 2014 Springer Science+Business Media New York.


Author Keywords
CNS tumors;  Feasibility;  Late effects;  Neurocognitive


Document Type: Article in Press
Source: Scopus

Derdeyn, C.P.a , Hankey, G.J.b
In intracranial artery stenosis, adding angioplasty and stenting to medical therapy increased stroke or death
(2014) Annals of Internal Medicine, 160 (6), pp. JC4. 


a Washington University, School of Medicine, Barnes Jewish Hospital, St. Louis, MO, United States
b School of Medicine and Pharmacology, University of Western, Australia Perth, WA, Australia


Document Type: Note
Source: Scopus

Born, H.A.a , Kim, J.-Y.a , Savjani, R.R.a h , Das, P.i , Dabaghian, Y.A.f j , Guo, Q.g , Yoo, J.W.b , Schuler, D.R.k , Cirrito, J.R.k , Zheng, H.a c d g , Golde, T.E.l , Noebels, J.L.a b d , Jankowsky, J.L.a b e g
Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer's disease
(2014) Journal of Neuroscience, 34 (11), pp. 3826-3840. 


a Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States
b Department of Neurology, Baylor College of Medicine, Houston, TX 77030, United States
c Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, United States
d Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, United States
e Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, United States
f The Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, United States
g The Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, United States
h Texas A and M Health Science Center, College Station, TX 77843, United States
i Department of Neuroscience, Mayo Clinic, Jacksonville, FL32224, United States
j Department of Computational and Applied Mathematics, Rice University, Houston, TX 77251, United States
k Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
l Department of Neuroscience, University of Florida, Gainesville, FL 32610, United States


Abstract
Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology. © 2014 the authors.


Author Keywords
Amyloid precursor protein;  EEG;  Epilepsy;  Seizure;  Sharp wave discharge;  Transgene suppression


Document Type: Article
Source: Scopus

Li, C.L.a , Sathyamurthy, A.b , Oldenborg, A.a , Tank, D.a , Ramanan, N.a c
SRF phosphorylation by glycogen synthase kinase-3 promotes axon growth in hippocampal neurons
(2014) Journal of Neuroscience, 34 (11), pp. 4027-4042. 


a Department of Anatomy and Neurobiology, Division of Endocrinology, Washington University School of Medicine, St.Louis, MO 63110, United States
b Department of Medicine, Division of Endocrinology, Washington University School of Medicine, St.Louis, MO 63110, United States
c Centre for Neuroscience, Indian Institute of Science, Bangalore 560 012, Karnataka, India


Abstract
The growth of axons is an intricately regulated process involving intracellular signaling cascades and gene transcription. We had previously shown that the stimulus-dependent transcription factor, serum response factor (SRF), plays a critical role in regulating axon growth in the mammalian brain. However, the molecular mechanisms underlying SRF-dependent axon growth remains unknown. Here we report that SRF is phosphorylated and activated by GSK-3 to promote axon outgrowth in mouse hippocampal neurons. GSK-3 binds to and directly phosphorylates SRF on a highly conserved serine residue. This serine phosphorylation is necessary for SRF activity and for its interaction with MKL-family cofactors, MKL1 and MKL2, but not with TCF-family cofactor, ELK-1. Axonal growth deficits caused by GSK-3 inhibition could be rescued by expression of a constitutively active SRF. The SRF target gene and actin-binding protein, vinculin, is sufficient to overcome the axonal growth deficits of SRF-deficient and GSK-3-inhibited neurons. Furthermore, short hairpin RNA-mediated knockdown of vinculin also attenuated axonal growth. Thus, our findings reveal a novel phosphorylation and activation of SRF by GSK-3 that is critical for SRF-dependent axon growth in mammalian central neurons. © 2014 the authors.


Author Keywords
Axon growth;  Filopodia;  GSK-3;  Neurite outgrowth;  Serum response factor


Document Type: Article
Source: Scopus

Vardarajan, B.N.a b , Faber, K.M.c , Bird, T.D.d e , Bennett, D.A.f , Rosenberg, R.g , Boeve, B.F.h , Graff-Radford, N.R.i , Goate, A.M.j k , Farlow, M.l , Sweet, R.A.m n o , Lantigua, R.a p , Medrano, M.Z.q r , Ottman, R.b c s t , Schaid, D.J.u , Foroud, T.M.c , Mayeux, R.a b v
Age-specific incidence rates for dementia and alzheimer disease in NIA-LOAD/NCRAD and EFIGA families: National Institute on Aging Genetics Initiative for late-onset Alzheimer disease/National Cell Repository for Alzheimer disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)
(2014) JAMA Neurology, 71 (3), pp. 315-323. 


a Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
b Gertrude H. Sergievsky Center, Columbia University, College of Physicians and Surgeons, 630 W 168th St., New York, NY 10032, United States
c Department of Medical and Molecular Genetics, Indiana University, Indianapolis, United States
d Department of Neurology, University of Washington, Seattle, United States
e Department of Medicine, University of Washington, Seattle, United States
f Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States
g Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States
h Department of Neurology, Mayo Clinic, Rochester, MN, United States
i Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
j Department of Psychiatry and Genetics, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, United States
k Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
l Department of Neurology, Indiana University, Center for Alzheimer's Disease and Related Disorders, Indianapolis, United States
m Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
n Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
o Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, United States
p Department of Medicine, Columbia University, New York, NY, United States
q Universidad Tecnológica de Santiago, Santiago, Dominican Republic
r Department of Geriatrics, Pontificia Universidad Católica Madre y Maestra, Santiago, Dominican Republic
s Department of Epidemiology, Columbia University, New York, NY, United States
t Division of Epidemiology, New York State Psychiatric Institute, New York, United States
u Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
v Department of Neurology, Columbia University, New York, NY, United States


Abstract
IMPORTANCE: Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD. OBJECTIVE: To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies. DESIGN, SETTING, AND PARTICIPANTS: Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study. MAIN OUTCOMES AND MEASURES: Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD. RESULTS: The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrastingthese results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71). CONCLUSIONS AND RELEVANCE: The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higherthan population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease-related genes in these families or shared environmental risks. Copyright 2014 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus

Hartz, S.M., Pato, C.N., Medeiros, H., Cavazos-Rehg, P., Sobell, J.L., Knowles, J.A., Bierut, L.J., Pato, M.T.
Comorbidity of severe psychotic disorders with measures of substance use
(2014) JAMA Psychiatry, 71 (3), pp. 248-254. Cited 1 time.


Department of Psychiatry, Washington University, School of Medicine, 660 S. Euclid Ave, Box 8134, St Louis, MO 63110, United States


Abstract
IMPORTANCE: Although early mortality in severe psychiatric illness is linked to smoking and alcohol, to our knowledge, no studies have comprehensively characterized substance use behavior in severe psychotic illness. In particular, recent assessments of substance use in individuals with mental illness are based on population surveys that do not include individuals with severe psychotic illness. OBJECTIVE: To compare substance use in individuals with severe psychotic illness with substance use in the general population. DESIGN, SETTING, AND PARTICIPANTS: We assessed comorbidity between substance use and severe psychotic disorders in the Genomic Psychiatry Cohort. The Genomic Psychiatry Cohort is a clinically assessed, multiethnic sample consisting of 9142 individuals with the diagnosis of schizophrenia, bipolar disorder with psychotic features, or schizoaffective disorder, and 10 195 population control individuals. MAIN OUTCOMES AND MEASURES Smoking (smoked >100 cigarettes in a lifetime), heavy alcohol use (>4 drinks/day), heavy marijuana use (>21 times of marijuana use/year), and recreational drug use. RESULTS: Relative to the general population, individuals with severe psychotic disorders have increased risks for smoking (odds ratio, 4.6; 95%CI, 4.3-4.9), heavy alcohol use (odds ratio, 4.0; 95%CI, 3.6-4.4), heavy marijuana use (odds ratio, 3.5; 95%CI, 3.2-3.7), and recreational drug use (odds ratio, 4.6; 95%CI, 4.3-5.0). All races/ethnicities (African American, Asian, European American, and Hispanic) and both sexes have greatly elevated risks for smoking and alcohol, marijuana, and drug use. Of specific concern, recent public health efforts that have successfully decreased smoking among individuals younger than age 30 years appear to have been ineffective among individuals with severe psychotic illness (interaction effect between age and severe mental illness on smoking initiation, P = 4.5 × 105). CONCLUSIONS AND RELEVANCE: In the largest assessment of substance use among individuals with severe psychotic illness to date, we found the odds of smoking and alcohol and other substance use to be dramatically higher than recent estimates of substance use in mild mental illness. © 2014 American Medical Association.


Document Type: Article
Source: Scopus

Vellimana, A.K.a , Yarbrough, C.K.a , Blackburn, S.d , Strom, R.G.a , Pilgram, T.K.b , Lee, J.-M.a , Grubb, R.L.a , Rich, K.M.a , Chicoine, M.R.a , Dacey, R.G.a , Derdeyn, C.P.a b c , Zipfel, G.J.a b c
Intravenous tissue-type plasminogen activator therapy is an independent risk factor for symptomatic intracerebral hemorrhage after carotid Endarterectomy
(2014) Neurosurgery, 74 (3), pp. 254-260. 


a Department of Neurological Surgery, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurosurgery, University of Florida, Gainesville, FL, United States


Abstract
Carotid endarterectomy (CEA) for symptomatic carotid artery stenosis and intravenous tissue-type plasminogen activator (IV-tPA) for acute ischemic stroke are proven therapies; however, the safety of CEA in stroke patients who recently received IV-tPA has not been established. OBJECTIVE:: To evaluate the safety of CEA in stroke patients who recently received IV-tPA. METHODS:: A retrospective review of patients who underwent CEA for symptomatic carotid artery stenosis was performed. The primary end point was postoperative symptomatic intracerebral hemorrhage (sICH). A univariate analysis of potential risk factors for sICH, including IV-tPA therapy, timing of CEA, degree of stenosis, and stroke severity, was performed. Factors with a value of P < .1 on univariate analysis were tested further. RESULTS:: Among 142 patients, 3 suffered sICH after CEA: 2 of 11 patients treated with IV-tPA (18.2%) and 1 of 131 patients not treated with IV-tPA (0.8%). Both IV-tPA patients suffering sICH underwent CEA within 3 days of tPA administration. On univariate analysis, IV-tPA (P = .02), female sex (P = .09), shorter time between ischemic event and CEA (P = .06), and lower mean arterial pressure during the first 48 hours of admission (P = .08) were identified as risk factors for sICH. On multivariate analysis, IV-tPA was the only significant risk factor (P = .002 by stepwise logistic regression; P = .03 by nominal logistic regression). CONCLUSION:: This study indicates that IV-tPA is an independent risk factor for sICH after CEA. This suggests that CEA should be pursued cautiously in patients who recently received IV-tPA. Early surgery may be associated with an increased risk for sICH. ABBREVIATIONS:: CEA, carotid endarterectomyIV-tPA, intravenous recombinant tissue-type plasminogen activatorMAP, mean arterial pressureNASCET, North American Symptomatic Carotid Endarterectomy TrialNIHSS, National Institutes of Health Stroke ScaleNINDS, National Institute of Neurological Disorders and StrokesICH, symptomatic intracerebral hemorrhageTIA, transient ischemic attack Copyright © 2013 by the Congress of Neurological Surgeons.


Author Keywords
Carotid endarterectomy;  Intracerebral hemorrhage;  Thrombolysis;  Tissue plasminogen activator


Document Type: Article
Source: Scopus

Vergés, A.a , Kushner, M.G.b , Jackson, K.M.c , Bucholz, K.K.d , Trull, T.J.a , Lane, S.P.a , Sher, K.J.a
Personality disorders and the persistence of anxiety disorders: Evidence of a time-of-measurement effect in NESARC
(2014) Journal of Anxiety Disorders, 28 (2), pp. 178-186. 


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


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


Author Keywords
Anxiety disorders;  NESARC;  Personality disorders


Document Type: Article
Source: Scopus

Scherrer, J.F.a b c , Svrakic, D.M.c d , Freedland, K.E.c , Chrusciel, T.a , Balasubramanian, S.a c , Bucholz, K.K.b , Lawler, E.V.e f , Lustman, P.J.c d
Prescription opioid analgesics increase the risk of depression
(2014) Journal of General Internal Medicine, 29 (3), pp. 491-499. Cited 1 time.


a Research Service, Clinical Research and Epidemiology Workgroup, St. Louis VA Medical Center, St. Louis, MO, United States
b Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Bell Street Clinic, John Cochran Hospital, St. Louis VA Medical Center, St. Louis, MO, United States
e Massachusetts Veterans Epidemiology Research and Information Center, VA Cooperative Studies Program, VA Boston Healthcare System, Jamaica Plain, MA, United States
f Harvard Medical School and Division of Aging, Brigham and Women's Hospital, Boston, MA, United States


Abstract
BACKGROUND: Prescription opioid analgesic use has quintupled recently. Evidence linking opioid use with depression emanates from animal models and studies of persons with co-occurring substance use and major depression. Little is known about depressogenic effects of opioid use in other populations. OBJECTIVE: The purpose of this study was to determine whether prescription opioids are associated with increased risk of diagnosed depression. DESIGN: Retrospective cohort study, new user design. PATIENTS: Medical record data from 49,770 US Department of Veterans Affairs (VA) health care system patients with no recent (24-month) history of opioid use or a diagnosis of depression in 1999 and 2000. MAIN MEASURES: Propensity scores were used to control for bias by indication, and the data were weighted to balance the distribution of covariates by duration of incident opioid exposure. Cox proportional hazard models with adjustment for painful conditions were used to estimate the association between duration of prescription opioid use and the subsequent risk of development of depression between 2001 and 2007. KEY RESULTS: Of 49,770 patients who were prescribed an opioid analgesic, 91 % had a prescription for < 90 days, 4 % for 90-180 days, and 5 % for > 180 days. Compared to patients whose prescription was for < 90 days, the risk of depression increased significantly as the duration of opioid prescription increased (HR = 1.25; 95 % CI: 1.05-1.46 for 90-180 days, and HR = 1.51; 95 % CI:1.31-1.74 for > 180 days). CONCLUSIONS: In this sample of veterans with no recent (24-month) history of depression or opioid analgesic use, the risk of development of depression increased as the duration of opioid analgesic exposure increased. The potential for depressogenic effect should be considered in risk-benefit discussions, and patients initiating opioid treatment should be monitored for development of depression. © 2013 Society of General Internal Medicine.


Author Keywords
administrative medical records;  depression;  epidemiology;  prescription opioid analgesics;  propensity score;  veteran


Document Type: Article
Source: Scopus

Gomez, G.G.a , Volinia, S.b , Croce, C.M.b , Zanca, C.a , Li, M.c , Emnett, R.d , Gutmann, D.H.d , Brennan, C.W.e , Furnari, F.B.a , Cavenee, W.K.a
Suppression of MicroRNA-9 by Mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity
(2014) Cancer Research, 74 (5), pp. 1429-1439. 


a Ludwig Institute for Cancer Research, University of California at San Diego, 9500 Gilman Dr, San Diego, CA 92093-0660, United States
b Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH, United States
c Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, United States
d Department of Neurology, Washington University, School of Medicine, St. Louis, Missouri, United States
e Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States


Abstract
The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (DEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that DEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that DEGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by DEGFR. Silencing of FOXP1, a miR-9 target, inhibits DEGFR-dependent tumor growth and, conversely, derepression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic DEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which DEGFR suppression of miR- 9 upregulates FOXP1 to increase tumorigenicity. © 2013 American Association for Cancer Research.


Document Type: Article
Source: Scopus

Deming, Y.a , Cruchaga, C.a b
TMEM106B: A strong FTLD disease modifier
(2014) Acta Neuropathologica, 127 (3), pp. 419-422. 


a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO 63110, United States
b Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, United States


Document Type: Note
Source: Scopus

Gallagher, M.D.a b , Suh, E.c , Grossman, M.b , Elman, L.b , McCluskey, L.b , Van Swieten, J.C.d e , Al-Sarraj, S.f , Neumann, M.g h , Gelpi, E.i , Ghetti, B.j , Rohrer, J.D.k , Halliday, G.l m , Van Broeckhoven, C.n , Seilhean, D.o , Shaw, P.J.p , Frosch, M.P.q , Alafuzoff, I.r , Antonell, A.s , Bogdanovic, N.t , Brooks, W.l m , Cairns, N.J.u , Cooper-Knock, J.p , Cotman, C.v , Cras, P.w x , Cruts, M.w y , De Deyn, P.P.w z , Decarli, C.aa , Dobson-Stone, C.l m , Engelborghs, S.w z , Fox, N.ab , Galasko, D.ac , Gearing, M.ad , Gijselinck, I.w y , Grafman, J.ae , Hartikainen, P.af , Hatanpaa, K.J.ag , Highley, J.R.p , Hodges, J.l m , Hulette, C.ah , Ince, P.G.p , Jin, L.-W.aa , Kirby, J.p , Kofler, J.ai , Kril, J.aj , Kwok, J.B.J.l m , Levey, A.ad , Lieberman, A.ak , Llado, A.s , Martin, J.-J.w , Masliah, E.ac , McDermott, C.J.p , McKee, A.al , McLean, C.am , Mead, S.ab , Miller, C.A.an , Miller, J.aa , Munoz, D.G.ao , Murrell, J.ap , Paulson, H.ak , Piguet, O.l m , Rossor, M.ab , Sanchez-Valle, R.s , Sano, M.aq , Schneider, J.ar , Silbert, L.C.as , Spina, S.ap , Van Der Zee, J.w y , Van Langenhove, T.w x y , Warren, J.ab , Wharton, S.B.p , White Iii, C.L.ag , Woltjer, R.L.as , Trojanowski, J.Q.c , Lee, V.M.Y.c , Van Deerlin, V.c , Chen-Plotkin, A.S.b
TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
(2014) Acta Neuropathologica, 127 (3), pp. 407-418. Cited 1 time.


a Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3 W Gates, 3400 Spruce St, Philadelphia, PA 19104, United States
c Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
d Erasmus Medical Centre, s'Gravendijkwal 230, Rotterdam, Netherlands
e Alzheimercenter Vumc, Boelelaan 1118 Amsterdam, Netherlands
f King's College Hospital, London, United Kingdom
g University of Tübingen, Calwerstr. 3, 72072 Tübingen, Germany
h German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
i Neurological Tissue Bank of the Biobank-Hospital Clinic, Insitut d'Investigacions Biomediques August Pi i Sunyer, Facultad de Medicina, c/Casanova 143, planta 0, ala sur., 08036 Barcelona, Spain
j Department of Pathology, Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
k Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
l Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia
m Faculty of Medicine, University of New South Wales, Sydney, Australia
n Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610 Antwerp, Belgium
o University Pierre et Marie Curie (UPMC), Sorbonne University, Paris, France
p University of Sheffield SITraN, 385a Glossop Road, Sheffield S10 2HQ, United Kingdom
q Massachusetts Alzheimer's Disease Research Center, Harvard Medical School, Boston, MA, United States
r Uppsala University, Uppsala, Sweden
s Alzheimer and Cognitive Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Spain, c/Villarroel 170, 08036 Barcelona, Spain
t Karolinska Institutet NVS, NOVUM Plan 5, Solna, Sweden
u Washington University School of Medicine, St. Louis, MO 63110, United States
v University of California Irvine, Irvine, United States
w Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
x Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
y Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610 Antwerp, Belgium
z Department of Neurology, Hospital Network Antwerp (ZNA), Middelheim Lindendreef 1, 2020 Antwerp, Belgium
aa University of California, Davis, United States
ab Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, United Kingdom
ac University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093-0948, United States
ad Emory University, Atlanta, United States
ae Northwestern University, Chicago, United States
af Kuopio University Hospital, Kuopio, Finland
ag University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9073, United States
ah Duke University Medical Center, Durham, NC, United States
ai Department of Pathology, University of Pittsburgh, 200 Lothrop Street, PUH South Tower, Pittsburgh, PA 15213, United States
aj Department of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
ak University of Michigan, Ann Arbor, United States
al Boston University, Boston, United States
am Australian Brain Bank Network, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Parkville, Australia
an Keck School of Medicine, University of Southern California, 2011 Zonal Ave., MCA-341, Los Angeles, United States
ao University of Toronto, Toronto, ON, United States
ap Indiana University, Bloomington, United States
aq Mount Sinai School of Medicine, NY, United States
ar Rush University Medical Center, Chicago, United States
as Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97230, United States


Abstract
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease. © 2014 Springer-Verlag Berlin Heidelberg.


Author Keywords
Amyotrophic lateral sclerosis;  C9orf72;  Frontotemporal dementia;  Frontotemporal lobar degeneration;  Genetic modifier;  TMEM106B


Document Type: Article
Source: Scopus

McEvoy, J.a , Nagahawatte, P.b , Finkelstein, D.b , Richards-Yutz, J.f , Valentine, M.m , Ma, J.n , Mullighan, C.n , Song, G.n , Chen, X.b , Wilson, M.n , Brennan, R.l , Pounds, S.c , Becksfort, J.b , Huether, R.b , Lu, C.g , Fulton, R.S.g h , Fulton, L.L.g h , Hong, X.g h , Dooling, D.J.g h , Ochoa, K.g h , Mardis, E.R.g h i , Wilson, R.K.g h j , Easton, J.b , Zhang, J.b , Downing, J.R.n , Ganguly, A.e f , Dyer, M.A.a d k
RB1 gene inactivation by chromothripsis in human retinoblastoma
(2014) Oncotarget, 5 (2), pp. 438-450. 


a Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, United States
b Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, United States
c Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, United States
d Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, United States
e Department of Genetics and the Genetic Diagnostic Laboratory, University of Pennsylvania, School of Medicine, Philadelphia, PA, United States
f Genetic Diagnostic Laboratory, University of Pennsylvania, School of Medicine, Philadelphia, PA, United States
g The Genome Institute, Washington University School of Medicine in St Louis, St Louis, MO, United States
h Department of Genetics, Washington University School of Medicine in St Louis, St Louis, MO, United States
i Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, MO, United States
j Department of Medicine, Washington University School of Medicine in St Louis, St Louis,MO, United States
k Howard Hughes Medical Institute, Chevy Chase, MD, United States
l Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States
m Department of Cytogenetics, St. Jude Children's Research Hospital, Memphis, TN, United States
n Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States


Abstract
Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA.In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.


Author Keywords
Chromothripsis;  MYCN;  RB1;  Retinoblastoma


Document Type: Article
Source: Scopus

Qiu, X.a b c , Johnson, J.R.b , Wilson, B.S.a , Gammon, S.T.c , Piwnica-Worms, D.b c , Barnett, E.M.a
Single-cell resolution imaging of retinal ganglion cell apoptosis in vivo using a cell-penetrating caspase-activatable peptide probe
(2014) PLoS ONE, 9 (2), art. no. e88855, . 


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Cancer Systems Imaging, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States


Abstract
Peptide probes for imaging retinal ganglion cell (RGC) apoptosis consist of a cell-penetrating peptide targeting moiety and a fluorophore-quencher pair flanking an effector caspase consensus sequence. Using ex vivo fluorescence imaging, we previously validated the capacity of these probes to identify apoptotic RGCs in cell culture and in an in vivo rat model of N-methyl-D-aspartate (NMDA)-induced neurotoxicity. Herein, using TcapQ488, a new probe designed and synthesized for compatibility with clinically-relevant imaging instruments, and real time imaging of a live rat RGC degeneration model, we fully characterized time- and dose-dependent probe activation, signal-to-noise ratios, and probe safety profiles in vivo. Adult rats received intravitreal injections of four NMDA concentrations followed by varying TcapQ488 doses. Fluorescence fundus imaging was performed sequentially in vivo using a confocal scanning laser ophthalmoscope and individual RGCs displaying activated probe were counted and analyzed. Rats also underwent electroretinography following intravitreal injection of probe. In vivo fluorescence fundus imaging revealed distinct single-cell probe activation as an indicator of RGC apoptosis induced by intravitreal NMDA injection that corresponded to the identical cells observed in retinal flat mounts of the same eye. Peak activation of probe in vivo was detected 12 hours post probe injection. Detectable fluorescent RGCs increased with increasing NMDA concentration; sensitivity of detection generally increased with increasing TcapQ488 dose until saturating at 0.387 nmol. Electroretinography following intravitreal injections of TcapQ488 showed no significant difference compared with control injections. We optimized the signal-to-noise ratio of a caspase-activatable cell penetrating peptide probe for quantitative non-invasive detection of RGC apoptosis in vivo. Full characterization of probe performance in this setting creates an important in vivo imaging standard for functional evaluation of future probe analogues and provides a basis for extending this strategy into glaucoma-specific animal models. © 2014 Qiu et al.

Document Type: Article
Source: Scopus