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WUSTL Neuroscience Publications Archive - March 2013

Scopus weekly report:

March 21, 2013

March 13, 2013

March 6, 2013

March 21, 2013

Lockhart, E.M.a , Willingham, M.D.b , Abdallah, A.B.a , Helsten, D.L.a , Bedair, B.A.c , Thomas, J.d , Duntley, S.e , Avidan, M.S.a 
Obstructive sleep apnea screening and postoperative mortality in a large surgical cohort
(2013) Sleep Medicine, . Article in Press. 
a Washington University School of Medicine, 660 S. Euclid, Box 8054, St. Louis, MO 63110, United States
b Internal Medicine - Infectious Disease, Washington University School of Medicine, 660 S. Euclid, Box 8051, St. Louis, MO 63110, United States
c Washington University School of Medicine, 660 S. Euclid, Box 8107, St. Louis, MO 63110, United States
d Periop Performance Improvement Administration and Information Systems, Barnes-Jewish Hospital, 1 Barnes-Jewish Hospital Drive, Mail Stop 90-72-408, St. Louis, MO 63110, United States
e Washington University School of Medicine, 660 S. Euclid, Box 8111, St. Louis, MO 63110, United States

Abstract
Objective: A recent investigation at Barnes-Jewish Hospital located in St. Louis, Missouri, found that an estimated 22% of adults presenting for inpatient surgery screened as high risk for obstructive sleep apnea (OSA). Surgical patients with OSA have multiple comorbidities and are at increased risk for perioperative complications. Our objective was to determine if a prior diagnosis of OSA or a positive screen for OSA was associated with increased risk for 30-day and one-year mortality. Methods: B-J APNEAS (Barnes-Jewish Apnea Prevalence in Every Admission Study) was a prospective cohort study. Unselected adult surgical patients at Barnes Jewish Hospital were prospectively enrolled between February 2006 and April 2010. All patients completed preoperative OSA screening and those who were at risk for OSA according to a combination of the Berlin and Flemons screening tools received targeted postoperative interventions. STOP (loud Snoring, daytime Tiredness, Observed apneas, and high blood Pressure) and STOP-BANG (STOP, plus body mass index [BMI], age, neck circumference, and gender) scores also were obtained. Results: Overall, the sample included 14,962 patients, of whom 1939 (12.9%) reported a history of OSA. All four screening tools identified a high prevalence of undiagnosed patients at risk for OSA (9.5%-41.6%), but agreement among screens was not strong with κ statistic ranging from 0.225 to 0.611. There was no significant difference in 30-day postoperative mortality between patients with possible OSA (based on their history or on a positive OSA screen with any of the four instruments) and the rest of the surgical population. Significant differences in one-year mortality were noted between the low-risk and high-risk groups as identified by the Flemons' (4.96% vs 6.91%; p < 0.0001), STOP (5.28% vs 7.57%; p < 0.0001) and STOP-BANG (4.13% vs 7.45%; p < 0.0001) screens. After adjusting for risk factors, none of the OSA screening tools independently predicted mortality rate up to one year postoperatively. Conclusion: Neither a prior diagnosis of OSA nor a positive screen for OSA risk was associated with increased 30-day or one-year postoperative mortality. Differences in 1 year postoperative mortality were noted with three of the screening tools. The results of our study highlight uncertainties and research priorities for the medical community. © 2012 Elsevier B.V. All rights reserved.

Author Keywords
Berlin;  Flemons;  Obstructive sleep apnea;  OSA screening tools;  Perioperative mortality;  Perioperative screening;  STOP;  STOP-BANG

Document Type: Article in Press
Source: Scopus

Zangwill, L.M.a , Jain, S.b , Dirkes, K.a , He, F.b , Medeiros, F.A.a , Trick, G.L.c , Brandt, J.D.d , Cioffi, G.A.e j , Coleman, A.L.f , Liebmann, J.M.g , Piltz-Seymour, J.R.h , Gordon, M.O.i , Kass, M.A.i , Weinreb, R.N.a 
The Rate of Structural Change: The Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study
(2013) American Journal of Ophthalmology, . Article in Press. 
a Hamilton Glaucoma Center, Department of Ophthalmology, University of California, San Diego, La Jolla, California
b Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California
c Henry Ford Health System, Detroit, Michigan
d Davis Eye Center, University of California Davis, Sacramento, California
e Devers Eye Institute, Portland, Oregon
f Jules Stein Eye Institute, Los Angeles, California
g New York Eye and Ear Infirmary, New York, New York
h Glaucoma Care Center, University of Pennsylvania Health System, Bristol, Pennsylvania
i Department of Ophthalmology and Visual Sciences Washington University School of Medicine Washington University, St. Louis, Missouri
j Dr Cioffi is now affiliated with Columbia University College and Physicians and Surgeons, New York City, New York

Abstract
Purpose: To compare rates of topographic change in ocular hypertensive eyes in which primary open-angle glaucoma (POAG) does or does not develop, and to identify factors that influence the rate of change. Design: Longitudinal, randomized clinical trial. Methods: Four hundred forty-one participants (832 eyes) in the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study were included. POAG was defined as repeatable visual field, photography-based optic disc changes, or both. The rate of topographic change in the 52 participants (66 eyes) who developed POAG was compared with that of participants who did not develop POAG using multivariable mixed effects models. Results: In both univariate and multivariate analyses, the rate of rim area loss was significantly faster in eyes in which POAG developed than in eyes in which it did not (univariate mean, -0.0131 mm2/year and -0.0026 mm2/year, respectively). The significantly faster rate of rim area loss in black persons found in the univariate analysis did not remain significant when baseline disc area was included in the model. In multivariate analyses, the rate of rim area loss and other topographic parameters also was significantly faster in eyes with worse baseline visual field pattern standard deviation and higher intraocular pressure during follow-up. Moreover, a significant rate of rim area loss was detected in eyes in which POAG did not develop (P &lt; .0001). The rate of rim area loss in eyes with an optic disc POAG endpoint was significantly faster than in those with a visual field POAG endpoint. Conclusions: The rate of rim area loss is approximately 5 times faster in eyes in which POAG developed compared with eyes in which it did not. These results suggest that measuring the rate of structural change can provide important information for the clinical management of ocular hypertensive patients. Additional follow-up is needed to determine whether the statistically significant change in the eyes in which POAG did not develop represents normal aging or glaucomatous change not detected by conventional methods. © 2013 Elsevier Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

Roest, A.M.a , Carney, R.M.b , Freedland, K.E.b , Martens, E.J.c , Denollet, J.c , de Jonge, P.a c c 
Changes in cognitive versus somatic symptoms of depression and event-free survival following acute myocardial infarction in the Enhancing Recovery In Coronary Heart Disease (ENRICHD) study
(2013) Journal of Affective Disorders, . Article in Press. 
a Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
b Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
c CoRPS - Center of Research on Psychology in Somatic diseases, Department of Medical Psychology, Tilburg University, Tilburg, The Netherlands

Abstract
Background: Randomized controlled trials focusing on the effects of antidepressant treatment in cardiac patients have found modest effects on depressive symptoms but not on cardiac outcomes. A secondary analysis was conducted on data from the Enhancing Recovery in Coronary Heart Disease trial to assess whether changes in somatic or cognitive depressive symptoms following acute MI predicted event-free survival and whether the results differed per treatment arm (cognitive behavior therapy or care as usual). Methods: Patients who met depression criteria and completed the 6th month depression assessment (n=1254) were included in this study. Measurements included demographic and clinical data and the Beck Depression Inventory at baseline and 6 months. The primary endpoint was a composite of recurrent MI and mortality over 2.4 years (standard deviation=0.9 years). Results: Positive changes (per 1 point increase) in somatic depressive symptoms (HR: 0.95; 95% CI: 0.92-0.98; p=0.001) but not in cognitive depressive symptoms (HR: 0.98; 95% CI: 0.96-1.01; p=0.19) were related to a reduced risk of recurrent MI and mortality after adjustment for baseline depression scores. There was a trend for an interaction effect between changes in somatic depressive symptoms and the intervention (p=0.08). After controlling for demographic and clinical variables, the association between changes in somatic depressive symptoms and event-free survival remained significant in the intervention arm (HR: 0.93; 95% CI: 0.88-0.98; p=0.01) only. Limitations: Secondary analyses. Conclusions: Changes in somatic depressive symptoms, and not cognitive symptoms, were related to improved outcomes in the intervention arm, independent of demographic and clinical variables. © 2013 Elsevier B.V.

Author Keywords
Cognitive behavior therapy;  Depression;  Dimensions;  Mortality;  Myocardial infarction

Document Type: Article in Press
Source: Scopus

Parrella, E.a , Maxim, T.a , Maialetti, F.b , Zhang, L.a , Wan, J.a , Wei, M.a , Cohen, P.a , Fontana, L.c d e , Longo, V.D.a 
Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer's disease mouse model
(2013) Aging Cell, . Article in Press. 
a Longevity Institute, Davis School of Gerontology, and Department of Biological Sciences University of Southern California Los Angeles, CA USA
b Division of Nutrition and Aging Istituto Superiore di Sanità Rome Italy
c Division of Geriatrics and Nutritional Science Washington University in St. Louis St. Louis, MO USA
d Department of Medicine Salerno University School of Medicine Salerno Italy
e Healthy Aging Platform CEINGE Biotecnologie Avanzate Napoli Italy

Abstract
In laboratory animals, calorie restriction (CR) protects against aging, oxidative stress, and neurodegenerative pathologies. Reduced levels of growth hormone and IGF-1, which mediate some of the protective effects of CR, can also extend longevity and/or protect against age-related diseases in rodents and humans. However, severely restricted diets are difficult to maintain and are associated with chronically low weight and other major side effects. Here we show that 4 months of periodic protein restriction cycles (PRCs) with supplementation of nonessential amino acids in mice already displaying significant cognitive impairment and Alzheimer's disease (AD)-like pathology reduced circulating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRCs did not affect the levels of β amyloid (Aβ), they decreased tau phosphorylation in the hippocampus and alleviated the age-dependent impairment in cognitive performance. These results indicate that periodic protein restriction cycles without CR can promote changes in circulating growth factors and tau phosphorylation associated with protection against age-related neuropathologies. © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Author Keywords
Aging;  Alzheimer;  IGF-1;  IGFBP-1;  Protein restriction;  Tau

Document Type: Article in Press
Source: Scopus

Tauber, S.K.a , Dunlosky, J.a , Rawson, K.A.a , Wahlheim, C.N.b , Jacoby, L.L.b 
Self-regulated learning of a natural category: Do people interleave or block exemplars during study?
(2013) Psychonomic Bulletin and Review, 20 (2), pp. 356-363. 
a Department of Psychology, Kent State University, Kent, OH, 44242, United States
b Department of Psychology, Washington University, St. Louis, MO, United States

Abstract
Despite decades of research focused on the representation of concepts, little is known about the influence of self-regulatory processes when learning natural categories. Such work is vital, as many contexts require self-regulation when we form complex concepts. Previous research has demonstrated that interleaving, as compared to blocking, can improve classification. Thus, as an initial step to explore self-regulated learning of natural concepts, we evaluated whether people chose to block or interleave their practice. According to the search-for-differences hypothesis, people attempt to identify features of birds that distinguish one category (i. e., bird family) from another, and hence should interleave their study. According to the search-for-similarities hypothesis, people attempt to identify features that indicate inclusion into a single category, and hence are expected to block their study. To evaluate these hypotheses, we had participants learn exemplar birds (e. g., Song Sparrow) with their respective bird families (e. g., Sparrow) by selecting the order in which to study bird families. Across four experiments, different formats for selecting exemplars for study were used, so as to provide converging evidence for how participants regulated their learning. Participants overwhelmingly preferred to block their study, even though interleaving is normatively better for learning. © 2012 Psychonomic Society, Inc.

Author Keywords
Blocked versus interleaved practice;  Concept formation;  Metacognition;  Self-regulated learning

Document Type: Article
Source: Scopus

Chiew, K.S., Braver, T.S.
Temporal dynamics of motivation-cognitive control interactions revealed by high-resolution pupillometry
(2013) Frontiers in Psychology, 4 (JAN), art. no. Article 15, . 
Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Motivational manipulations, such as the presence of performance-contingent reward incen-tives, can have substantial influences on cognitive control. Previous evidence suggests that reward incentives may enhance cognitive performance specifically through increased preparatory, or proactive, control processes. The present study examined reward influ-ences on cognitive control dynamics in the AX-Continuous Performance Task (AX-CPT), using high-resolution pupillometry. In the AX-CPT, contextual cues must be actively main-tained over a delay in order to appropriately respond to ambiguous target probes. A key feature of the task is that it permits dissociable characterization of preparatory, proac-tive control processes (i.e., utilization of context) and reactive control processes (i.e., target-evoked interference resolution). Task performance profiles suggested that reward incentives enhanced proactive control (context utilization). Critically, pupil dilation was also increased on reward incentive trials during context maintenance periods, suggesting trial-specific shifts in proactive control, particularly when context cues indicated the need to overcome the dominant target response bias. Reward incentives had both transient (i.e., trial-by-trial) and sustained (i.e., block-based) effects on pupil dilation, which may reflect distinct underlying processes. The transient pupillary effects were present even when comparing against trials matched in task performance, suggesting a unique motivational influence of reward incentives. These results suggest that pupillometry may be a use-ful technique for investigating reward motivational signals and their dynamic influence on cognitive control.

Author Keywords
Cognitive control;  Incentive;  Motivation;  Pupillometry;  Reward

Document Type: Article
Source: Scopus

Bui, D.C., Maddox, G.B., Balota, D.A.
The roles of working memory and intervening task difficulty in determining the benefits of repetition
(2013) Psychonomic Bulletin and Review, 20 (2), pp. 341-347. 
Department of Psychology, Washington University in St. Louis, St. Louis, MO, 63130, United States

Abstract
Memory is better when learning events are spaced, as compared with massed (i. e., the spacing effect). Recent theories posit that retrieval of an item's earlier presentation contributes to the spacing effect, which suggests that individual differences in the ability to retrieve an earlier event may influence the benefit of spaced repetition. The present study examined (1) the difficulty of task demands between repetitions, which should modulate the ability to retrieve the earlier information, and (2) individual differences in working memory in a spaced repetition paradigm. Across two experiments, participants studied a word set twice, each separated by an interval where duration was held constant, and the difficulty of the intervening task was manipulated. After a short retention interval following the second presentation, participants recalled the word set. Those who scored high on working memory measures benefited more from repeated study than did those who scored lower on working memory measures, regardless of task difficulty. Critically, a crossover interaction was observed between working memory and intervening task difficulty: Individuals with low working memory scores benefited more when task difficulty was easy than when it was difficult, but individuals with high working memory scores produced the opposite effect. These results suggest that individual differences in working memory should be considered in optimizing the benefits of repetition learning. © 2012 Psychonomic Society, Inc.

Author Keywords
Attention and memory;  Individual differences in memory capacity;  Repetition effects;  Working memory

Document Type: Article
Source: Scopus

Zheng, Z.a , Li, A.a , Holmes, B.B.a , Marasa, J.C.b , Diamond, M.I.a 
An N-terminal nuclear export signal regulates trafficking and aggregation of huntingtin (Htt) protein exon 1
(2013) Journal of Biological Chemistry, 288 (9), pp. 6063-6071. 
a Department of Neurology, Washington University, 660 S. Euclid Ave., St. Louis, MI 63110, United States
b Department of Radiology, Washington University, St. Louis, MI 63110, United States

Abstract
Huntington disease is a dominantly inherited neurodegenerative condition caused by polyglutamine expansion in the N terminus of the huntingtin protein (Htt). The first 17 amino acids (N17) of Htt play a key role in regulating its toxicity and aggregation. Both nuclear export and cytoplasm retention functions have been ascribed to N17.Wehave determined that N17 acts as a nuclear export sequence (NES) within Htt exon and when fused to yellow fluorescent protein. We have defined amino acids within N17 that constitute the nuclear export sequence (NES). Mutation of any of the conserved residues increases nuclear accumulation of Htt exon 1. Nuclear export of Htt is sensitive to leptomycin B and is reduced by knockdown of exportin 1. In HEK293 cells, NES mutations decrease overall Htt aggregation but increase the fraction of cells with nuclear inclusions. In primary cultured neurons, NES mutations increase nuclear accumulation and increase overall aggregation. This work defines a bona fide nuclear export sequence within N17 and links it to effects on protein aggregation. This may help explain the important role of N17 in controlling Htt toxicity. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

Hussmann, K.L.a , Samuel, M.A.b , Kim, K.S.c , Diamond, M.S.b d , Fredericksen, B.L.a 
Differential replication of pathogenic and nonpathogenic strains of West Nile virus within astrocytes
(2013) Journal of Virology, 87 (5), pp. 2814-2822. 
a Department of Cell Biology and Molecular Genetics, University of Maryland College Park, College Park, MD, United States
b Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University, St. Louis, MO, United States
c Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, United States
d Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA, United States

Abstract
The severity of West Nile virus (WNV) infection in immunocompetent animals is highly strain dependent, ranging from avirulent to highly neuropathogenic. Here, we investigatethe nature of this strain-specific restriction by analyzing the replication of avirulent (WNV-MAD78) and highly virulent (WNV-NY) strains in neurons, astrocytes, and microvascular endothelial cells,which comprise the neurovascular unit within the central nervous system (CNS). We demonstrate that WNV-MAD78 replicated in and traversed brain microvascular endothelial cells as efficiently as WNV-NY. Likewise, similar levels of replication were detected in neurons. Thus, WNV-MAD78's nonneuropathogenic phenotype is not due to an intrinsic inability to replicate in key target cells within the CNS. In contrast, replication of WNV-MAD78 was delayed and reduced compared to that of WNV-NY in astrocytes. The reduced susceptibility of astrocytes to WNV-MAD78 was due to a delay in viral genome replication and an interferon-independent reduction in cell-to-cell spread. Together, our data suggest that astrocytes regulate WNV spread within the CNS and therefore are an attractive target for ameliorating WNV-induced neuropathology. © 2013, American Society for Microbiology.

Document Type: Article
Source: Scopus

Kurata, H.T.a , Akrouh, A.b c , Li, J.B.W.a , Marton, L.J.d , Nichols, C.G.b c 
Scanning the topography of polyamine blocker binding in an inwardly rectifying potassium channel
(2013) Journal of Biological Chemistry, 288 (9), pp. 6591-6601. 
a Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MI 63110, United States
c Center for Investigation of Membrane Excitability Diseases (CIMED), Washington University School of Medicine, St. Louis, MI 63110, United States
d Department of Laboratory Medicine, University of California, San Francisco, Palo Alto, CA 94306, United States

Abstract
Steeply voltage-dependent inward rectification of Kir (inwardly rectifying potassium) channels arises from blockade by cytoplasmic polyamines. These polycationic blockers traverse a long (>70 Å) pore, displacing multiple permeant ions, en route to a high affinity binding site that remains loosely defined. Wehave scanned the effects of cysteine modification at multiple pore-lining positions on the blocking properties of a library of polyamine analogs, demonstrating that the effects of cysteine modification are position- and blocker-dependent. Specifically, introduction of positively charged adducts results in two distinct phenotypes: either disruption of blocker binding or generation of a barrier to blocker migration, in a consistent pattern that depends on both the length of the polyamine blocker and the position of the modified cysteine. These findings reveal important details about the chemical basis and specific location of high affinity polyamine binding. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

Deshields, T.a , Zebrack, B.b , Kennedy, V.c 
The state of psychosocial services in cancer care in the United States
(2013) Psycho-Oncology, 22 (3), pp. 699-703. 
a Siteman Cancer Center, Barnes-Jewish Hospital and Washington University, MS: 90-35-703, 4921 Parkview Place, St. Louis, MO 63110, United States
b University of Michigan School of Social Work, Ann Arbor, MI, United States
c Cancer Support Community, WA, United States

Abstract
Objective In 2009, the APOS commissioned a survey of its members and attendees of the annual meetings in 2008 and 2009. The goal of the survey was to assess the scope of psychosocial support services for cancer patients in the USA. Methods Two hundred thirty-three individuals (27% response rate) completed the survey, which included questions assessing the extent to which respondents' institutions provided informational and psychosocial support services and conducted screening for psychosocial distress. Results Respondents were primarily psychologists, although oncologists, nurses, social workers, and others were represented, as well. A broad array of informational and support services were endorsed as being provided to cancer patients, both at no charge or for a fee. Respondents identified social workers as the professionals most often providing psychosocial services to cancer patients. Respondents also indicated that most psychosocial services have not been tailored to fit a culturally diverse population. Furthermore, most of the organizations represented in the survey do not routinely screen cancer patients for psychosocial distress. Conclusions A broad range of psychosocial services are provided in cancer treatment settings; however, despite National Comprehensive Cancer Network and Institute of Medicine recommendations, routine screening for distress is not offered in a majority of cancer care organizations. Despite the racial, ethnic, cultural, and linguistic diversity of the US population, most organizations have not adapted their educational materials nor their psychosocial services to meet the needs of a diverse patient population. Copyright © 2012 John Wiley & Sons, Ltd. Copyright © 2012 John Wiley & Sons, Ltd.

Author Keywords
cancer;  diversity;  oncology;  psychosocial services;  support services

Document Type: Review
Source: Scopus

Metcalfe, J.a , Finn, B.b 
Metacognition and control of study choice in children
(2013) Metacognition and Learning, 8 (1), pp. 19-46. 
a Department of Psychology, Columbia University, NY, NY, 10027, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, United States

Abstract
Middle childhood may be crucial for the development of metacognitive monitoring and study control processes. The first three experiments, using different materials, showed that Grade 3 and Grade 5 children exhibited excellent metacognitive resolution when asked to make delayed judgments of learning (JOLs, using an analogue scale) or binary judgments of knowing (JOKs, 'know' or 'don't know') without the target being present. (The delayed method used here also results in excellent metacognitive resolution in adults). In three subsequent experiments after making JOLs the children were asked to choose which items they would like to restudy to optimize learning. We then either honored or dishonored the children's restudy choices, and tested their memory performance. In Experiment 4, honoring the children's choices made no difference to final recall performance. Experiments 5 and 6 showed that when the computer, rather than the children, chose the items for restudy based on theoretical constraints proposed by the Region of Proximal Learning model of study time allocation, the children's recall performance improved. In all three experiments, Grade 3 children's choices were random. Whereas the Grade 5 children showed some indication of a metacognitively guided strategy of choosing the lowest JOL items for study, it did not, consistently, improve performance. Apparently, accurate metacognitive monitoring is largely in place in middle childhood, but is not yet converted into effective implementation strategies. This dissociation between metaknowledge and its implementation in choice behavior needs to be taken into account by educators aiming to design interventions to enhance learning in children at this age. © 2013 Springer Science+Business Media New York.

Author Keywords
Children;  Development;  Metacognitive monitoring and control

Document Type: Article
Source: Scopus

Yang, J.a b c e , Yang, H.b c d , Sun, X.b c d , Delaloye, K.b c d , Yang, X.b c d , Moller, A.b c d , Shi, J.b c d , Cui, J.b c d 
Interaction between residues in the Mg2+-binding site regulates BK channel activation
(2013) Journal of General Physiology, 141 (2), pp. 217-228. 
a Department of Energy, Environmental and Chemical Engineering, Washington University, Saint Louis, MO 63130, United States
b Cardiac Bioelectricity and Arrhythmia Center, Washington University, Saint Louis, MO 63130, United States
c Center for the Investigation of Membrane Excitability Disorders, Washington University, Saint Louis, MO 63130, United States
d Department of Biomedical Engineering, Washington University, Saint Louis, MO 63130, United States
e Dept. of Physiology and Dept. of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, United States

Abstract
As a unique member of the voltage-gated potassium channel family, a large conductance, voltage- and Ca2+-activated K+ (BK) channel has a large cytosolic domain that serves as the Ca2+ sensor, in addition to a membranespanning domain that contains the voltage-sensing (VSD) and pore-gate domains. The conformational changes of the cytosolic domain induced by Ca2+ binding and the conformational changes of the VSD induced by membrane voltage changes trigger the opening of the pore-gate domain. Although some structural information of these individual functional domains is available, how the interactions among these domains, especially the noncovalent interactions, control the dynamic gating process of BK channels is still not clear. Previous studies discovered that intracellular Mg2+ binds to an interdomain binding site consisting of D99 and N172 from the membrane-spanning domain and E374 and E399 from the cytosolic domain. The bound Mg2+ at this narrow interdomain interface activates the BK channel through an electrostatic interaction with a positively charged residue in the VSD. In this study, we investigated the potential interdomain interactions between the Mg2+-coordination residues and their effects on channel gating. By introducing different charges to these residues, we discovered a native interdomain interaction between D99 and E374 that can affect BK channel activation. To understand the underlying mechanism of the interdomain interactions between the Mg2+-coordination residues, we introduced artificial electrostatic interactions between residues 172 and 399 from two different domains. We found that the interdomain interactions between these two positions not only alter the local conformations near the Mg2+-binding site but also change distant conformations including the pore-gate domain, thereby affecting the voltage- and Ca2+-dependent activation of the BK channel. These results illustrate the importance of interdomain interactions to the allosteric gating mechanisms of BK channels. © 2013 Yang et al.

Document Type: Article
Source: Scopus

Hicks, J.K.a , Swen, J.J.b , Thorn, C.F.c , Sangkuhl, K.c , Kharasch, E.D.d , Ellingrod, V.L.e f , Skaar, T.C.g , Müller, D.J.h , Gaedigk, A.i , Stingl, J.C.j 
Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants
(2013) Clinical Pharmacology and Therapeutics, . Article in Press. 
a Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
b Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
c Department of Genetics, Stanford University, Stanford, California, USA
d Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA
e 1] Department of Clinical, Social and Administrative Sciences, College of Pharmacy, Ann Arbor, Michigan, USA
f Department of Psychiatry, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
g Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
h Neurogenetics Section, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
i Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospital and Clinics, Kansas City, Missouri, USA
j Division of Research, Federal Institute for Drugs and Medical Devices, Bonn, Germany

Abstract
Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.Clinical Pharmacology & Therapeutics (2013); advance online publication 13 March 2013. doi:10.1038/clpt.2013.2.

Document Type: Article in Press
Source: Scopus

Asnaghi, L.a , Handa, J.T.b , Merbs, S.L.b , Harbour, J.W.c , Eberhart, C.G.a b 
A role for Jag2 in promoting uveal melanoma dissemination and growth
(2013) Investigative Ophthalmology and Visual Science, 54 (1), pp. 295-306. 
a Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
b Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
c Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
PURPOSE. Controlling the spread of uveal melanoma is key to improving survival of patients with this common intraocular malignancy. The Notch ligand Jag2 has been shown to be upregulated in primary tumors that metastasize, and we therefore investigated its role in promoting invasion and clonogenic growth of uveal melanoma cells. METHODS. mRNA and protein expression of Notch pathway components were measured using qPCR and Western blot in uveal melanoma cell lines. Expression of Jag2 ligand was upregulated using Jag2-GFP-MSCV constructs or downregulated by sh-Jag2 in the uveal melanoma cell lines Mel285, Mel290, 92.1, and OMM1, and the effects on growth and invasion were assessed. RESULTS. Jag2 was introduced into Mel285 and Mel290 cells, which have low baseline levels of both this ligand and Notch activity. Overall growth of the Jag2-expressing cultures increased somewhat, and a significant 3-fold increase in clonogenic growth in soft agar was also noted. Introduction of Jag2 increased motility in both wound-healing and transwell invasion assays. We also observed a significant increase in Jag2 and Hes1 mRNA in invasive OMM1 cells that had passed through a Matrigel-coated filter in the transwell assay when compared with noninvading cells. Loss-of-function studies performed in 92.1 and OMM1 lines using Jag2 shRNAs showed that downregulation of the ligand significantly suppressed cellular growth, invasion, and migration. CONCLUSIONS. Our data suggest that Jag2 may play an important role in promoting Notch activity, growth, and metastasis in uveal melanoma. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

 

Document Type: Article
Source: Scopus 

March 13, 2013

Neta, M.a , Kelley, W.M.b , Whalen, P.J.b 
Neural responses to ambiguity involve domain-general and domain-specific emotion processing systems
(2013) Journal of Cognitive Neuroscience, 25 (4), pp. 547-557. 
a Washington University School of Medicine, United States
b Dartmouth College, United States

Abstract
Extant research has examined the process of decision making under uncertainty, specifically in situations of ambiguity. However, much of this work has been conducted in the context of semantic and low-level visual processing. An open question is whether ambiguity in social signals (e.g., emotional facial expressions) is processed similarly or whether a unique set of processors come on-line to resolve ambiguity in a social context. Our work has examined ambiguity using surprised facial expressions, as they have predicted both positive and negative outcomes in the past. Specifically, whereas some people tended to interpret surprise as negatively valenced, others tended toward a more positive interpretation. Here, we examined neural responses to social ambiguity using faces (surprise) and nonface emotional scenes (International Affective Picture System). Moreover, we examined whether these effects are specific to ambiguity resolution (i.e., judgments about the ambiguity) or whether similar effects would be demonstrated for incidental judgments (e.g., nonvalence judgments about ambiguously valenced stimuli). We found that a distinct task control (i.e., cingulo-opercular) network was more active when resolving ambiguity. We also found that activity in the ventral amygdala was greater to faces and scenes that were rated explicitly along the dimension of valence, consistent with findings that the ventral amygdala tracks valence. Taken together, there is a complex neural architecture that supports decision making in the presence of ambiguity: (a) a core set of cortical structures engaged for explicit ambiguity processing across stimulus boundaries and (b) other dedicated circuits for biologically relevant learning situations involving faces. © 2013 Massachusetts Institute of Technology.

Document Type: Article
Source: Scopus

Anticevic, A.a d e , Brumbaugh, M.S.f , Winkler, A.M.a f , Lombardo, L.E.f , Barrett, J.f , Corlett, P.R.a , Kober, H.a b , Gruber, J.a b , Repovs, G.g , Cole, M.W.h , Krystal, J.H.a d e , Pearlson, G.D.a c f , Glahn, D.C.a f 
Global prefrontal and fronto-amygdala dysconnectivity in bipolar i disorder with psychosis history
(2013) Biological Psychiatry, 73 (6), pp. 565-573. Cited 1 time.
a Yale University, Department of Psychiatry, 34 Park St., New Haven, CT 06519, United States
b Department of Psychology, Yale University, New Haven, United States
c Department of Neurobiology, Yale University, New Haven, United States
d NIAAA Center for the Translational Neuroscience of Alcoholism, Connecticut Mental Health Center, New Haven, United States
e Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, United States
f Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, CT, United States
g Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
h Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Pathophysiological models of bipolar disorder postulate that mood dysregulation arises from fronto-limbic dysfunction, marked by reduced prefrontal cortex (PFC) inhibitory control. This might occur due to both disruptions within PFC networks and abnormal inhibition over subcortical structures involved in emotional processing. However, no study has examined global PFC dysconnectivity in bipolar disorder and tested whether regions with within-PFC dysconnectivity also exhibit fronto-limbic connectivity deficits. Furthermore, no study has investigated whether such connectivity disruptions differ for bipolar patients with psychosis history, who might exhibit a more severe clinical course. Methods: We collected resting-state functional magnetic resonance imaging at 3 T in 68 remitted bipolar I patients (34 with psychosis history) and 51 demographically matched healthy participants. We employed a recently developed global brain connectivity method, restricted to PFC (rGBC). We also independently tested connectivity between anatomically defined amygdala and PFC. Results: Bipolar patients exhibited reduced medial prefrontal cortex (mPFC) rGBC, increased amygdala-mPFC connectivity, and reduced connectivity between amygdala and dorsolateral PFC. All effects were driven by psychosis history. Moreover, the magnitude of observed effects was significantly associated with lifetime psychotic symptom severity. Conclusions: This convergence between rGBC, seed-based amygdala findings, and symptom severity analyses highlights that mPFC, a core emotion regulation region, exhibits both within-PFC dysconnectivity and connectivity abnormalities with limbic structures in bipolar illness. Furthermore, lateral PFC dysconnectivity in patients with psychosis history converges with published work in schizophrenia, indicating possible shared risk factors. Observed dysconnectivity in remitted patients suggests a bipolar trait characteristic and might constitute a risk factor for phasic features of the disorder. © 2013 Society of Biological Psychiatry.


Author Keywords
Amygdala;  bipolar disorder;  connectivity;  prefrontal cortex;  psychosis;  resting-state

Document Type: Article
Source: Scopus

Sartor, C.E.a , Waldron, M.b , Duncan, A.E.c , Grant, J.D.d , Mccutcheon, V.V.d , Nelson, E.C.d , Madden, P.A.F.d , Bucholz, K.K.d , Heath, A.C.d 
Childhood sexual abuse and early substance use in adolescent girls: The role of familial influences
(2013) Addiction, . Article in Press. 
a Department of Psychiatry Yale University School of Medicine New Haven, CT USA
b Indiana University School of Education Bloomington, IN USA
c George Warren Brown School of Social Work Washington University St. Louis, MO USA
d Department of Psychiatry Washington University School of Medicine St. Louis, MO USA

Abstract
Aim: To assess the extent to which the association between childhood sexual abuse (CSA) and early use of alcohol, cigarettes and cannabis in adolescent girls is mediated by risk factors that tend to cluster in families where CSA occurs. Design: An abridged version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered by telephone. Participants: A total of 3761 female twins aged 18-29 (14.6% African American, 85.4% European American). Measurements: CSA experiences and history of substance use were queried in the SSAGA-based interviews. Findings: After controlling for familial influences on early substance use by including co-twin early use status in models, separate Cox proportional hazards regression analyses predicting onset of alcohol, cigarette and cannabis use revealed a significant association with CSA. The effect was observed to age 19years for cigarettes and to age 21years for cannabis, but was limited to age 14years or younger for alcohol, with the most pronounced risk before age 10 [hazard ratio (HR)=4.59; confidence interval (CI): 1.96-10.74]. CSA-associated risk for initiation of cigarette and cannabis use was also highest in the youngest age range, but the decline with age was much more gradual and the hazard ratios significantly lower (HR: 1.70; CI: 1.13-2.56 for cigarettes and HR: 2.34, CI: 1.57-3.48 for cannabis). Conclusions: Childhood sexual abuse history is a distinct risk factor for use of cigarettes and cannabis, and a very strong predictor of early age at first drink. © 2013 Society for the Study of Addiction.

Author Keywords
Alcohol;  Cannabis;  Cigarettes;  Sexual abuse;  Twins;  Women

Document Type: Article in Press
Source: Scopus

Brunner, P.a b c , Schalk, G.a b d e f 
Toward gaze-independent brain-computer interfaces
(2013) Clinical Neurophysiology, . Article in Press. 
a Brain-Computer Interface R and D Program, Wadsworth Center, New York State Department of Health, Albany, NY, USA

b Department of Neurology, Albany Medical College, Albany, NY, USA
c Institute for Computer Graphics and Vision, Graz University of Technology, Graz, Austria
d Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
e Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
f Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Albany, NY, USA

Document Type: Article in Press
Source: Scopus


Cho, H.a , Proll, S.C.b , Szretter, K.J.c , Katze, M.G.b , Gale Jr, M.d , Diamond, M.S.c e f 
Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses
(2013) Nature Medicine, . Article in Press. 
a Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA

b Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA
c Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
d Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA
e 1] Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

Abstract
Although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. Here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded RNA viruses. Granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptibility to viral infection ex vivo and in vivo. By transducing cortical neurons with genes that were expressed more highly in granule cell neurons, we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses. Moreover, we found that the epigenetic state and microRNA (miRNA)-mediated regulation of ISGs correlates with enhanced antiviral response in granule cell neurons. Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, which probably contribute to their relative permissiveness to infection.

Document Type: Article in Press
Source: Scopus

Schulz, A.a , Baader, S.L.b , Niwa-Kawakita, M.c , Jung, M.J.a , Bauer, R.d , Garcia, C.e , Zoch, A.a , Schacke, S.a , Hagel, C.f , Mautner, V.-F.g , Hanemann, C.O.h , Dun, X.-P.h , Parkinson, D.B.h , Weis, J.i , Schröder, J.M.i , Gutmann, D.H.e , Giovannini, M.j , Morrison, H.a 
Merlin isoform 2 in neurofibromatosis type 2-associated polyneuropathy
(2013) Nature Neuroscience, . Article in Press. 
a Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany

b 1] Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Bonn, Germany
c 1]
d Institute of Molecular Cell Biology and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University, Jena, Germany
e Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
f Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
g Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
h Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
i Institute of Neuropathology, RWTH Aachen, University Hospital Aachen, Aachen, Germany
j House Ear Institute, Center for Neural Tumor Research, Los Angeles, California, USA

Abstract
The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2-dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2-deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.

Document Type: Article in Press
Source: Scopus

Kim, H.J.a , Kim, N.C.a , Wang, Y.-D.b , Scarborough, E.A.c , Moore, J.a , Diaz, Z.c , MacLea, K.S.d , Freibaum, B.e , Li, S.e , Molliex, A.e , Kanagaraj, A.P.e , Carter, R.f , Boylan, K.B.g , Wojtas, A.M.g , Rademakers, R.g , Pinkus, J.L.h , Greenberg, S.A.h , Trojanowski, J.Q.i , Traynor, B.J.j , Smith, B.N.i , Topp, S.k , Gkazi, A.-S.k , Miller, J.k , Shaw, C.E.k , Kottlors, M.l , Kirschner, J.l , Pestronk, A.m , Li, Y.R.n , Ford, A.F.o , Gitler, A.D.p , Benatar, M.q , King, O.D.r , Kimonis, V.E.s , Ross, E.D.d , Weihl, C.C.m , Shorter, J.o , Taylor, J.P.e 
Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS
(2013) Nature, . Article in Press. 
a 1] Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA

b 1] Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA
c 1] Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
d Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523, USA
e Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA
f Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA
g Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA
h Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
i Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
j Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA
k King's College London Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, London SE5 8AF, UK
l Division of Neuropediatrics and Muscle Disorders, University Children's Hospital Freiburg, 79106 Freiburg, Germany
m Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
n Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
o Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
p Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
q Neurology Department, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
r Boston Biomedical Research Institute, Watertown, Massachusetts 02472, USA
s Department of Pediatrics, Division of Genetics and Metabolism, University of California-Irvine, 2501 Hewitt Hall, Irvine, California 92696, USA

Abstract
Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

Document Type: Article in Press
Source: Scopus

Ching, J.K., Elizabeth, S.V., Ju, J.-S., Lusk, C., Pittman, S.K., Weihl, C.C.
mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy
(2013) Human Molecular Genetics, 22 (6), pp. 1167-1179. 
Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid (AA) stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease. © The Author 2012. Published by Oxford University Press. All rights reserved.

Document Type: Article
Source: Scopus

Carlson, E.N.
Overcoming the Barriers to Self-Knowledge: Mindfulness as a Path to Seeing Yourself as You Really Are
(2013) Perspectives on Psychological Science, 8 (2), pp. 173-186. 
Washington University, St. Louis, United States

Abstract
People's beliefs about their personality, or how they typically think, feel, and behave, correspond somewhat to objective accuracy criteria. Yet recent research has highlighted the fact that there are many blind spots in self-knowledge and that these blind spots can have fairly negative consequences. What can people do to improve self-knowledge? The current article suggests that the construct of mindfulness, defined as paying attention to one's current experience in a nonevaluative way, may serve as a path to self-knowledge. Specifically, mindfulness appears to directly address the two major barriers to self-knowledge: informational barriers (i.e., the quantity and quality of information people have about themselves) and motivational barriers (i.e., ego-protective motives that affect how people process information about themselves). This article reviews the available evidence supporting the hypothesis that mindfulness improves self-knowledge and outlines promising future directions that might firmly establish an empirical link between mindfulness and self-knowledge. © The Author(s) 2013.

Author Keywords
cognition;  mental health;  mindfulness;  personality;  self-knowledge

Document Type: Review
Source: Scopus

Galanek, J.D.
The Cultural Construction of Mental Illness in Prison: A Perfect Storm of Pathology
(2013) Culture, Medicine and Psychiatry, 37 (1), pp. 195-225. 
Brown School of Social Work, Washington University in St Louis, St. Louis, MO, United States

Abstract
Large numbers of individuals in U. S. prisons meet DSM criteria for severe psychiatric disorder. These individuals also have co-occurring personality and substance abuse disorders, medical conditions, and histories of exposure to social pathologies. Based on nine months of ethnographic fieldwork in a U. S. prison, focusing on staff narratives, I utilize interpretivist and constructivist perspectives to analyze how mental health clinicians construct psychiatric disorder among inmates. Discrete categorization of disorders may be confounded by the clinical co-morbidities of inmates and the prison context. Incarcerated individuals' responses to the institutional context substantially inform mental health staffs' illness construction and the prison itself is identified as an etiological agent for disordered behaviors. In addition, diagnostic processes are found to be indeterminate, contested, and shaped by interactions with staff. Analysis of illness construction reveals that what is at stake for clinicians is not only provision of appropriate treatment, but also mandates for the safety and security of the institution. Enmeshed in these mandates, prison mental health becomes a particular local form of psychiatric knowledge. This paper contributes to anthropological approaches to mental disorder by demonstrating how local contexts mediate psychiatric knowledge and contribute to the limited ethnographic record of prisons. © 2012 Springer Science+Business Media New York.

Author Keywords
Co-occurring disorders;  Illness construction;  Medical anthropology;  Mental illness;  Prison

Document Type: Article
Source: Scopus

Plunk, A.D., Cavazaos-Rehg, P., Bierut, L.J., Grucza, R.A.
The Persistent Effects of Minimum Legal Drinking Age Laws on Drinking Patterns Later in Life
(2013) Alcoholism: Clinical and Experimental Research, 37 (3), pp. 463-469. 
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Exposure to permissive minimum legal drinking age (MLDA) laws not only affects young adults in the short term, but also later in life; for example, individuals who could legally purchase alcohol before the age of 21 are more likely to suffer from drinking problems as older adults, long after the laws had been changed. However, it is not known how permissive MLDA exposure affects specific drinking behavior. This present study uses changes in MLDA laws during the 1970s and 1980s as a natural experiment to investigate the potential impact of permissive MLDA exposure on average alcohol consumption, frequency of drinking, and patterns of binging and more moderate, nonheavy drinking. Methods: Policy exposure data were paired with alcohol use data from the 1991 to 1992 National Longitudinal Alcohol Epidemiologic Survey and the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions. Past-year drinkers born between 1949 and 1972 (n = 24,088) were included. Average daily intake, overall drinking frequency, and frequency of both binge episodes (5+ drinks) and days without a binge episode (nonheavy drinking) for the previous year at the time of interview were tracked for each respondent. Results: Exposure to permissive MLDAs was associated with higher odds to report frequent binging and lower odds to report any moderate drinking; these associations were largely driven by men and those who did not attend college. Overall drinking frequency and average alcohol consumption were not affected by MLDA exposure. Conclusions: The ability to legally purchase alcohol before the age of 21 does not seem to increase overall drinking frequency, but our findings suggest that it is associated with certain types of problematic drinking behaviors that persist into later adulthood: more frequent binge episodes and less frequent nonheavy drinking. We also propose that policymakers and critics should not focus on college drinking when evaluating the effectiveness of MLDAs. © 2013 by the Research Society on Alcoholism.

Author Keywords
Binge Drinking;  Drinking Patterns;  Minimum Legal Drinking Age;  Moderate Drinking

Document Type: Article
Source: Scopus

 

Garai, K., Frieden, C.
Quantitative analysis of the time course of Aβ oligomerization and subsequent growth steps using tetramethylrhodamine-labeled Aβ
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (9), pp. 3321-3326.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Although amyloid β (Aβ) is a critical player in the pathology of Alzheimer's disease, there is currently little Information on the rate and extent of formation of oligomers that lead to the presence of Aβ fibrils observed in amyloid plaques. Here we describe a unique method to monitor the full time course of Aβ aggregation. In this method, Aβ is labeled with tetramethylrhodamine at a lysine residue on the N-terminal end. During aggregation, the fluorescence is quenched in a time-dependent manner in three distinct phases: an early oligomerization phase, an intermediate phase, and a growth phase. The oligomerization phase can be characterized as a monomer-dimer-trimer process for which we have determined the rate and equilibrium constants. The rate constants differ markedly between Aβ1-42 and Aβ1-40, with Aβ1-42 showing a greater oligomerization propensity. The intermediate phase reflects slow clustering and reorganization of the oligomers, whereas the growth phase ultimately results in the formation of fibrillar material. The data are consistent with a conformational change being an important rate-limiting step in the overall aggregation process. The rates of all phases are highly sensitive to temperature and pH, with the pH-dependent data indicating important roles for lysine and histidine residues. From the temperaturedependent data, activation energies of oligomerization and fibrillization are estimated to be 5.5 and 12.1 kCal/mol, respectively. The methodologies presented here are simple and can be applied to other amyloidogenic peptides or proteins.

Author Keywords
Fluorescence quenching;  Kinetics of aggregation;  Nucleation;  Oligomer formation

Document Type: Article
Source: Scopus

Tokuda, K.a , Izumi, Y.a c , Zorumski, C.F.a b c 
Locally-generated acetaldehyde is involved in ethanol-mediated LTP inhibition in the hippocampus
(2013) Neuroscience Letters, 537, pp. 40-43. 
a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

b Department of Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Consistent with the ability of severe alcohol intoxication to impair memory, high concentrations of ethanol (60. mM) acutely inhibit long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. To account for this, we hypothesized that local metabolism to acetaldehyde may contribute to the effects of high ethanol on synaptic function. However, sodium azide, a catalase inhibitor, and allyl sulfide, an inhibitor of cytochrome P450 2E1 (CYP2E1), failed to overcome LTP inhibition by 60. mM ethanol. In contrast, LTP was successfully induced in the presence of ethanol plus 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that local metabolism via alcohol dehydrogenase contributes to synaptic effects. Furthermore, exogenously administered acetaldehyde overcame the effects of 4MP on LTP inhibition mediated by ethanol. These observations indicate that acetaldehyde generated by local metabolism within the hippocampus participates in the synaptic dysfunction associated with severe alcohol intoxication. © 2013 Elsevier Ireland Ltd.

Author Keywords
ADH3;  Alcoholism;  Amnesia;  Blackout;  CNS;  Synaptic plasticity

Document Type: Article
Source: Scopus

Steinel, N.C.a b c , Lee, B.S.d , Tubbs, A.T.d , Bednarski, J.J.e , Schulte, E.e , Yang-Iott, K.S.c , Schatz, D.G.f g , Sleckman, B.P.d , Bassing, C.H.a b c 
The Ataxia telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements
(2013) Journal of Experimental Medicine, 210 (2), pp. 233-239. 
a Immunology Graduate Group, Philadelphia, PA 19104, United States

b Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States
c Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States
d Department of Pathology and Immunology, St. Louis, MO 63110, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, United States
g Howard Hughes Medical Institute, New Haven, CT 06520, United States

Abstract
Allelic exclusion is enforced through the ability of antigen receptor chains expressed from one allele to signal feedback inhibition of V-to-(D)J recombination on the other allele. To achieve allelic exclusion by such means, only one allele can initiate V-to-(D)J recombination within the time required to signal feedback inhibition. DNA double-strand breaks (DSBs) induced by the RAG endonuclease during V(D)J recombination activate the Ataxia Telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) kinases. We demonstrate that ATM enforces Igκ allelic exclusion, and that RAG DSBs induced during Igκ recombination in primary pre-B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Igκ rearrangements. ATM promotes high-density histone H2AX phosphorylation to create binding sites for MDC1, which functions with H2AX to amplify a subset of ATMdependent signals. However, neither H2AX nor MDC1 is required for ATM to enforce Igκ allelic exclusion and suppress Igκ rearrangements. Upon activation in response to RAG Igκ cleavage, ATM signals down-regulation of Gadd45? with concomitant repression of the Gadd45α targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Igκ recombination transduce transient H2AX/MDC1-independent signals that suppress initiation of further Igκ rearrangements to control Igκ allelic exclusion. © 2013 Steinel et al.

Document Type: Article
Source: Scopus

Kotipatruni, R.P.a , Ferraro, D.J.a , Ren, X.a , Vanderwaal, R.P.a , Thotala, D.K.a b , Hallahan, D.E.a b c , Jaboin, J.J.a b 
NDRG4, the N-Myc downstream regulated gene, is important for cell survival, tumor invasion and angiogenesis in meningiomas
(2012) Integrative Biology (United Kingdom), 4 (10), pp. 1185-1197. 
a Department of Radiation Oncology, Washington University in St Louis, St Louis, MO 63108, United States

b Siteman Cancer Center, St Louis, MO 63110, United States
c Mallinckrodt Institute of Radiology, St Louis, MO 63110, United States

Abstract
Meningiomas are the second most common brain tumor, and 20-30% of these tumors are aggressive. The aggressive subtypes are characterized by a capacity for invasion of normal brain with frequent and destructive recurrence patterns. Effective local therapies include surgery and radiation, but there is a need for novel molecular targets to improve survival and reduce morbidity for this group or cancer patients. We have recently identified the N-Myc downstream regulated gene 4, NDRG4, protein as being overexpressed in aggressive meningioma, and in this report, demonstrate its role in cell survival, invasion/migration and angiogenesis. Downregulation of NDRG4 mRNA and protein expression in two high-grade meningioma cancer cell lines, IOMM-Lee and CH-157 MN resulted in reduction in cell survival, DNA fragmentation and G2-M cell cycle arrest. NDRG4 downregulation also decreased cellular invasion and migration, as determined by spheroid migration, linear and radial wound healing, Boyden chamber matrigel invasion, and 3D invasion assays. To determine the effect of NDRG4 depletion on angiogenesis, we studied the immortalized brain endothelial cell line, bEnd.3. We treated bEnd.3 cells with conditioned media from NDRG4-depleted IOMM-Lee and CH-157 MN cells and abrogated their ability to elicit bEnd.3 capillary-like tubes, to proliferate, and to invade. NDRG4 is not overexpressed in bEnd.3 cells and direct NDRG4 depletion had no effect on the cells. This study is significant as it is the first to demonstrate the functional role of NDRG4 in various aspects of meningioma tumor biology. NDRG4 is involved in modulating cell proliferation, invasion, migration and angiogenesis in meningioma, and may play a valuable role as a molecular target in its treatment. © 2012 The Royal Society of Chemistry.

Document Type: Article
Source: Scopus

Disney, K.L., Weinstein, Y., Oltmanns, T.F.
Personality disorder symptoms are differentially related to divorce frequency
(2012) Journal of Family Psychology, 26 (6), pp. 959-965. 
Department of Psychology, Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
Divorce is associated with a multitude of outcomes related to health and well-being. Data from a representative community sample (N = 1,241) of St. Louis residents (ages 55-64) were used to examine associations between personality pathology and divorce in late midlife. Symptoms of the 10 DSM-IV personality disorders were assessed with the Structured Interview for DSM-IV Personality and the Multisource Assessment of Personality Pathology (both self and informant versions). Multiple regression analyses showed Paranoid and Histrionic personality disorder symptoms to be consistently and positively associated with number of divorces across all three sources of personality assessment. Conversely, Avoidant personality disorder symptoms were negatively associated with number of divorces. The present paper provides new information about the relationship between divorce and personality pathology at a developmental stage that is understudied in both domains. © 2012 American Psychological Association.

Author Keywords
Avoidant Personality Disorder;  Divorce;  Marital Status;  Midlife;  Paranoid Personality Disorder

Document Type: Article
Source: Scopus

Janos, A.L.a , Grange, D.K.b , Steiner, R.D.c , White, D.A.a 
Processing speed and executive abilities in children with phenylketonuria
(2012) Neuropsychology, 26 (6), pp. 735-743. 
a Department of Psychology, Washington University, St. Louis, United States

b Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, United States
c Departments of Pediatrics and Molecular and Medical Genetics, Oregon Health and Science University, United States

Abstract
Objective: Phenylketonuria (PKU) is a hereditary metabolic disorder that often results in neuropsychological impairment, even in individuals treated early and continuously. This study was conducted to examine processing speed, variability in processing speed, and the relationship between processing speed variables and executive abilities in children with early and continuously treated PKU. Method: Participants were 42 children with PKU and 81 typically developing children from 7 to 18 years of age. Children completed 3 computerized reaction time (RT) tasks (simple RT, go/no-go, stimulus-response compatibility) and 7 tasks assessing executive abilities (working memory, inhibitory control, strategic processing). Results: Performance of children with PKU was significantly slower and more variable than that of controls across the 3 tasks administered. When age was considered, it was shown that processing speed improved with age to a comparable degree for both groups. Variability in processing speed, however, decreased more with age for the PKU than control group, reflecting the fact that variability in younger, but not older, children with PKU was greater than that of controls. With regard to executive abilities, processing speed and variability contributed to performance on most, but not all, executive tasks; and after controlling for processing speed and variability, executive impairments were still identified in working memory and inhibitory control (not strategic processing). Conclusions: These findings indicate that information processing is slower and less efficient in children with PKU. In addition, processing speed and variability contribute to some, but not all, of the impairments in executive abilities observed in children with PKU. © 2012 American Psychological Association.

Author Keywords
Executive;  Phenylketonuria;  Processing speed;  RT;  Variability

Document Type: Article
Source: Scopus

Burnett-Zeigler, I.E.a b , Pfeiffer, P.a b , Zivin, K.a b , Ilgen, M.A.a b , Austin, K.a , Glass, J.E.c , Flynn, H.A.b , Chermack, S.T.a 
Psychotherapy Utilization for Acute Depression Within the Veterans Affairs Health Care System
(2012) Psychological Services, 9 (4), pp. 325-335.
a VA Serious Mental Illness Treatment Research and Evaluation Center, VA Ann Arbor Healthcare System, Ann Arbor, MI, United States

b University of Michigan Medical School, Department of Psychiatry, University of Michigan, United States
c George Warren Brown School of Social Work, Washington University in St. Louis, United States

Abstract
This study examined the demographic characteristics and psychiatric comorbidities associated with the receipt of psychotherapy. The sample included 217,816 VA patients with a new depression diagnosis. Multinomial logistic regression analyses examined the relationships between the independent variables and the initiation of individual, group, or both individual and group psychotherapy within 90 days of a new diagnosis. Eighteen percent of VA patients received some form of psychotherapy. Veterans received a greater mean number of group therapy than individual therapy visits. Veterans who were female, younger than 35, unmarried, and with substance use, anxiety, or personality disorders were more likely to receive individual therapy only. Veterans who were male, 35-49 years old, Black, Other, or Hispanic, and with substance-use or anxiety disorders were more likely to receive group therapy only than no psychotherapy. Veterans who were male, 35-49 years old, Black, or Other race and with substance-use or anxiety disorders were more likely to receive both individual and group psychotherapy. Increased efforts are needed to encourage early initiation of psychotherapy treatment among depressed veterans. © 2012 American Psychological Association.

Author Keywords
Depression;  Psychotherapy;  Veterans

Document Type: Article
Source: Scopus

Oltmanns, T.F., Kring, A.M.
John M. Neale (1943-2011).
(2012) The American psychologist, 67 (6), p. 497. 
Washington University in St. Louis.

Abstract
Presents an obituary for John M. Neale. Neale died in Hilton Head, South Carolina, on November 19, 2011, after a long illness. He was born on August 31, 1943, in Toronto, Canada. He received his bachelor's degree from the University of Toronto in 1965, where his interest in psychology had been sparked by an introductory course taught by George Mandler. After working at a residential treatment center for emotionally disturbed children, he decided to pursue graduate training in clinical psychology and enrolled at Vanderbilt University. Rue Cromwell served as John's mentor and stimulated his interest in the investigation of perception and cognition in schizophrenia. His doctorate was awarded in 1969, after completion of his internship at the Langley Porter Neuropsychiatric Institute in San Francisco. John was hired in 1969 as an assistant professor in the new and exciting psychology department (founded in 1965) at the State University of New York at Stony Brook. That department remained his academic home for his entire career. Outside of his academic pursuits, John was an avid New York Giants fan, an extensive traveler, an excellent skier and tennis player, a music lover and jukebox collector, an outstanding cook, a terrific dancer, and a devoted dog owner. He continued to pursue these interests throughout his life, taking cooking classes, traveling to exotic locales with his wife Gail, and, when his health precluded more rigorous athletic pursuits, faithfully walking and playing with his dogs. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Document Type: Article
Source: Scopus

Hausmann-Stabile, C.a , Kuhlberg, J.A.a , Zayas, L.H.b , Nolle, A.P.a , Cintron, S.L.c 
Means, intent, lethality, behaviors, and psychiatric diagnosis in Latina adolescent suicide attempters
(2012) Professional Psychology: Research and Practice, 43 (3), pp. 241-248. 
a Warren Brown School of Social Work, Washington University, St. Louis, United States

b School of Social Work, The University of Texas, Austin, United States
c School-Clinical Child Psychology, Pace University, United States

Abstract
This article describes the means, intent, lethality, behavioral profiles, and psychiatric diagnoses of adolescent Latina suicide attempters. From a large, mixed-method project studying the sociocultural processes of Latina suicide attempts, we selected 76 participants for this report. In addition to quantitative research data, medical records were available for all 76 participants, as was qualitative data from in-depth interviews for 34 of them. Using the qualitative and quantitative research data, we explored intent and behavioral profiles of the suicidal adolescents. Medical records provided additional information about the means the adolescents used in their attempts, and about their psychiatric diagnoses. The lethality of suicide attempts was coded using the Lethality of Suicide Attempt Rating Scale (LSARS) and the Lethality of Suicide Attempt Rating Scale-Updated (LSARS-II). Findings showed that Latina adolescent suicide attempts are low in lethality. Consistent with the literature, most adolescents reported that they attempted by using means available in their homes (cutting and overdosing with medications were the predominant methods). Interesting discrepancies emerged when comparing adolescents' self-reported behavioral profiles with clinicians' psychiatric diagnoses. This report has implications for diagnosis and treatment approaches for both inpatient and outpatient service providers. © 2012 American Psychological Association.

Author Keywords
Behavioral profile;  Intent;  Latina adolescent;  Lethality;  Means;  Psychiatric diagnosis;  Suicide attempt

Document Type: Article
Source: Scopus

Hong, B.A.a , Robiner, W.N.b , Dixon, K.E.c , Miner, J.L.d 
Psychologists' medical staff membership in academic healthcare: Past, present, and future challenges
(2012) Professional Psychology: Research and Practice, 43 (1), pp. 50-57. 
a Department of Psychiatry, Washington University, School of Medicine, United States

b Departments of Medicine and Pediatrics, University of Minnesota Medical School, Minneapolis, MN, United States
c Tuscaloosa VA Medical Center, Tuscaloosa, AL, United States
d Division on Substance Abuse, Department of Psychiatry, Columbia University College of Physicians and Surgeons, United States

Abstract
Medical staff membership has important implications for psychologists in academic medical settings for clinical practice and parity. This study surveyed 311 psychologists practicing in academic health centers about their status on the medical or professional staff, institutional privileges and governance, and other issues relevant to practice in medical settings. Data from the survey revealed that only 36.7% of respondents held full membership on the medical staff of their facility, 22.9% were classified as allied health staff, 14.5% were limited members of the medical staff, and 13.8% fell within a category of professional staff. The advent of health care reform and a call for interprofessional collaboration provides a renewed opportunity for psychologists to continue to advocate for full medical staff membership in the same way as physicians, dentists, and podiatrists. Without ongoing efforts and advocacy, medical staff membership for some psychologists could be abridged and the role of psychologists in the new developing health reform organizations could be eclipsed or attenuated. © 2012 American Psychological Association.

Author Keywords
Academic health centers;  Medical school psychologists;  Medical staff privileges

Document Type: Article
Source: Scopus

 

 

March 6, 2013

 Gupta, S.a , Chatni, M.R.b , Rao, A.L.N.c , Vullev, V.I.a , Wang, L.V.b , Anvari, B.a 
Virus-mimicking nano-constructs as a contrast agent for near infrared photoacoustic imaging
(2013) Nanoscale, 5 (5), pp. 1772-1776. 
a Department of Bioengineering, University of California Riverside, Riverside, CA 92521, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 963130, United States
c Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, CA 92521, United States

Abstract
We report the first proof-of-principle demonstration of photoacoustic imaging using a contrast agent composed of a plant virus protein shell, which encapsulates indocyanine green (ICG), the only FDA-approved near infrared chromophore. These nano-constructs can provide higher photoacoustic signals than blood in tissue phantoms, and display superior photostability compared to non-encapsulated ICG. Our preliminary results suggest that the constructs do not elicit an acute immunogenic response in healthy mice. © 2013 The Royal Society of Chemistry.

Document Type: Article
Source: Scopus

Lee, J.J.c , Mouannes-Srour, J.J.a b , Derdeyn, C.P.c , Carroll, T.J.a , Vakil, P.a 
Cerebrovascular occlusive disease: Quantitative cerebral blood flow using dynamic susceptibility contrast MR imaging correlates with quantitative H 2[15O] PET
(2013) Radiology, 266 (3), pp. 879-886. 
a Department of Biomedical Engineering, Feinberg School of Medicine, Northwestern University, 737 N Michigan Ave, Chicago, IL 60611, United States
b Department of Radiology, Northwestern University, 737 N Michigan Ave, Chicago, IL 60611, United States
c Mallinckrodt Institute of Radiology, Departments of Neurology and Neurologic Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Purpose: To compare quantitative values of cerebral blood flow (CBF) derived from dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging with reference standard positron emission tomography (PET) in patients with confirmed cerebrovascular occlusive disease. Materials and Methods: Local institutional review board approval and informed consent were obtained for a prospective study of 18 patients (six men, 12 women; age range, 28-71 years; mean age, 45 years ± 10.4 [standard deviation]) with angiographically confirmed Moyamoya (n = 8) or internal carotid artery occlusions (n = 10). DSC MR images and oxygen 15-labeled water (H2[15O]) PET images were acquired on the same day. DSC images were postprocessed to yield parametric images of CBF (in mL/100 g/min), coregistered, and analyzed using grid-based regions of interest. Mean values of CBF in each region of interest from MR imaging and PET data sets were compared. Correlations for each patient were determined and overall agreement between pooled MR imaging and PET CBF was reported using linear regression analysis and Bland-Altman plots. Results: Strong correlations (r2 ≥ 0.55) were found between MR imaging and PET CBF values in all patients. Use of the bookend approach was found to underestimate CBF predictably across the patient cohort (mean slope, 0.82; standard deviation, 0.18; slope of aggregated data, 0.75). This allowed for a simple rescaling of MR imaging values producing strong agreement with PET values in the aggregated data (r2 = 0.66; slope = 1.00; intercept = 0.00). Conclusion: The data show that the bookend MR imaging technique produces similar results for quantitative CBF between DSC MR imaging and H2[ 15O] PET. Although MR-derived CBF underestimated PET-derived CBF, the patient-to-patient variability in the slopes of the linear MR and PET relationships was significantly smaller than a competing quantitation technique. As a result, the bookend technique appears to more predictably measure quantitative CBF in a clinical setting. © RSNA, 2012.

Document Type: Article
Source: Scopus

Xiong, C.a , van Belle, G.b , Chen, K.c , Tian, L.d , Luo, J.a , Gao, F.a , Yan, Y.a , Chen, L.a , Morris, J.C.e , Crane, P.f 
Combining Multiple Markers to Improve the Longitudinal Rate of Progression: Application to Clinical Trials on the Early Stage of Alzheimer's Disease
(2013) Statistics in Biopharmaceutical Research, 5 (1), pp. 54-66. 
a Division of Biostatistics, Washington University, St. Louis, MO, 63110, United States
b School of Public Health, Department of Biostatistics and Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, 98195-4691, United States
c Banner Alzheimer's Institute, Phoenix, AZ, 85006, United States
d Department of Biostatistics, SUNY, Buffalo, NY, United States
e Department of Neurology, Pathology and Immunology, Washington University Alzheimer's Disease Research Center, St. Louis, MO, 63110, United States
f Department of Medicine, University of Washington, Seattle, WA, 98195-4691, United States

Abstract
Clinical trials in early-stage Alzheimer's disease (AD) are reaching a bottleneck because none of the current disease markers changes appreciably early in the disease process and therefore a huge sample is required to adequately power such trials. We propose a method to combine multiple markers so that the longitudinal rate of progression can be improved. The criterion is to maximize the probability that the combined marker will be decreased over time (assuming a negative mean slope for each marker). We propose estimating the weights of markers in the optimum combination and a confidence interval estimate of the combined rate of progression through the maximum likelihood estimates and a bootstrap procedure. We conduct simulations to assess the performance of our estimates and compare our approach with the first principal component from a principal component analysis. The proposed method is applied to a real-world sample of individuals with preclinical AD to combine measures from two cognitive domains. The combined cognitive marker is finally used to design future clinical trials on preclinical AD, demonstrating a significant reduction in the sample sizes needed to power such trials when compared with individual markers alone. © 2013 Copyright Taylor and Francis Group, LLC.

Author Keywords
Bootstrap estimate;  Delta method;  Multivariate random coefficients models;  Power;  Preclinical Alzheimer's disease (AD);  Randomized clinical trials (RCT);  Sample size

Document Type: Article
Source: Scopus

Duncan, R.P.a , Earhart, G.M.a b 
Four Square Step Test performance in people with parkinson disease
(2013) Journal of Neurologic Physical Therapy, 37 (1), pp. 2-8. 
a Program in Physical Therapy, Washington University School of Medicine, Campus Box 8502, 4444 Forest Park Blvd, St. Louis, MO 63108, United States
b Department of Anatomy and Neurobiology, Department of Neurology, Washington University, St. Louis, MI, United States

Abstract
Background and purpose:: The Four Square Step Test (4SST), a quick and simple test of multidirectional stepping, may be useful in predicting falls in people with Parkinson disease (PD). We studied the reliability of the 4SST and its ability to discriminate between freezers and nonfreezers, between fallers and nonfallers, and factors predictive of 4SST performance in people with PD. METHODS:: Fifty-three individuals with idiopathic PD completed the full protocol, including the 4SST as well as measures of balance, walking, and disease severity on anti-PD medication. RESULTS:: Interrater (intraclass correlation coefficient [ICC] = 0.99) and test-retest reliability were high (ICC = 0.78). The median 4SST performance was 9.52 seconds. There was a significant difference between 4SST time on-medication versus off (P = 0.03), while differences between fallers and nonfallers (P = 0.06) and between freezers and nonfreezers (P = 0.08) did not reach significance. All outcome measures were significantly related to 4SST time. In an exploratory, simultaneous regression analysis, 56% of the variance in 4SST performance could be accounted for by 3 measures: Mini-Balance Evaluation Systems Test (Mini-BESTest), Five Time Sit to Stand, and Nine Hole Peg Test. The 4SST cutoff score for distinguishing fallers from nonfallers was 9.68 seconds (Area under curve = 0.65, sensitivity = 0.73, specificity = 0.57). The posttest probability of an individual with a score greater than the cutoff being a faller was 31% (pretest probability = 21%). DISCUSSION AND CONCLUSIONS:: The 4SST is a reliable, quick test that can distinguish between on-and off-medication conditions in PD but is not as good as other tests (eg, Mini-BESTest) for distinguishing between fallers and nonfallers. © 2013 Neurology Section, APTA.

Author Keywords
balance;  fall risk;  Four Square Step Test;  Parkinson disease

Document Type: Article
Source: Scopus

Earhart, G.M., McNeely, M.E.
Response to "Does STN-DBS Improve Balance in Parkinson Disease?"
(2013) Parkinsonism and Related Disorders, 19 (3), p. 382. 
Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63108, United States

Document Type: Letter
Source: Scopus

Kong, L.a , Chen, K.a , Womer, F.b , Jiang, W.a , Luo, X.c , Driesen, N.c , Liu, J.c , Blumberg, H.c , Tang, Y.a , Xu, K.d , Wang, F.c d 
Sex differences of gray matter morphology in cortico-limbic-striatal neural system in major depressive disorder
(2013) Journal of Psychiatric Research, . Article in Press. 
a Department of Psychiatry, The First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang 110001, Liaoning, PR China
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
c Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA
d Department of Radiology, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang 110001, Liaoning, PR China

Abstract
Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naïve participants with MDD. Participants included 29 medication-naïve individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyzes of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p < 0.05, corrected) in the left ventral prefrontal cortex, right amygdala, right hippocampus and bilateral caudate when comparing the MDD and HC groups. Posthoc analyzes showed that females with MDD had significant GM decreases in limbic regions (p < 0.05, corrected), compared to female HC; while males with MDD demonstrated significant GM reduction in striatal regions, (p < 0.05, corrected), compared to HC males. The observed sex-related patterns of abnormalities within the cortico-limbic-strial neural system, such as predominant prefrontal-limbic abnormalities in MDD females vs. predominant prefrontal-striatal abnormalities in MDD males, suggest differences in neural circuitry that may mediate sex differences in the clinical presentation of MDD and potential targets for sex-differentiated treatment of the disorder. © 2013 Elsevier Ltd. All rights reserved.

Author Keywords
Amygdala;  Caudate;  Hippocampus;  Magnetic resonance imaging;  Major depressive disorder;  Voxel-based morphometry

Document Type: Article in Press
Source: Scopus

Edmond, T.a , Bowland, S.b , Yu, M.c 
Use of mental health services by survivors of intimate partner violence
(2013) Social Work in Mental Health, 11 (1), pp. 34-54. 
a George Warren Brown School of Social Work, Washington University, Campus Box 1196, St. Louis, MO 63130, United States
b Kent School of Social Work, University of Louisville, Louisville, KY, United States
c School of Social Work, University of Missouri, Columbia, MO, United States

Abstract
Fifty women survivors of intimate partner violence (IPV) were recruited from a legal advocacy program to participate in a study designed to assess current rates of posttraumatic stress disorder (PTSD), depression, and alcohol and substance abuse among a sample of abused women and to examine the types of services survivors of IPV had used in the previous 12 months. In addition, the authors sought to understand how the presence of substance abuse, PTSD, and/or depression affects access and utilization of services by IPV survivors. Fifty-four percent of these IPV survivors were experiencing either PTSD, clinical depression, or both. While women with either PTSD or depression used a significantly larger number of services overall, the majority had not used any mental health services, even though they frequently reported services were accessible. Given the high rates of PTSD and depression in this sample, these abused women were clearly not receiving adequate mental health care. Furthermore, many reported having trouble accessing housing, legal services, crisis lines, and medical care-services that are fundamental to safety. Practitioners working with abused women should assess for PTSD and depression, and be prepared to either treat each condition or provide effective referrals. Copyright © Taylor & Francis Group, LLC.

Author Keywords
Depression;  Intimate partner violence;  Mental health services;  PTSD;  Service utilization

Document Type: Article
Source: Scopus

Mallya, A.a , Purnell, A.L.a , Svrakic, D.M.a b , Lovell, A.M.a , Freedland, K.E.b , Gott, B.M.a b , Sayuk, G.S.a b c , Cicero, T.J.b , Brawer, P.A.a b , Trafton, J.A.d , Scherrer, J.F.a b , Lustman, P.J.a b 
Witnessed versus Unwitnessed Random Urine Tests in the Treatment of Opioid Dependence
(2013) American Journal on Addictions, 22 (2), pp. 175-177. 
a Bell Street Clinic Opioid Treatment Program (OTP), Mental Health Service, John Cochran Hospital, St. Louis VA Medical Center, St. Louis, MO, United States
b Department of Psychiatry, Washington University, School of Medicine, 660 S. Euclid, Medical, St. Louis, MO 63110, United States
c Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
d VA Palo Alto Health Care System, Palo Alto, CA, United States

Abstract
Background and Objectives Clinics licensed to provide pharmacotherapy for opiate dependence disorder are required to perform random urine drug screen (RUDS) tests. The results provide the empirical basis of individual treatment and programmatic effectiveness, and public health policy. Patients consent to witnessed testing but most tests are unwitnessed. The purpose of the present study was to compare treatment effectiveness estimates derived from witnessed versus unwitnessed urine samples. Methods We adopted a policy requiring visually witnessed urine drug screens (WUDS) and studied its impact (a single group, pretest-posttest design) on the RUDS test results in 115 male veterans enrolled in the St. Louis VA Opioid Treatment Program. Results The percentage of opioid-positive urine samples increased significantly following implementation of WUDS (25% vs. 41%, χ2 = 66.5, p &lt;.001). Conclusions and Scientific Significance Results of this preliminary study suggest that random testing alone does not ensure the integrity of UDS testing. Outcome calculations based on random unwitnessed tests may overestimate the effectiveness of opioid dependence disorder treatment. (Am J Addict 2013;22:175-177) © American Academy of Addiction Psychiatry.

Document Type: Article
Source: Scopus

Mcdaniel, M.A., Thomas, R.C., Agarwal, P.K., Mcdermott, K.B., Roediger, H.L.
Quizzing in Middle-School Science: Successful Transfer Performance on Classroom Exams
(2013) Applied Cognitive Psychology, . Article in Press. 
Washington University in St. Louis St. Louis, MO USA

Abstract
We examined whether learning from quizzing arises from memorization of answers or fosters more complete understanding of the quizzed content. In middle-school science classes, we spaced three multiple-choice quizzes on content in a unit. In Experiment 1, the class exams included questions given on quizzes, transfer questions targeting the same content, and content that had not been quizzed (control content). The quizzing procedure was associated with significant learning benefits with large effect sizes and similar effect sizes for both transfer items and identical items. In Experiment 2, quiz questions focused on definitional information or application of the principle. Application questions increased exam performance for definitional-type questions and for different application questions. Definition questions did not confer benefits for application questions. Test-enhanced learning, in addition to other factors in the present quizzing protocol (repeated, spaced presentation of the content), may create deeper understanding that leads to certain types of transfer. © 2013 John Wiley & Sons, Ltd.

Document Type: Article in Press
Source: Scopus

Kennedy, S.C.a , Tripodi, S.J.a , Pettus-Davis, C.b 
The Relationship Between Childhood Abuse and Psychosis for Women Prisoners: Assessing the Importance of Frequency and Type of Victimization
(2013) Psychiatric Quarterly, pp. 1-15. Article in Press. 
a College of Social Work, Florida State University, 296 Champions Way, University Center C, Tallahassee, 32306, United States
b Brown School, Washington University in St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, 63130, United States

Abstract
This study examines the relationship between childhood victimization and self-reported current symptoms of psychosis in an incarcerated female population in the United States. Participants are 159 randomly selected women incarcerated in two North Carolina state prisons. Participants completed a battery of self-report measures to assess childhood victimization and current and lifetime experience of audio/visual hallucinations and delusions. In accordance with the dose-response model, we hypothesized a predictive relationship between severity, frequency, and type of victimization and psychosis for this sample of women prisoners. Results indicate that women who experienced multi-victimization were 2.4 times more likely to report current symptoms of psychosis than other women prisoners who experienced only physical or sexual victimization in childhood. Likewise, a one-unit increase in frequency of childhood victimization was associated with a 3.2 % increased likelihood of having reported symptoms of current psychosis. These results provide support for the dose-response model hypothesis that multi-victimization is an important predictor of psychosis for the women prisoner population. Results indicate that adjusting prison-based mental health services to address the relationship of childhood victimization and symptoms of psychosis may be a key factor in improving outcomes among this population. © 2013 Springer Science+Business Media New York.

Author Keywords
Childhood victimization;  Dose-response model;  Psychosis;  Women prisoners

Document Type: Article in Press
Source: Scopus

Srinivasakumar, P.a , Zempel, J.b , Wallendorf, M.c , Lawrence, R.a , Inder, T.a , Mathur, A.a 
Therapeutic Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy: Electrographic Seizures and Magnetic Resonance Imaging Evidence of Injury
(2013) Journal of Pediatrics, . Article in Press. 
a Department of Pediatrics, Washington University in St Louis, St Louis, MO
b Department of Neurology, Washington University in St Louis, St Louis, MO
c Department of Biostatistics, Washington University in St Louis, St Louis, MO

Abstract
Objective: To evaluate the electrographic seizure burden in neonates with hypoxic ischemic encephalopathy (HIE) treated with or without therapeutic hypothermia and stratified results by severity of HIE and severity of injury as assessed by magnetic resonance imaging (MRI). Study design: Between 2007 and 2011, video-electroencephalography (EEG) monitoring was initiated in neonates with moderate to severe HIE. Seizure burden (in seconds) was calculated, and brain MRI scans were quantitatively scored. Data were analyzed by ANOVA, the Student t test, and the χ2 test. Results: Sixty-nine neonates with moderate or severe HIE were prospectively enrolled, including 51 who received therapeutic hypothermia and 18 who did not. The mean duration of video-EEG monitoring was longer in the therapeutic hypothermia group (72 ± 34 hours vs 48 ± 34 hours; P = .01). The therapeutic hypothermia group had a lower electrographic seizure burden (log units) after controlling for injury, as assessed by MRI (2.9 ± 0.6 vs 6.2 ± 0.9; P = .003). A reduction in seizure burden was seen in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80). Among neonates with injury assessed by MRI, seizure burden was lower in those with mild (P = .0004) and moderate (P = .02) injury, but not in those with severe injury (P = .90). Conclusion: Therapeutic hypothermia was associated with reduced electrographic seizure burden in neonatal HIE. This effect was detected on video-EEG in infants with moderate HIE, but not in those with severe HIE. When stratified by injury as assessed by MRI, therapeutic hypothermia was associated with a reduced seizure burden in infants with mild and moderate injury, but not in those with severe injury. © 2013 Mosby, Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

Conway, C.R.a b , Chibnall, J.T.b , Gebara, M.A.a , Price, J.L.c , Snyder, A.Z.d e , Mintun, M.A.a e f , Craig, A.D.(B.)g , Cornell, M.E.a , Perantie, D.C.a , Giuffra, L.A.a , Bucholz, R.D.h , Sheline, Y.I.a d e 
Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression
(2013Brain Stimulation, . Article in Press. 
a Department of Psychiatry, Washington University, St. Louis, MO, USA
b Department of Neurology and Psychiatry, Saint Louis University, St. Louis, MO, USA
c Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA
d Department of Neurology, Washington University, St. Louis, MO, USA
e Department of Radiology, Washington University, St. Louis, MO, USA
f Avid Radiopharmaceuticals, Philadelphia, PA, USA
g Atkinson Research Laboratory, Barrow Neurological Institute, Phoenix, AZ, USA
h Department of Neurosurgery, Saint Louis University, St. Louis, MO, USA

Abstract
Background: Vagus nerve stimulation (VNS) has antidepressant effects in treatment resistant major depression (TRMD); these effects are poorly understood. This trial examines associations of subacute (3 months) and chronic (12 months) VNS with cerebral metabolism in TRMD. Objective: 17Fluorodeoxyglucose positron emission tomography was used to examine associations between 12-month antidepressant VNS response and cerebral metabolic rate for glucose (CMRGlu) changes at 3 and 12 months. Methods: Thirteen TRMD patients received 12 months of VNS. Depression assessments (Hamilton Depression Rating Scale [HDRS]) and PET scans were obtained at baseline (pre-VNS) and 3/12 months. CMRGlu was assessed in eight a priori selected brain regions (bilateral anterior insular [AIC], orbitofrontal [OFC], dorsolateral prefrontal [DLPFC], and anterior cingulate cortices [ACC]). Regional CMRGlu changes over time were studied in VNS responders (decreased 12 month HDRS by ≥50%) and nonresponders. Results: A significant trend (decreased 3 month CMRGlu) in the right DLPFC was observed over time in VNS responders (n = 9; P = 0.006). An exploratory whole brain analysis (Puncorrected = 0.005) demonstrated decreased 3 month right rostral cingulate and DLPFC CMRGlu, and increased 12 month left ventral tegmental CMRGlu in responders. Conclusions/Limitations: VNS response may involve gradual (months in duration) brain adaptations. Early on, this process may involve decreased right-sided DLPFC/cingulate cortical activity; longer term effects (12 months) may lead to brainstem dopaminergic activation. Study limitations included: a) a small VNS nonresponders sample (N = 4), which limited conclusions about nonresponder CMRGlu changes; b) no control group; and, c) patients maintained their psychotropic medications. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Antidepressant;  Depression;  Positron emission tomography;  Treatment resistant depression;  Vagus nerve stimulation

Document Type: Article in Press
Source: Scopus

Mantini, D.a b c , Corbetta, M.b c d e , Romani, G.L.b c , Orban, G.A.a f , Vanduffel, W.a g h 
Evolutionarily novel functional networks in the human brain?
(2013) Journal of Neuroscience, 33 (8), pp. 3259-3275. 
a Laboratory of Neuro-and Psychophysiology, KU Leuven Medical School, Leuven, 3000, Belgium
b Department of Neuroscience and Imaging, D'Annunzio University, Chieti, 66013, Italy
c Institute for Advanced Biomedical Technology, D'Annunzio University Foundation, Chieti, 66013, Italy
d Departments of Neurology, Washington University, St. Louis, MO 63110, United States
e Departments of Radiology, Washington University, St. Louis, MO 63110, United States
f Department of Neuroscience, University of Parma Medical School, Parma, 43100, Italy
g Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA 02129, United States
h Department of Radiology, Harvard Medical School, Boston, MA 02115, United States

Abstract
Primate evolution has been accompanied by complex reorganizations in brain anatomy and function. Little is known, however, about the relationship between anatomical and functional changes induced through primate evolution. Using functional magnetic resonance imaging, we assessed spatial and temporal correspondences of cortical networks in humans and monkeys. We provided evidence for topologically and functionally correspondent networks in sensory-motor and attention regions. More specifically, we revealed a possible monkey equivalent of the human ventral attention network. For other human networks, such as the language and the default-mode networks, we detected topological correspondent networks in the monkey, but with different functional signatures. Furthermore, we observed two lateralized human frontoparietal networks in the cortical regions displaying the greatest evolutionary expansion, having neither topological nor functional monkey correspondents. This finding may indicate that these two human networks are evolutionarily novel. Thus, our findings confirm the existence of networks where evolution has conserved both topology and function but also suggest that functions of structurally preserved networks can diverge over time and that novel, hence human-specific networks, have emerged during human evolution. © 2013 the authors.

Document Type: Article
Source: Scopus

Deng, P.-Y.a , Rotman, Z.a , Blundon, J.c , Cho, Y.b , Cui, J.a , Cavalli, V.b , Zakharenko, S.c , Klyachko, V.a 
FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels
(2013) Neuron, 77 (4), pp. 696-711. Cited 1 time.
a Departments of Biomedical Engineering and Cell Biology and Physiology, CIMED, Washington University, St. Louis, MO 63110, United States
b Department of Anatomy and Neurobiology, Washington University, St. Louis, MO 63110, United States
c Department of Developmental Neurobiology, St Jude Children's Hospital, Memphis, TN 38105, United States

Abstract
Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology. Deng et al. find that FMRP, a protein implicated in fragile X syndrome, regulates neurotransmitter release and information transmission by modulating action potential duration in hippocampal and cortical neurons. These actions are presynaptic, translation independent, and mediated by interaction with BK channels. © 2013 Elsevier Inc.

Document Type: Article
Source: Scopus

Zhang, B., McDaniel, S.S., Rensing, N.R., Wong, M.
Vigabatrin Inhibits Seizures and mTOR Pathway Activation in a Mouse Model of Tuberous Sclerosis Complex
(2013) PLoS ONE, 8 (2), art. no. e57445, .
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Epilepsy is a common neurological disorder and cause of significant morbidity and mortality. Although antiseizure medication is the first-line treatment for epilepsy, currently available medications are ineffective in a significant percentage of patients and have not clearly been demonstrated to have disease-specific effects for epilepsy. While seizures are usually intractable to medication in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, vigabatrin appears to have unique efficacy for epilepsy in TSC. While vigabatrin increases gamma-aminobutyric acid (GABA) levels, the precise mechanism of action of vigabatrin in TSC is not known. In this study, we investigated the effects of vigabatrin on epilepsy in a knock-out mouse model of TSC and tested the novel hypothesis that vigabatrin inhibits the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in TSC. We found that vigabatrin caused a modest increase in brain GABA levels and inhibited seizures in the mouse model of TSC. Furthermore, vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the knock-out mice in vivo, as well as reduced mTOR pathway activation in cultured astrocytes from both knock-out and control mice. This study identifies a potential novel mechanism of action of an antiseizure medication involving the mTOR pathway, which may account for the unique efficacy of this drug for a genetic epilepsy. © 2013 Zhang et al.

Document Type: Article
Source: Scopus

Carlson, B.A.
In reply
(2013) JAMA Neurology, 70 (2), pp. 271-272. 
Department of Biology, Washington University in St Louis, 1 Brookings Dr., St Louis, MO 63130-4899, United States

Document Type: Letter
Source: Scopus

Rudick, R.a , Polman, C.b , Clifford, D.c , Miller, D.d , Steinman, L.e 
Natalizumab: Bench to bedside and beyond
(2013) JAMA Neurology, 70 (2), pp. 172-182. 
a Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, United States
b Department of Neurology, VU Medical Center, Amsterdam, Netherlands
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
d Department of Neuroinflammation, Institute of Neurology, University College London, London, United Kingdom
e Departments of Neurology and Neurological Sciences and Pediatrics, Stanford University School of Medicine, Stanford, CA, United States

Abstract
Natalizumab has been available as a multiple sclerosis treatment for more than 5 years in Europe and the United States. Natalizumab was granted approval by the US Food and Drug Administration in 2004, only 12 years after its molecular target was cloned. Shortly after initial approval, natalizumab use was suspended pending a safety review when several natalizumab recipients were diagnosed as having progressive multifocal leukoencephalopathy. After the safety review, natalizumab was reintroduced to the market in 2006. Since then, more than 92 000 patients have been treated with the drug. Risk stratification algorithms and progressive multifocal leukoencephalopathy management strategies have been developed, which facilitate more personalized decision making and safer natalizumab use. This review article summarizes the evolution of natalizumab from target molecule discovery through regulatory approval, voluntary suspension, reapproval, and clinical use. The natalizumab story highlights both the opportunities and risks inherent in a novel biological therapy for a progressive neurologic disease. © 2013 American Medical Association. All rights reserved.

Document Type: Review
Source: Scopus

Ushe, M.a , Perlmutter, J.S.a b c d e 
Sex, drugs and Parkinson's disease
(2013) Brain, 136 (2), pp. 371-373. 
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Programs in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
e Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Note
Source: Scopus

Winer, L.a , Srinivasan, D.a , Chun, S.a , Lacomis, D.b , Jaffa, M.d , Fagan, A.a , Holtzman, D.M.a , Wancewicz, E.e , Bennett, C.F.e , Bowser, R.c , Cudkowicz, M.d , Miller, T.M.a 
SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy
(2013) JAMA Neurology, 70 (2), pp. 201-207. 
a Department of Neurology, Washington University, 115 Biotech Bldg., St Louis, MO 63110, United States
b Departments of Neurology, University of Pittsburgh, PA, United States
c Department of Pathology, University of Pittsburgh, PA, United States
d Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General Hospital, Boston, United States
e Isis Pharmaceuticals, Carlsbad, CA, United States

Abstract
Background: Therapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Objective: To determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS. Design: Antisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40. Participants: Ninety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy). Results: Antisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). Inhuman CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172 [8] ng/mL; P&lt;.05) and the controls with a neurological disease (mean [SE] level, 172 [6] ng/mL; P&lt;.05) than in the healthy controls (mean [SE] level, 134 [4] ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type. Conclusions: SOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time. © 2013 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

Dasanayake, I., Li, J.-S.
Charge-balanced time-optimal control for spiking neuron oscillators
(2012) Proceedings of the IEEE Conference on Decision and Control, art. no. 6425878, pp. 1651-1656. 
Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
In this paper, we investigate the fundamental limits on how the inter-spike time of a neuron oscillator can be perturbed by the application of an external control input (a current stimulus) with zero net electric charge accumulation. We derive the minimum and maximum inter-spike time assignment controls for phase models using the maximum principle, and fully characterize the possible range of neuronal spiking times with respect to a given bound on the control amplitude. We apply the derived optimal controls to both mathematically ideal and experimentally observed phase models of spiking neurons to demonstrate their applicability to neuroscience. © 2012 IEEE.

 

Document Type: Conference Paper
Source: Scopus