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WUSTL Neuroscience Publications Archive - July 2015

July 2015

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July 29, 2015 

Eling, P.a , Finger, S.b
Franz Joseph Gall on greatness in the fine arts: A collaboration of multiple cortical faculties of mind
(2015) Cortex, 71, pp. 102-115. 

DOI: 10.1016/j.cortex.2015.06.017


a Department of Psychology and Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
b Department of Psychology, Center for the History of Medicine, Washington University, St. Louis, MO, United States


Abstract
Although Franz Joseph Gall (1758-1828) is well known for his organology, i.e., his theory of cortical localization of function largely derived from skull features, little has been written about his ideas pertaining to specific faculties other than speech, and even less attention has been drawn to how the individual faculties might work together in specific situations. Our focus shall be on how Franz Joseph Gall viewed the fine arts, with special emphasis on what one must possess to be outstanding in this field, which he associated with perceiving and understanding relationships, and several higher faculties of mind, including color, "constructiveness," locality, and recognizing people. How these faculties are utilized, he tells us, will vary with whether an artist does portraits, landscapes, historical scenes, still life compositions, etc., as well as with the selected medium (e.g., oil paints, sketching on paper, stones to be carved). To put Gall's thoughts about the fine arts in context, brief mention will be made of his scientific career, his guiding philosophy, the questions he most wanted to answer, what he construed as "evidence," how he eliminated the soul or "controller" from his system, and how he presented his work to the public. Some comparisons will be made to what he wrote about having a talent for music. © 2015 Elsevier Ltd.


Author Keywords
"Constructiveness";  Body image;  Color perception;  Cortical localization of function;  Fine arts;  Gall (Franz Joseph);  History of neuroscience;  Organology;  Painting;  Phrenology;  Spatial perception


Document Type: Article
Source: Scopus



Nair, S.a , Diamond, M.S.a b c d
Innate immune interactions within the central nervous system modulate pathogenesis of viral infections
(2015) Current Opinion in Immunology, 36, pp. 47-53. 

DOI: 10.1016/j.coi.2015.06.011


a Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
b Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
d Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, United States


Abstract
The innate immune system mediates protection against neurotropic viruses that replicate in the central nervous system (CNS). Virus infection within specific cells of the CNS triggers activation of several families of pattern recognition receptors including Toll-like receptors, retinoic acid-inducible gene I like receptors, nucleotide-binding oligomerization domain-like receptors, and cytosolic DNA sensors. In this review, we highlight recent advances in our understanding of how cell-intrinsic host defenses within the CNS modulate infection of different DNA and RNA viruses. © 2015 Elsevier Ltd.


Document Type: Review
Source: Scopus



Au, A.K.a , Chen, Y.a , Du, L.a , Smith, C.M.b , Manole, M.D.c , Baltagi, S.A.d , Chu, C.T.e , Aneja, R.K.a c , Bayir, H.a c f , Kochanek, P.M.a c g , Clark, R.S.B.a c h
Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing rat brain and in primary cortical neurons in vitro
(2015) Biochimica et Biophysica Acta - Molecular Basis of Disease, 1852 (9), pp. 1902-1911. 

DOI: 10.1016/j.bbadis.2015.06.007


a Department of Critical Care Medicine, The Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
b Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
c Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
f Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, United States
g Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
h Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, United States


Abstract
Increased autophagy/mitophagy is thought to contribute to cerebellar dysfunction in Purkinje cell degeneration mice. Intriguingly, cerebellar Purkinje cells are highly vulnerable to hypoxia-ischemia (HI), related at least in part to their high metabolic activity. Whether or not excessive or supraphysiologic autophagy plays a role in Purkinje cell susceptibility to HI is unknown. Accordingly, we evaluated the role of autophagy in the cerebellum after global ischemia produced by asphyxial cardiac arrest in postnatal day (PND) 16-18 rats, using siRNA-targeted inhibition of Atg7, necessary for microtubule-associated protein light chain 3-II (LC3-II) and Atg12-Atg5 complex formation. Two days before a 9. min asphyxial cardiac arrest or sham surgery, Atg7 or control siRNA was injected intracisternally to target the cerebellum. Treatment with Atg7 siRNA: 1) reduced Atg7 protein expression in the cerebellum by 56%; 2) prevented the typical ischemia-induced formation of LC3-II in the cerebellum 24. h after asphyxial cardiac arrest; 3) improved performance on the beam-balance apparatus on days 1-5; and 4) increased calbindin-labeled Purkinje cell survival assessed on day 14. Improved Purkinje cell survival was more consistent in female vs. male rats, and improved beam-balance performance was only seen in female rats. Similar responses to Atg7 siRNA i.e. reduced autophagy and neurodegeneration vs. control siRNA were seen when exposing sex-segregated green fluorescent protein-LC3 tagged mouse primary cortical neurons to oxygen glucose deprivation in vitro. Thus, inhibition of autophagy after global ischemia in PND 16-18 rats leads to increased survival of Purkinje cells and improved motor performance in a sex-dependent manner. © 2015.


Author Keywords
Asphyxia;  Atg7;  Cardiac arrest;  Cerebellum;  Hypoxia-ischemia;  Ischemic brain injury;  Oxygen glucose deprivation;  Purkinje neuron;  Small interfering RNA


Document Type: Article
Source: Scopus




Yue, X.a , Jin, H.a , Liu, H.a , Rosenberg, A.J.a , Klein, R.S.b , Tu, Z.a
A potent and selective C-11 labeled PET tracer for imaging sphingosine-1-phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression
(2015) Organic and Biomolecular Chemistry, 13 (29), pp. 7928-7939. 

DOI: 10.1039/c5ob00951k


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


Abstract
Sphingosine-1-phosphate receptor 2 (S1PR2) plays an essential role in regulating blood-brain barrier (BBB) function during demyelinating central nervous system (CNS) disease. Increased expression of S1PR2 occurs in disease-susceptible CNS regions of female versus male SJL mice and in female multiple sclerosis (MS) patients. Here we reported a novel sensitive and noninvasive method to quantitatively assess S1PR2 expression using a C-11 labeled positron emission tomography (PET) radioligand [11C]5a for in vivo imaging of S1PR2. Compound 5a exhibited promising binding potency with IC<inf>50</inf> value of 9.52 ± 0.70 nM for S1PR2 and high selectivity over S1PR1 and S1PR3 (both IC<inf>50</inf> > 1000 nM). [11C]5a was synthesized in
40 min with radiochemistry yield of 20 ± 5% (decayed to the end of bombardment (EOB), n > 10), specific activity of 222-370 GBq μmol-1 (decayed to EOB). The biodistribution study in female SJL mice showed the cerebellar uptake of radioactivity at 30 min of post-injection of [11C]5a was increased by Cyclosporin A (CsA) pretreatment (from 0.84 ± 0.04 ID% per g to 2.21 ± 0.21 ID% per g, n = 4, p < 0.01). MicroPET data revealed that naive female SJL mice exhibited higher cerebellar uptake compared with males following CsA pretreatment (standardized uptake values (SUV) 0.58 ± 0.16 vs. 0.48 ± 0.12 at 30 min of post-injection, n = 4, p < 0.05), which was consistent with the autoradiographic results. This data suggested that [11C]5a had the capability in assessing the sexual dimorphism of S1PR2 expression in the cerebellum of the SJL mice. The development of radioligands for S1PR2 to identify a clinical suitable S1PR2 PET radiotracer, may greatly contribute to investigating sex differences in S1PR2 expression that contribute to MS subtype and disease progression and it will be very useful for detecting MS in early state and differentiating MS with other patients with neuroinflammatory diseases, and monitoring the efficacy of treating diseases using S1PR2 antagonism. © 2015 The Royal Society of Chemistry.


Document Type: Article
Source: Scopus




Yang, X.a , Sheng, W.b , Ridgley, D.M.c , Haidekker, M.A.d , Sun, G.Y.b , Lee, J.C.c e
Astrocytes regulate α-secretase-cleaved soluble amyloid precursor protein secretion in neuronal cells: Involvement of group IIA secretory phospholipase A2
(2015) Neuroscience, 300, pp. 508-517. 

DOI: 10.1016/j.neuroscience.2015.05.052


a Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biochemistry, University of Missouri, Columbia, MO, United States
c Department of Bioengineering, University of Missouri, Columbia, MO, United States
d College of Engineering, Driftmier Engineering Center, University of Georgia, Athens, GA, United States
e Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, United States


Abstract
Astrocytes are major supportive cells in brains with important functions including providing nutrients and regulating neuronal activities. In this study, we demonstrated that astrocytes regulate amyloid precursor protein (APP) processing in neuronal cells through secretion of group IIA secretory phospholipase A<inf>2</inf> (sPLA<inf>2</inf>-IIA). When astrocytic cells (DITNC) were mildly stimulated with the pro-inflammatory cytokines, such as TNF α and IL-1β, sPLA<inf>2</inf>-IIA was secreted into the medium. When conditioned medium containing sPLA<inf>2</inf>-IIA was applied to human neuroblastoma (SH-SY5Y) cells, there was an increase in both cell membrane fluidity and secretion of α-secretase-cleaved soluble amyloid precursor protein (sAPP<inf>α</inf>). These changes were abrogated by KH064, a selective inhibitor of sPLA<inf>2</inf>-IIA. In addition, exposing SH-SY5Y cells to recombinant human sPLA<inf>2</inf>-IIA also increased membrane fluidity, accumulation of APP at the cell surface, and secretion of sAPP<inf>α</inf>, but without altering total expressions of APP, α-secretases and β-site APP cleaving enzyme (BACE1). Taken together, our results provide novel information regarding a functional role of sPLA<inf>2</inf>-IIA in astrocytes for regulating APP processing in neuronal cells. © 2015 IBRO.


Author Keywords
Astrocytes;  Cytokine;  Membrane fluidity;  SAPP<inf>α</inf>;  SH-SY5Y;  SPLA<inf>2</inf>-IIA


Document Type: Article
Source: Scopus




Li, T.-T.a , Fan, M.-L.a , Hou, S.-X.a b , Li, X.-Y.c , Barry, D.M.d , Jin, H.e , Luo, S.-Y.f , Kong, F.a , Lau, L.-F.c , Dai, X.-R.c , Zhang, G.-H.b c , Zhou, L.-L.a
A novel snake venom-derived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury
(2015) British Journal of Pharmacology, 172 (15), pp. 3904-3916. 

DOI: 10.1111/bph.13178


a Department of Pharmacology, School of Basic Medical Science, Anhui Medical University, Hefei, China
b Department of Pharmacy, Xuancheng People's Hospital, Xuancheng, China
c Zhaoke Pharmaceutical Co. Ltd, Hefei, Anhui, China
d Department of Anesthesiology, School of Medicine, Washington University, St. Louis, MO, United States
e Department of Pharmaceutical Chemistry, Jiangsu Changjiang Pharmaceutical Co. Ltd, Shanghai, China
f Department of Pharmacology, Anhui Academy of Medical Sciences, Hefei, Anhui, China


Abstract
Background and Purpose Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein (GP)Ib binding to von Willebrand factor (vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice. Experimental Approach Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). These mice were then treated with anfibatide (4, 2, 1 μg·kg-1), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/IIIα antagonist, was used as a positive control. Key Results Twenty-four hours after MCAO, anfibatide-treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbα, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice. Conclusions and Implications Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke. © 2015 The British Pharmacological Society.


Document Type: Article
Source: Scopus




Silverstein, S.M.a , Harms, M.P.b , Carter, C.S.c , Gold, J.M.d , Keane, B.P.a , MacDonald, A., IIIe , Daniel Ragland, J.c , Barch, D.M.b
Cortical contributions to impaired contour integration in schizophrenia
(2015) Neuropsychologia, 75, pp. 469-480. 

DOI: 10.1016/j.neuropsychologia.2015.07.003


a Rutgers, The State University of New Jersey, United States
b Washington University in St. Louis, United States
c University of California at Davis, United States
d University of Maryland, Maryland Psychiatric Research Center, United States
e University of Minnesota, United States


Abstract
Objectives: Visual perceptual organization impairments in schizophrenia (SCZ) are well established, but their neurobiological bases are not. The current study used the previously validated Jittered Orientation Visual Integration (JOVI) task, along with fMRI, to examine the neural basis of contour integration (CI), and its impairment in SCZ. CI is an aspect of perceptual organization in which multiple distinct oriented elements are grouped into a single continuous boundary or shape. Methods: On the JOVI, five levels of orientational jitter were added to non-contiguous closed contour elements embedded in background noise to progressively increase the difficulty in perceiving contour elements as left- or right-pointing ovals. Multi-site fMRI data were analyzed for 56 healthy control subjects and 47 people with SCZ. Results: SCZ patients demonstrated poorer CI, and this was associated with increased activation in regions involved in global shape processing and visual attention, namely the lateral occipital complex and superior parietal lobules. There were no brain regions where controls demonstrated more activation than patients. Conclusions: CI impairment in this sample of outpatients with SCZ was related to excessive activation in regions associated with object processing and allocation of visual-spatial attention. There was no evidence for basic impairments in contour element linking in the fMRI data. The latter may be limited to poor outcome patients, where more extensive structural and functional changes in the occipital lobe have been observed. © 2015 Elsevier Ltd.


Author Keywords
Contour integration;  FMRI;  Lateral occipital complex;  Perception;  Perceptual organization;  Schizophrenia;  Vision


Document Type: Article
Source: Scopus




Kennedy, S.C.a , Tripodi, S.J.a , Pettus-Davis, C.b , Ayers, J.a
Examining Dose–Response Relationships Between Childhood Victimization, Depression, Symptoms of Psychosis, and Substance Misuse for Incarcerated Women
(2015) Women and Criminal Justice, 22 p. Article in Press. 

DOI: 10.1080/08974454.2015.1023486


a College of Social Work, Florida State University, Tallahassee, Florida, USA
b George Warren Brown School of Social Work, Washington University in St. Louis, St. Louis, Missouri, USA


Abstract
The current study uses the dose–response model to examine the relationships between childhood victimization events and subsequent depression, symptoms of psychosis, and substance misuse in a sample of 230 randomly selected incarcerated women in the United States. Results on the frequency of victimization were mixed. In this sample, both frequency of physical abuse and frequency of sexual abuse significantly predicted current symptoms of psychosis, but only frequency of physical abuse significantly predicted substance misuse. Incarcerated women who experienced multivictimization were 5.7 times as likely to report depression, 4.2 times as likely to report current symptoms of psychosis, and 3.8 times as likely to meet criteria for a substance use disorder. Results indicate that adjusting prison-based interventions to address multivictimization may improve outcomes and reduce recidivism among this population. 2015 Copyright © Taylor & Francis Group, LLC


Author Keywords
childhood victimization;  dose–response model;  incarcerated women;  mental health;  substance misuse


Document Type: Article in Press
Source: Scopus




Wilems, T.S., Sakiyama-Elbert, S.E.
Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury
(2015) Journal of Controlled Release, 213, pp. 103-111. 

DOI: 10.1016/j.jconrel.2015.06.031


Department of Biomedical Engineering, Washington University, 1097 Brookings Dr., St. Louis, MO, United States


Abstract
Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) are major contributors to axon growth inhibition following spinal cord injury and limit functional recovery. The NEP1-40 peptide competitively binds the Nogo receptor and partially blocks inhibition from MAIs, while chondroitinase ABC (ChABC) enzymatically digests CSPGs, which are upregulated at the site of injury. In vitro studies showed that the combination of ChABC and NEP1-40 increased neurite extension compared to either treatment alone when dissociated embryonic dorsal root ganglia were seeded onto inhibitory substrates containing both MAIs and CSPGs. Furthermore, the ability to provide sustained delivery of biologically active ChABC and NEP1-40 from biomaterial scaffolds was achieved by loading ChABC into lipid microtubes and NEP1-40 into poly (lactic-co-glycolic acid) (PLGA) microspheres, obviating the need for invasive intrathecal pumps or catheters. Fibrin scaffolds embedded with the drug delivery systems (PLGA microspheres and lipid microtubes) were capable of releasing active ChABC for up to one week and active NEP1-40 for over two weeks in vitro. In addition, the loaded drug delivery systems in fibrin scaffolds decreased CSPG deposition and development of a glial scar, while also increasing axon growth after spinal cord injury in vivo. Therefore, the sustained, local delivery of ChABC and NEP1-40 within the injured spinal cord may block both myelin and CSPG-associated inhibition and allow for improved axon growth. © 2015 Elsevier B.V. All rights reserved.


Author Keywords
Chondroitinase ABC;  Controlled release;  Lipid microtubes;  NEP1-40;  PLGA microspheres


Document Type: Article
Source: Scopus




Cheng, Y.a , Mitchell-Flack, M.J.b , Wang, A.b , Levy, R.J.b
Carbon monoxide modulates cytochrome oxidase activity and oxidative stress in the developing murine brain during isoflurane exposure
(2015) Free Radical Biology and Medicine, 86, pp. 191-199. 

DOI: 10.1016/j.freeradbiomed.2015.05.029


a Children's National Medical Center, George Washington University, School of Medicine and Health Sciences, United States
b Department of Anesthesiology, College of Physicians, Columbia University, 622W. 168th Street, New York, NY, United States


Abstract
Commonly used anesthetics induce widespread neuronal degeneration in the developing mammalian brain via the oxidative-stress-associated mitochondrial apoptosis pathway. Dysregulation of cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, can result in reactive oxygen species (ROS) formation. Isoflurane has previously been shown to activate this enzyme. Carbon monoxide (CO), as a modulator of CcOX, is of interest because infants and children are routinely exposed to CO during low-flow anesthesia. We have recently demonstrated that low concentrations of CO limit and prevent isoflurane-induced neurotoxicity in the forebrains of newborn mice in a dose-dependent manner. However, the effect of CO on CcOX in the context of anesthetic-induced oxidative stress is unknown. Seven-day-old male CD-1 mice underwent 1 h exposure to 0 (air), 5, or 100 ppm CO in air with or without isoflurane. Exposure to isoflurane or CO independently increased CcOX kinetic activity and increased ROS within forebrain mitochondria. However, exposure to CO combined with isoflurane paradoxically limited CcOX activation and oxidative stress. There were no changes seen in steady-state levels of CcOX I protein, indicating post-translational modification of CcOX as an etiology for changes in enzyme activity. CO exposure led to differential effects on CcOX subunit I tyrosine phosphorylation depending on concentration, while combined exposure to isoflurane with CO markedly increased the enzyme phosphorylation state. Phosphorylation of tyrosine 304 of CcOX subunit I has been shown to result in strong enzyme inhibition, and the relative reduction in CcOX kinetics following exposure to CO combined with isoflurane may have been due, in part, to such phosphorylation. Taken together, the data suggest that CO modulates CcOX in the developing brain during isoflurane exposure, thereby limiting oxidative stress. These CO-mediated effects could have implications for the development of low-flow anesthesia in infants and children to prevent anesthesia-induced oxidative stress. © 2015 Elsevier Inc.


Author Keywords
Abbreviations CcOX Cytochrome oxidase;  CO Carbon monoxide;  ROS Reactive oxygen species


Document Type: Article
Source: Scopus




Dixon-Gordon, K.L.a , Whalen, D.J.b , Scott, L.N.c , Cummins, N.D.d , Stepp, S.D.c e
The Main and Interactive Effects of Maternal Interpersonal Emotion Regulation and Negative Affect on Adolescent Girls’ Borderline Personality Disorder Symptoms
(2015) Cognitive Therapy and Research, 13 p. Article in Press. 

DOI: 10.1007/s10608-015-9706-4


a Department of Psychological and Brain Sciences, University of Massachusetts Amherst, Amherst, MA, United States
b Department of Psychiatry, Washington University School of Medicine, Box 8511, St. Louis, MO, United States
c Department of Psychiatry, University of Pittsburgh Medical Center, 3811 O’Hara St., Pittsburgh, PA, United States
d Department of Psychology, University of Oregon, 1227 University of Oregon, Eugene, OR, United States
e Department of Psychology, University of Pittsburgh, 3811 O’Hara St., Pittsburgh, PA, United States


Abstract
The transaction of adolescent’s expressed negative affect and parental interpersonal emotion regulation are theoretically implicated in the development of borderline personality disorder (BPD). Although problem solving and support/validation are interpersonal strategies that foster emotion regulation, little is known about whether these strategies are associated with less BPD severity among adolescents. Adolescent girls (age 16; N = 74) and their mothers completed a conflict discussion task, and maternal problem solving, support/validation, and girls’ negative affect were coded. Girls’ BPD symptoms were assessed at four time points. A 3-way interaction of girls’ negative affect, problem solving, and support/validation indicated that girls’ negative affect was only associated with BPD severity in the context of low maternal support/validation and high maternal problem solving. These variables did not predict changes in BPD symptoms over time. Although high negative affect is a risk for BPD severity in adolescent girls, maternal interpersonal emotion regulation strategies moderate this link. Whereas maternal problem solving coupled with low support/validation is associated with a stronger negative affect-BPD relation, maternal problem solving paired with high support/validation is associated with an attenuated relationship. © 2015 Springer Science+Business Media New York


Author Keywords
Borderline personality disorder;  Interpersonal emotion regulation;  Mother–adolescent conflict;  Parenting


Document Type: Article in Press
Source: Scopus




Malmstrom, T.K.a b , Voss, V.B.c , Cruz-Oliver, D.M.b , Cummings-Vaughn, L.A.d e , Tumosa, N.d , Grossberg, G.T.a , Morley, J.E.b
The Rapid Cognitive Screen (RCS): A point-of-care screening for dementia and mild cognitive impairment
(2015) Journal of Nutrition, Health and Aging, 4 p. Article in Press. 

DOI: 10.1007/s12603-015-0564-2


a Department of Neurology & Psychiatry, School of Medicine, Saint Louis University, 1438 South Grand Boulevard, St. Louis, Missouri, United States
b Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, United States
c Saint Louis University School of Medicine, St. Louis, Missouri, United States
d Jefferson Barracks Division, Geriatric Research Education and Clinical Center, Veterans Affairs Saint Louis Health System, St. Louis, Missouri, United States
e Division of Geriatrics and Nutritional Science, Washington University in St. Louis, St. Louis, Missouri, United States


Abstract
Objectives: There is a need for a rapid screening test for mild cognitive impairment (MCI) and dementia to be used by primary care physicians. The Rapid Cognitive Screen (RCS) is a brief screening tool (< 3 min) for cognitive dysfunction. RCS includes 3-items from the Veterans Affairs Saint Louis University Mental Status (SLUMS) exam: recall, clock drawing, and insight. Study objectives were to: 1) examine the RCS sensitivity and specificity for MCI and dementia, 2) evaluate the RCS predictive validity for nursing home placement and mortality, and 3) compare the RCS to the clock drawing test (CDT) plus recall. Methods: Patients were recruited from the St. Louis, MO Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Medical Center (VAMC) hospitals (study 1) or the Saint Louis University Geriatric Medicine and Psychiatry outpatient clinics (study 2). Study 1 participants (N=702; ages 65–92) completed cognitive evaluations and 76% (n=533/706) were followed up to 7.5 years for nursing home placement and mortality. Receiver operator characteristic (ROC) curves were computed to determine sensitivity and specificity for MCI (n=180) and dementia (n=82). Logistic regressions were computed for nursing home placement (n=31) and mortality (n=176). Study 2 participants (N=168; ages 60–90) completed the RCS and SLUMS exam. ROC curves were computed to determine sensitivity and specificity for MCI (n=61) and dementia (n=74). Results: RCS predicted dementia and MCI in study 1 with optimal cutoff scores of ≤ 5 for dementia (sensitivity=0.89, specificity=0.94) and ≤ 7 for MCI (sensitivity=0.87, specificity=0.70). The CDT plus recall predicted dementia and MCI in study 1 with optimal cutoff scores of ≤ 2 for dementia (sensitivity=0.87, specificity=0.85) and ≤ 3 for MCI (sensitivity=0.62, specificity=0.62). Higher RCS scores were protective against nursing home placement and mortality. The RCS predicted dementia and MCI in study 2. Conclusions: The 3-item RCS exhibits good sensitivity and specificity for the detection of MCI and dementia, and higher cognitive function on the RCS is protective against nursing home placement and mortality. The RCS may be a useful screening instrument for the detection of cognitive dysfunction in the primary care setting. © 2015 Serdi and Springer-Verlag France


Document Type: Article in Press
Source: Scopus




McMillen, J.C.a , Narendorf, S.C.b , Robinson, D.c , Havlicek, J.d , Fedoravicius, N.e , Bertram, J.f , McNelly, D.g
Development and piloting of a treatment foster care program for older youth with psychiatric problems
(2015) Child and Adolescent Psychiatry and Mental Health, . Article in Press. 

DOI: 10.1186/s13034-015-0057-4


a School of Social Service Administration, University of Chicago, 969 E. 60th, Chicago, IL, 60636 USA
b Graduate College of Social Work, University of Houston, 110HA Social Work Building, Houston, TX, 77204 USA
c Washington University School of Medicine, Campus Box 1007, St. Louis, MO, 63105 USA
d School of Social Work, University of Illinois, 1010 W. Nevada Street, Urbana, IL, 61801 USA
e Research Consultant, Charlottesville, VA, USA
f St. Louis University School of Nursing, 3525 Caroline St, St. Louis, MO, 63104 USA
g Jackson County (Ohio) Board of Developmental Disabilities, 822 Sellars Drive, P.O. Box 607, Jackson, OH, 45640 USA


Abstract
Background: Older youth in out-of-home care often live in restrictive settings and face psychiatric issues without sufficient family support. This paper reports on the development and piloting of a manualized treatment foster care program designed to step down older youth with high psychiatric needs from residential programs to treatment foster care homes. Methods: A team of researchers and agency partners set out to develop a treatment foster care model for older youth based on Multi-dimensional Treatment Foster Care (MTFC). After matching youth by mental health condition and determining for whom randomization would be allowed, 14 youth were randomized to treatment as usual or a treatment foster home intervention. Stakeholders were interviewed qualitatively at multiple time points. Quantitative measures assessed mental health symptoms, days in locked facilities, employment and educational outcomes. Results: Development efforts led to substantial variations from the MTFC model and a new model, Treatment Foster Care for Older Youth was piloted. Feasibility monitoring suggested that it was difficult, but possible to recruit and randomize youth from and out of residential homes and that foster parents could be recruited to serve them. Qualitative data pointed to some qualified clinical successes. Stakeholders viewed two team roles - that of psychiatric nurse and skills coaches - very highly. However, results also suggested that foster parents and some staff did not tolerate the intervention well and struggled to address the emotion dysregulation issues of the young people they served. Quantitative data demonstrated that the intervention was not keeping youth out of locked facilities. Conclusions: The intervention needed further refinement prior to a broader trial. Intervention development work continued until components were developed to help address emotion regulation problems among fostered youth. Psychiatric nurses and skills coaches who work with youth in community settings hold promise as important supports for older youth with psychiatric needs. © 2015 McMillen et al.


Author Keywords
Emerging adulthood;  Emotion regulation;  Foster care;  Treatment foster care


Document Type: Article in Press
Source: Scopus




Boyer, P.a b c , Parren, N.c
Threat-related information suggests competence: A possible factor in the spread of rumors
(2015) PLoS ONE, 10 (6), art. no. e0128421, . 

DOI: 10.1371/journal.pone.0128421


a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Anthropology, Washington University in St. Louis, St. Louis, MO, United States
c University of Lyon, Lyon, France


Abstract
Information about potential danger is a central component of many rumors, urban legends, ritual prescriptions, religious prohibitions and witchcraft crazes. We investigate a potential factor in the cultural success of such material, namely that a source of threat-related information may be intuitively judged as more competent than a source that does not convey such information. In five studies, we asked participants to judge which of two sources of information, only one of which conveyed threat-related information, was more knowledgeable. Results suggest that mention of potential danger makes a source appear more competent than others, that the effect is not due to a general negativity bias, and that it concerns competence rather than a more generally positive evaluation of the source. © 2015 Boyer, Parren. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Document Type: Article
Source: Scopus




Izumi, Y., O’Dell, K.A., Zorumski, C.F.
Corticosterone enhances the potency of ethanol against hippocampal long-term potentiation via local neurosteroid synthesis
(2015) Frontiers in Cellular Neuroscience, 9 (JULY), art. no. 254, 8 p. 

DOI: 10.3389/fncel.2015.00254


Department of Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Corticosterone is known to accumulate in brain after various stressors including alcohol intoxication. Just as severe alcohol intoxication is typically required to impair memory formation only high concentrations of ethanol (60 mM) acutely inhibit longterm potentiation (LTP), a cellular memory mechanism, in naïve hippocampal slices. This LTP inhibition involves synthesis of neurosteroids, including allopregnanolone, and appears to involve a form of cellular stress. In the CA1 region of rat hippocampal slices, we examined whether a lower concentration of ethanol (20 mM) inhibits LTP in the presence of corticosterone, a stress-related modulator, and whether corticosterone stimulates local neurosteroid synthesis. Although low micromolar corticosterone alone did not inhibit LTP induction, we found that 20 mM ethanol inhibited LTP in the presence of corticosterone. At 20 mM, ethanol alone did not stimulate neurosteroid synthesis or inhibit LTP. LTP inhibition by corticosterone plus ethanol was blocked by finasteride, an inhibitor of 5α-reductase, suggesting a role for neurosteroid synthesis. We also found that corticosterone alone enhanced neurosteroid immunostaining in CA1 pyramidal neurons and that this immunostaining was further augmented by 20 mM ethanol. The enhanced neurosteroid staining was blocked by finasteride and the N-methyl-D-aspartate antagonist, 2-amino-5-phosphonovalerate (APV). These results indicate that corticosterone promotes neurosteroid synthesis in hippocampal pyramidal neurons and can participate in ethanol-mediated synaptic dysfunction even at moderate ethanol levels. These effects may contribute to the influence of stress on alcohol-induced cognitive impairment. ©2015Izumi,O’DellandZorumski.


Author Keywords
Allopregnanolone;  Binge drinking;  Blackout;  Corticosterone;  LTP;  Stress


Document Type: Article
Source: Scopus




Jeong, J.-W.a b , McCall, J.c d e , Shin, G.b , Zhang, Y.f g , Al-Hasani, R.c d , Kim, M.b , Li, S.b , Sim, J.Y.h , Jang, K.-I.b , Shi, Y.f i , Hong, D.Y.c , Liu, Y.b , Schmitz, G.P.c , Xia, L.c j , He, Z.f k , Gamble, P.l , Ray, W.Z.l , Huang, Y.f , Bruchas, M.R.c d e j , Rogers, J.A.b m n o
Wireless Optofluidic Systems for Programmable InVivo Pharmacology and Optogenetics
(2015) Cell, . Article in Press. 

DOI: 10.1016/j.cell.2015.06.058


a Department of Electrical, Computer, and Energy Engineering, University of Colorado, Boulder, CO 80309, USA
b Department of Materials Science and Engineering, Beckman Institute for Advanced Science and Technology and Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
c Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO 63110, USA
d Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
e Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
f Departments of Civil and Environmental Engineering and Mechanical Engineering, Center for Engineering and Health, Skin Disease Research Center, Northwestern University, Evanston, IL 60208, USA
g Center for Mechanics and Materials, Tsinghua University, Beijing 100084, China
h Bio-Medical IT Convergence Research Department, Electronics and Telecommunications Research Institute, Daejeon 305-700, Republic of Korea
i State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, China
j Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA
k School of Materials Science and Engineering, Harbin Institute of Technology, Harbin 150001, China
l Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA
m Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
n Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
o Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA


Abstract
Invivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (μ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine. Ultrathin, flexible optofluidic neural probes enable wireless delivery of agents and optical manipulation in deep brain tissue of freely behaving animals. Combinatorial optogenetic, pharmacological, and viral approaches yield a powerful tool for invivo dissection of neural circuitry. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Albersheim-Carter, J.a , Blubaum, A.a , Ballagh, I.H.b c , Missaghi, K.d e , Siuda, E.R.a , McMurray, G.a , Bass, A.H.c , Dubuc, R.d e , Kelley, D.B.b , Schmidt, M.F.f , Wilson, R.J.A.g , Gray, P.A.a
Testing the evolutionary conservation of vocal motoneurons in vertebrates
(2015) Respiratory Physiology and Neurobiology, . Article in Press. 

DOI: 10.1016/j.resp.2015.06.010


a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Biological Sciences, Columbia University, New York, NY 10027, USA
c Department of Neurobiology and Behavior, Cornell University, Ithaca, NY 14853, USA
d Department of Exercise Science, Faculté des Sciences, Université du Québec à Montréal, Montréal, Québec H3C 3P8, Canada
e Department of Neuroscience, Université de Montréal, Montréal, Québec H3C 3J7, Canada
f Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
g Hotchkiss Brain Institute and ACH Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N4N1, Canada


Abstract
Medullary motoneurons drive vocalization in many vertebrate lineages including fish, amphibians, birds, and mammals. The developmental history of vocal motoneuron populations in each of these lineages remains largely unknown. The highly conserved transcription factor Paired-like Homeobox 2b (Phox2b) is presumed to be expressed in all vertebrate hindbrain branchial motoneurons, including laryngeal motoneurons essential for vocalization in humans. We used immunohistochemistry and in situ hybridization to examine Phox2b protein and mRNA expression in caudal hindbrain and rostral spinal cord motoneuron populations in seven species across five chordate classes. Phox2b was present in motoneurons dedicated to sound production in mice and frogs (bullfrog, African clawed frog), but not those in bird (zebra finch) or bony fish (midshipman, channel catfish). Overall, the pattern of caudal medullary motoneuron Phox2b expression was conserved across vertebrates and similar to expression in sea lamprey. These observations suggest that motoneurons dedicated to sound production in vertebrates are not derived from a single developmentally or evolutionarily conserved progenitor pool. © 2015 Elsevier B.V.


Author Keywords
Hypoglossal;  Lamprey;  Midshipman;  Respiration;  Vocalization;  Zebra Finch


Document Type: Article in Press
Source: Scopus




Wolff, J.J.a , Gerig, G.b , Lewis, J.D.c , Soda, T.d e , Styner, M.A.e f , Vachet, C.b , Botteron, K.N.g , Elison, J.T.h , Dager, S.R.i , Estes, A.M.j , Hazlett, H.C.e f , Schultz, R.T.k , Zwaigenbaum, L.l , Piven, J.e f
Altered corpus callosum morphology associated with autism over the first 2 years of life
(2015) Brain, 138 (7), pp. 2046-2058. 

DOI: 10.1093/brain/awv118


a Department of Educational Psychology, University of Minnesota, 56 East River Road, Minneapolis, MN, United States
b Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
c Montreal Neurological Institute, McGill University, Montreal, QC, Canada
d Health Sciences and Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, United States
e Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
f Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
g Department of Psychiatry, Washington University at St. Louis, St. Louis, MO, United States
h Institute for Child Development, University of Minnesota, Minneapolis, MN, United States
i Department of Radiology, University of Washington, Seattle, WA, United States
j Department of Speech and Hearing Science, University of Washington, Seattle, WA, United States
k Centre for Autism Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States
l Department of Paediatrics, University of Alberta, Edmonton, AB, Canada


Abstract
Numerous brain imaging studies indicate that the corpus callosum is smaller in older children and adults with autism spectrum disorder. However, there are no published studies examining the morphological development of this connective pathway in infants at-risk for the disorder. Magnetic resonance imaging data were collected from 270 infants at high familial risk for autism spectrum disorder and 108 low-risk controls at 6, 12 and 24 months of age, with 83% of infants contributing two or more data points. Fifty-seven children met criteria for ASD based on clinical-best estimate diagnosis at age 2 years. Corpora callosa were measured for area, length and thickness by automated segmentation. We found significantly increased corpus callosum area and thickness in children with autism spectrum disorder starting at 6 months of age. These differences were particularly robust in the anterior corpus callosum at the 6 and 12 month time points. Regression analysis indicated that radial diffusivity in this region, measured by diffusion tensor imaging, inversely predicted thickness. Measures of area and thickness in the first year of life were correlated with repetitive behaviours at age 2 years. In contrast to work from older children and adults, our findings suggest that the corpus callosum may be larger in infants who go on to develop autism spectrum disorder. This result was apparent with or without adjustment for total brain volume. Although we did not see a significant interaction between group and age, cross-sectional data indicated that area and thickness differences diminish by age 2 years. Regression data incorporating diffusion tensor imaging suggest that microstructural properties of callosal white matter, which includes myelination and axon composition, may explain group differences in morphology. © 2015 The Author.


Author Keywords
autism;  brain development;  corpus callosum;  infants


Document Type: Article
Source: Scopus




Balsis, S.a , Cooper, L.D.a , Oltmanns, T.F.b
Are Informant Reports of Personality More Internally Consistent Than Self Reports of Personality?
(2015) Assessment, 22 (4), pp. 399-404. 

DOI: 10.1177/1073191114556100


a Texas A&M University, College Station, TX, United States
b Washington University in St. Louis, St. Louis, MO, United States


Abstract
The present study examined whether informant-reported personality was more or less internally consistent than self-reported personality in an epidemiological community sample (n = 1,449). Results indicated that across the 5 NEO (Neuroticism–Extraversion–Openness) personality factors and the 10 personality disorder trait dimensions, informant reports tended to be more internally consistent than self reports, as indicated by equal or higher Cronbach’s alpha scores and higher average interitem correlations. In addition, the informant reports collectively outperformed the self reports for predicting responses on a global measure of health, indicating that the informant reports are not only more reliable than self reports, but they can also be useful in predicting an external criterion. Collectively these findings indicate that informant reports tend to have greater internal consistency than self reports. © The Author(s) 2014.


Author Keywords
informant report;  internal consistency;  personality;  personality disorder;  reliability;  self report


Document Type: Article
Source: Scopus




Pineda, R.a , Melchior, K.b , Oberle, S.c , Inder, T.d , Rogers, C.e
Assessment of autism symptoms during the neonatal period: Is there early evidence of autism risk?
(2015) American Journal of Occupational Therapy, 69 (4), art. no. 6904220010, . 

DOI: 10.5014/ajot.2015.015925


a Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO, United States
b Program in Occupational Therapy, School of Medicine, Washington University, St. Louis, MO, United States
c Field of Newborn Medicine, Harvard Medical School, Boston, MA, United States
d Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, United States
e Departmentof Psychiatry and Pediatrics, School of Medicine, Washington University, St. Louis, MO, United States


Abstract
OBJECTIVE. To define neonatal social characteristics related to autism risk. METHOD. Sixty-two preterm infants underwent neonatal neurobehavioral testing. At age 2 yr, participants were assessed with the Modified Checklist for Autism in Toddlers and Bayley Scales of Infant and Toddler Development, 3rd edition. RESULTS. Positive autism screening was associated with absence of gaze aversion, X = 5.90, p = .01, odds ratio = 5.05, and absence of endpoint nystagmus, X = 4.78, p = .02, odds ratio = 8.47. Demonstrating gaze aversion was related to better language outcomes, t(55) = -3.07, p ≤ .003. Displaying endpoint nystagmus was related to better language outcomes, t(61) = -3.06, p = .003, cognitive outcomes, t(63) = -5.04, p < .001, and motor outcomes, t(62) = -2.82, p = .006. CONCLUSION. Atypical social interactions were not observed among infants who later screened positive for autism. Instead, the presence of gaze aversion and endpoint nystagmus was related to better developmental outcomes. Understanding early behaviors associated with autism may enable early identification and lead to timely therapy activation to improve function.

 


Document Type: Article
Source: Scopus

July 22, 2015 

Chaudhary, N.S.a b , Kampman, K.M.a c , Kranzler, H.R.a c , Grandner, M.A.a c , Debbarma, S.a d , Chakravorty, S.a c 
Insomnia in alcohol dependent subjects is associated with greater psychosocial problem severity
(2015) Addictive Behaviors, 50, pp. 165-172. 

DOI: 10.1016/j.addbeh.2015.06.021

a Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, United States
b Washington University in St. Louis, St. Louis, MO, United States
c Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States
d Thomas Jefferson University, Philadelphia, PA, United States

Abstract
Introduction: Although psychosocial problems are commonly associated with both alcohol misuse and insomnia, very little is known about the combined effects of insomnia and current alcohol dependence on the severity of psychosocial problems. The present study evaluates whether the co-occurrence of insomnia and alcohol dependence is associated with greater psychosocial problem severity. Methods: Alcohol dependent individuals (N. = 123) were evaluated prior to participation in a placebo-controlled medication trial. The Short Index of Problems (SIP), Addiction Severity Index (ASI), Insomnia Severity Index (ISI), and Time Line Follow Back (TLFB), were used to assess psychosocial, employment, and legal problems; insomnia symptoms; and alcohol consumption, respectively. Bivariate and multivariate analyses were used to evaluate the relations between insomnia and psychosocial problems. Results: Subjects' mean age was 44. years (SD. = 10.3), 83% were male, and their SIP sub-scale scores approximated the median for normative data. A quarter of subjects reported no insomnia; 29% reported mild insomnia; and 45% reported moderate-severe insomnia. The insomnia groups did not differ on alcohol consumption measures. The ISI total score was associated with the SIP total scale score (β. = 0.23, p. = 0.008). Subjects with moderate-severe insomnia had significantly higher scores on the SIP total score, and on the social and impulse control sub-scales, and more ASI employment problems and conflicts with their spouses than others on the ASI. Conclusion: In treatment-seeking alcohol dependent subjects, insomnia may increase alcohol-related adverse psychosocial consequences. Longitudinal studies are needed to clarify the relations between insomnia and psychosocial problems in these subjects. © 2015 Published by Elsevier Ltd.

Author Keywords
Alcoholism;  Insomnia and sleep and maintenance disorders;  Psychosocial factors

Document Type: Article
Source: Scopus
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Wallace, A.N.a , Vyhmeister, R.b , Viets, R.c , Whisenant, J.T.d , Chatterjee, A.R.a , Kansagra, A.P.a , Cross, D.T., IIIa , Moran, C.J.a , Derdeyn, C.P.a 
Quadrigeminal perimesencephalic subarachnoid hemorrhage
(2015) Clinical Neurology and Neurosurgery, 137, pp. 67-71. 

DOI: 10.1016/j.clineuro.2015.06.018

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Saint Louis, MO, United States
b Washington University School of Medicine, Saint Louis, MO, United States
c Sharp Grossmont Hospital, San Diego, CA, United States
d Texas Radiology Associates, Plano, TX, United States

Abstract
Objective A variant of perimesencephalic subarachnoid hemorrhage (PSAH) has been described characterized by blood centered in the quadrigeminal cistern and limited to the superior vermian and perimesencephalic cisterns. Herein, three cases of quadrigeminal PSAH are presented. Materials and methods Medical records of all patients who underwent digital subtraction angiography for evaluation of non-traumatic SAH between July 2002 and April 2012 were reviewed. Patients with anterior circulation aneurysms were excluded. Two blinded reviewers identified admission noncontrast CT scans with pretruncal and quadrigeminal patterns of PSAH. Results The total cohort included 106 patients: 53% (56/106) with one or more negative digital subtraction angiograms and 47% (50/106) with posterior circulation or posterior communicating artery aneurysms. Three patients with quadrigeminal PSAH were identified, two with nonaneurysmal SAH and one with a posterior circulation aneurysm. Seventeen patients (16%; 17/106) with pretruncal PSAH were identified, none of whom were found to have an aneurysm. The quadrigeminal pattern comprised 11% (2/19) of cases of pretruncal or quadrigeminal nonaneurysmal PSAH. Conclusion A small subset of patients with nonaneurysmal PSAH present with blood centered in the quadrigeminal cistern, and the etiology of this pattern may be similar to that of the classic pretruncal variant. However, patients with quadrigeminal PSAH must still undergo thorough vascular imaging, including at least two digital subtraction angiograms, to exclude a ruptured aneurysm. © 2015 Elsevier B.V. All rights reserved.

Author Keywords
Aneurysm;  Computed tomography angiography;  Digital subtraction angiography;  Nonaneurysmal subarachnoid hemorrhage;  Perimesencephalic subarachnoid hemorrhage;  Quadrigeminal perimesencephalic subarachnoid hemorrhage

Document Type: Article
Source: Scopus
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Luo, J.a , Feng, J.a , Liu, S.a , Walters, E.T.b , Hu, H.a 
Erratum to: Molecular and cellular mechanisms that initiate pain and itch
(2015) Cellular and Molecular Life Sciences, 2 p. Article in Press. 

DOI: 10.1007/s00018-015-1979-y

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

Document Type: Article in Press
Source: Scopus
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Kang, P.a , Raya, A.a , Zipfel, G.J.b , Dhar, R.a 
Factors Associated with Acute and Chronic Hydrocephalus in Nonaneurysmal Subarachnoid Hemorrhage
(2015) Neurocritical Care, 6 p. Article in Press. 

DOI: 10.1007/s12028-015-0152-7

a Neurocritical Care Section, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8111, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8057, St. Louis, MO, United States

Abstract
Background: Hydrocephalus requiring external ventricular drain (EVD) or shunt placement commonly complicates aneurysmal subarachnoid hemorrhage (SAH), but its frequency is not as well known for nonaneurysmal SAH (NA-SAH). Those with diffuse bleeding may have greater risk of hydrocephalus compared to those with a perimesencephalic pattern. We evaluated the frequency of hydrocephalus in NA-SAH and whether imaging factors could predict the need for EVD and shunting. Methods: We collected admission clinical and imaging variables for 105 NA-SAH patients, including bicaudate index (BI), Hijdra sum score (HSS), intraventricular hemorrhage (IVH) score, modified Fisher scale (mFS), and bleeding pattern. Hydrocephalus was categorized as acute (need for EVD) or chronic (shunt). We applied logistic regression to determine whether hydrocephalus risk was independently related to bleeding pattern or mediated through blood volume or ventriculomegaly. Results: Acute hydrocephalus was seen in 26 (25 %) patients but was more common with diffuse (15/28, 54 %) versus perimesencephalic (10/59, 17 %, p < 0.001) bleeding. Patients developing acute hydrocephalus had worse clinical grade and higher BI, HSS, and IVH scores. Adjusting the relationship between hydrocephalus and diffuse bleeding for HSS (but not BI) nullified this association. Nine (35 %) patients requiring EVD eventually required shunting for chronic hydrocephalus, which was associated with greater blood burden but not poor clinical grade. Conclusion: Acute hydrocephalus occurs in one-quarter of NA-SAH patients. The greater risk in diffuse bleeding appears to be mediated by greater cisternal blood volume but not by greater ventriculomegaly. Imaging characteristics may aid in anticipatory management of hydrocephalus in NA-SAH. © 2015 Springer Science+Business Media New York

Author Keywords
Angiogram negative;  External ventricular drain;  Hydrocephalus;  Nonaneurysmal;  Subarachnoid hemorrhage;  Ventriculoperitoneal shunt

Document Type: Article in Press
Source: Scopus
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Araujo, G.C.a b , Mandoske, V.R.a , White, D.A.a 
Response monitoring during typical development
(2015) Cognitive Development, 35, pp. 151-162. 

DOI: 10.1016/j.cogdev.2015.05.002

a Department of Psychology, Washington University, One Brookings Drive, Campus Box 1125, St. Louis, MO, United States
b Department of Psychology, Saint Louis Children's Hospital, One Children's Place, St. Louis, MO, United States

Abstract
This study was conducted to gain a more comprehensive understanding of the normative development of response monitoring. We examined response monitoring under both relatively simple and more cognitively demanding conditions by measuring behavioral modifications that occurred in the presence of error and conflict. Eighty-nine participants between 4 and 24 years of age were administered two tasks (i.e., Simon and go/no-go). Data were analyzed using t-tests and hierarchical regression. We found that children (4-10 years of age), adolescents (11-17 years of age), and young adults (18-24 years of age) demonstrated significant reaction time slowing in the presence of either error or conflict, and that the magnitude of the slowing in these relatively simple conditions decreased with age. Under more cognitively demanding task conditions, adolescents and young adults demonstrated additional slowing beyond what they exhibited when task conditions were relatively simple. In contrast, children did not show any additional slowing in response to more cognitively demanding task conditions. The findings suggest that older individuals more efficiently modify their behavior in response to subtle changes in task demands. © 2015.

Author Keywords
Development;  Executive functioning;  Response monitoring

Document Type: Article
Source: Scopus
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Ong, C.J.a , Keyrouz, S.G.b , Diringer, M.N.b 
The Role of Osmotic Therapy in Hemispheric Stroke
(2015) Neurocritical Care, 7 p. Article in Press. 

DOI: 10.1007/s12028-015-0173-2

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

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

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

Document Type: Article in Press
Source: Scopus
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Meyerson, C., Van Stavern, G., McClelland, C.
Leber hereditary optic neuropathy: Current perspectives
(2015) Clinical Ophthalmology, 9, pp. 1165-1176. 

DOI: 10.2147/OPTH.S62021

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

Abstract
Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. © 2015 Meyerson et al.

Author Keywords
Leber hereditary optic neuropathy;  Mitochondria;  Mitochondrial DNA;  Neuro-ophthalmology

Document Type: Article
Source: Scopus
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Illes-Toth, E.a c , Ramos, M.R.a , Cappai, R.b , Dalton, C.a , Smith, D.P.a 
Distinct higher-order α -synuclein oligomers induce intracellular aggregation
(2015) Biochemical Journal, 468 (3), pp. 485-493. 

DOI: 10.1042/BJ20150159

a Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield, United Kingdom
b Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, University of MelbourneVIC, Australia
c Department of Biomedical Engineering, School of Engineering and Applied Science, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO, United States

Abstract
Misfolding and aggregation of α -synuclein (α -syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α -syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α -syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomerswere shownto be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases. © The Authors Journal compilation © 2015 Biochemical Society.

Author Keywords
Aggregation;  Amyloid;  Ionmobility;  Mass spectrometry (ms);  Oligomer;  α -synuclein

Document Type: Article
Source: Scopus
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Bland, M.D.a , Whitson, M.b , Harris, H.c , Edmiaston, J.d , Connor, L.T.e , Fucetola, R.f , Carter, A.g , Corbetta, M.h , Lang, C.E.i 
Descriptive data analysis examining how standardized assessments are used to guide post-acute discharge recommendations for rehabilitation services after stroke
(2015) Physical therapy, 95 (5), pp. 710-719. 

DOI: 10.2522/ptj.20140347

a M.D. Bland, PT, DPT, NCS, MSCI, Program in Physical Therapy, Department of Neurology, and Program in Occupational Therapy, Washington University. Mailing address: Program in Physical Therapy, Washington University, 4444 Forest Park, Campus Box 8502, St Louis, MO 63108 (USA). blandm@wusm.wustl.edu
b M. Whitson, PT, MHS, MA, MBA, Barnes Jewish Hospital Rehabilitation Services, St Louis, Missouri
c H. Harris, MSPT, Barnes Jewish Hospital Rehabilitation Services
d J. Edmiaston, MS, CCC-SLP, Barnes Jewish Hospital Rehabilitation Services
e L.T. Connor, PhD, MSOT, Department of Occupational Therapy, MGH Institute of Health Professions, Boston, Massachusetts
f R. Fucetola, PhD, Department of Neurology, Washington University
g A. Carter, MD, PhD, Department of Neurology, Washington University
h M. Corbetta, MD, Department of Neurology and Department of Radiology, Washington University
i C.E. Lang, PT, PhD, Program in Physical Therapy, Department of Neurology, and Program in Occupational Therapy, Washington University

Abstract
BACKGROUND: Use of standardized assessments in acute rehabilitation is continuing to grow, a key objective being to assist clinicians in determining services needed postdischarge.

OBJECTIVE: The purpose of this study was to examine how standardized assessment scores from initial acute care physical therapist and occupational therapist evaluations contribute to discharge recommendations for poststroke rehabilitation services.

DESIGN: A descriptive analysis was conducted.

METHODS: A total of 2,738 records of patients admitted to an acute care hospital with a diagnosis of stroke or transient ischemic attack were identified. Participants received an initial physical therapist and occupational therapist evaluation with standardized assessments and a discharge recommendation of home with no services, home with services, inpatient rehabilitation facility (IRF), or skilled nursing facility (SNF). A K-means clustering algorithm determined if it was feasible to categorize participants into the 4 groups based on their assessment scores. These results were compared with the physical therapist and occupational therapist discharge recommendations to determine if assessment scores guided postacute care recommendations.

RESULTS: Participants could be separated into 4 clusters (A, B, C, and D) based on assessment scores. Cluster A was the least impaired, followed by clusters B, C, and D. In cluster A, 50% of the participants were recommended for discharge to home without services, whereas 1% were recommended for discharge to an SNF. Clusters B, C, and D each had a large proportion of individuals recommended for discharge to an IRF (74%-80%). There was a difference in percentage of recommendations across the clusters that was largely driven by the differences between cluster A and clusters B, C, and D.

LIMITATIONS: Additional unknown factors may have influenced the discharge recommendations.

CONCLUSIONS: Participants poststroke can be classified into meaningful groups based on assessment scores from their initial physical therapist and occupational therapist evaluations. These assessment scores, in part, guide poststroke acute care discharge recommendations. © 2015 American Physical Therapy Association.

Document Type: Article
Source: Scopus
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Stowe, J.D.a , Cooney, T.M.e , Bonne, S.a , Meuser, T.M.b , Berg-Weger, M.c , Schmidt, N.d , Coughenour, J.d 
A randomized crash injury prevention trial of transitioning high-risk elders from driving
(2015) Journal of Trauma and Acute Care Surgery, 79 (1), pp. 132-137. 

DOI: 10.1097/TA.0000000000000690

a Washington University, School of Medicine, Campus Box 8303, 660 S Euclid Ave, St. Louis, MO, United States
b University of Missouri-St. Louis, St. Louis, MO, United States
c Saint Louis University, St. Louis, MO, United States
d University of Missouri, Columbia, MO, United States
e University of Colorado Denver, Denver, CO, United States

Abstract
BACKGROUND: Older adults with medical conditions that impair function are at risk for experiencing a motor vehicle crash. This randomized controlled trial tested an intervention to reduce crash-related risk among older patients. METHODS: A 2-to-1 allocation ratio resulted in comparisons between 26 intervention and 13 attention control (n = 39) group members who were recruited from inpatient and outpatient settings. The intervention consisted of two sessions of facilitated planning in which participants' health, transportation alternatives, attitudes/emotions regarding a change in mobility, and actions to ensure continued safe mobility were discussed. Moreover, all participants received supportive telephone calls during the 6-month intervention period. RESULTS: Results showed that when compared with the control group, the intervention group had significantly better subjective health, had fewer high-risk driving behaviors, and drove less distance on excursions from home at follow-up. Yet, simple repeated-measures analyses were not significant. CONCLUSION: Results suggest that facilitated planning may help ease the transition to driving retirement among some high-risk older patients. Larger samples and longer study duration are needed to confirm these effects and to measure direct crash and injury outcomes. A significant proportion of high-risk patients do not plan for driving retirement and remain a crash risk. LEVEL OF EVIDENCE: Therapeutic/care management study, level III. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
geriatric trauma;  Injury prevention;  motor vehicle crash;  older adult

Document Type: Article
Source: Scopus
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Sun, W.-L.a , Eisenstein, S.A.b , Zelek-Molik, A.c , McGinty, J.F.a 
A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal
(2015) International Journal of Neuropsychopharmacology, 18 (1), art. no. pyu049, . 

DOI: 10.1093/ijnp/pyu049

a Department of Neurosciences and Neurobiology, Addiction Research Center, Medical University of South Carolina, 173 Ashley Ave MSC 510, Charleston, SC, United States
b Department of Psychiatry, Washington University, St Louis, MO, United States
c Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland

Abstract
Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaineseeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine selfadministration- induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. © The Author 2014. Published by Oxford University Press on behalf of CINP.

Author Keywords
Cocaine self-administration;  Immunoblotting;  Nucleus accumbens;  Phosphatase;  Synapsin

Document Type: Article
Source: Scopus
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Luking, K.R., Pagliaccio, D., Luby, J.L., Barch, D.M.
Child Gain Approach and Loss Avoidance Behavior: Relationships With Depression Risk, Negative Mood, andAnhedonia
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.05.010

Neuroscience Program at Washington University in St. Louis

Abstract
Objective: Reduced reward responsiveness and altered response to loss of reward are observed in adults with major depressive disorder (MDD) and adolescents at increased risk for MDD based on family history. However, it is unclear whether altered behavioral responsiveness to reward/loss is a lifelong marker of MDD risk, which is evident before the normative adolescent increase in incentive responding. Method: Healthy 7- to 10-year-old children of mothers with MDD (high risk: n= 27) or without MDD (low risk: n= 42) performed 2 signal detection tasks assessing response bias toward reward (approach) and away from loss (avoidance). Differences in approach/avoidance were related to MDD risk, child general depressive symptoms (maternal report), child-reported anhedonic symptoms, and child-reported negative mood symptoms via repeated-measures analysis of variance. Results: MDD risk did not significantly relate to gain approach or loss avoidance. However, within high-risk children, higher numbers of maternal depressive episodes predicted blunted loss avoidance. Blunted gain approach was related to elevated anhedonic symptoms, whereas enhanced loss avoidance was related to elevated negative mood. Elevated negative mood was further related to blunted gain approach in high-risk children but related to enhanced gain approach in low-risk children. Conclusion: In children, individual differences in specific depressive symptoms and recurrence of maternal depression significantly predicted gain approach/loss avoidance, but the presence/absence of maternal MDD did not. Child depressive symptoms characterized by low positive affect (anhedonia) were related to blunted gain responsiveness, whereas elevated depressed/negative mood was related to enhanced loss responsiveness. Findings suggest that relations between gain approach and negative mood may be an important distinction between those at high versus low risk for MDD. © 2015 American Academy of Child and Adolescent Psychiatry.

Author Keywords
Anhedonia;  Depression risk;  Punishment;  Reward

Document Type: Article in Press
Source: Scopus
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Kubanek, J.a b , Hill, J.c , Snyder, L.H.a b , Schalk, G.c 
Cortical alpha activity reflects the degree of confidence in committing to an action
(2015) Frontiers in Neuroscience, 9 (JUN), art. no. 243, . 

DOI: 10.3389/fnins.2015.00243

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Wadsworth Center, New York State Department of Health, Albany, NY, United States

Abstract
When we make a decision, we experience a degree of confidence that our choice may lead to a desirable outcome. Recent studies in animals have probed the subjective aspects of the choice confidence using confidence-reporting tasks. These studies showed that estimates of the choice confidence substantially modulate neural activity in multiple regions of the brain. Building on these findings, we investigated the neural representation of the confidence in a choice in humans who explicitly reported the confidence in their choice. Subjects performed a perceptual decision task in which they decided between choosing a button press or a saccade while we recorded EEG activity. Following each choice, subjects indicated whether they were sure or unsure about the choice. We found that alpha activity strongly encodes a subject's confidence level in a forthcoming button press choice. The neural effect of the subjects' confidence was independent of the reaction time, of eye movement, and of activity of forearm muscles. Furthermore, the effect was not explained by the sensory input modeled by a decision variable. Neither could the effect be explained by a general cognitive state, such as arousal or reward expectation, because the effect was specifically observed during button press choices and not during saccade choices. The neural effect of the confidence in the ensuing button press choice was strong enough that we could predict, from independent single trial neural signals, whether a subject was going to be sure or unsure of its button press choice. In sum, alpha activity in human cortex provides a window into the degree of a forming commitment to make a hand movement. © 2015 Kubanek, Hill, Snyder and Schalk.

Author Keywords
Certainty;  EEG;  Human;  Neural correlates;  Perceptual decision-making

Document Type: Article
Source: Scopus
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Petsiti, A.a , Tassoudis, V.a , Vretzakis, G.a , Zacharoulis, D.b , Tepetes, K.b , Ganeli, G.a , Karanikolas, M.c 
Depth of anesthesia as a risk factor for perioperative morbidity
(2015) Anesthesiology Research and Practice, 2015, art. no. 829151, . 

DOI: 10.1155/2015/829151

a Department of Anesthesiology, University of Larissa, Larissa, Greece
b Department of Surgery, University of Larissa, Larissa, Greece
c Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, United States

Abstract
Introduction. The prognostic value of age, physical status, and duration of surgery on perioperative course has been extensively studied. However, the impact of deep hypnotic time (time when Bispectral Index values are less than 40) has not been well evaluated. Methods. We designed an observational study to clarify the relative influence of deep hypnotic time (DHT) on outcome. Eligible participants were mentally stable patients over 18 years old scheduled for elective major abdominal surgery. In total, 248 patients enrolled. Data were analyzed using Fisher's exact test and multiple logistic regression. Results. Five variables (DHT, hypotension, age, comorbidity, and duration of surgery) showed statistically significant association with complications, when examined independently. However, when all variables were examined together in a multiple logistic regression model, age and comorbidity were no longer associated with outcome. DHT, hypotension, and duration of surgery were significant predictors of "complications," and "hypotension" was a significant predictor of prolonged hospital stay (P < 0.001). Conclusion. Deep hypnotic time emerged as a new factor associated with outcome, and its impact compared to other factors such as age, surgery duration, hypotension, and comorbidity is redefined. Monitoring and managing depth of anesthesia during surgery are important and should be part of careful operation planning. © 2015 Argyro Petsiti et al.

Document Type: Article
Source: Scopus
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Spehar, B.a , Tye-Murray, N.a b 
Effects of context type on lipreading and listening performance and implications for sentence processing
(2015) Journal of Speech, Language, and Hearing Research, 58 (3), pp. 1093-1102. 

DOI: 10.1044/2015_JSLHR-H-14-0360

a Washington University in St. Louis School of Medicine, United States
b Children’s Healthcare of AtlantaGA, United States

Abstract
Purpose: This study compared the use of 2 different types of contextual cues (sentence based and situation based) in 2 different modalities (visual only and auditory only). Method: Twenty young adults were tested with the Illustrated Sentence Test (Tye-Murray, Hale, Spehar, Myerson, & Sommers, 2014) and the Speech Perception in Noise Test (Bilger, Nuetzel, Rabinowitz, & Rzeczkowski, 1984; Kalikow, Stevens, & Elliott, 1977) in the 2 modalities. The Illustrated Sentences Test presents sentences with no context and sentences accompanied by picture-based situational context cues. The Speech Perception in Noise Test presents sentences with low sentence-based context and sentences with high sentence-based context. Results: Participants benefited from both types of context and received more benefit when testing occurred in the visual-only modality than when it occurred in the auditory-only modality. Participants’ use of sentencebased context did not correlate with use of situation based context. Cue usage did not correlate between the 2 modalities. Conclusions: The ability to use contextual cues appears to be dependent on the type of cue and the presentation modality of the target word(s). In a theoretical sense, the results suggest that models of word recognition and sentence processing should incorporate the influence of multiple sources of information and recognize that the 2 types of context have different influences on speech perception. In a clinical sense, the results suggest that aural rehabilitation programs might provide training to optimize use of both kinds of contextual cues. © 2015 American Speech-Language-Hearing Association

Document Type: Article
Source: Scopus
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Checkoway, H.a , Nielsen, S.S.b , Racette, B.A.c 
Epidemiological studies of parkinsonism in welders
(2015) Issues in Toxicology, 2015-January (22), pp. 513-523. 

a Department of Family and Preventive Medicine, University of California, San Diego, CA, United States
b Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States
c Department of Neurology, Washington University, St. Louis, MO, United States

Document Type: Article
Source: Scopus
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Drake, A.B.a , Milne, W.K.b , Carpenter, C.R.c 
Hot Off the Press: Subdissociative-dose Ketamine for Acute Pain in the Emergency Department
(2015) Academic Emergency Medicine, . Article in Press. 

DOI: 10.1111/acem.12705

a Department of Emergency Medicine Mount Sinai at St. Luke's-Roosevelt Hospital New York City, NY
b Division of Emergency Medicine Western University London, Ontario Canada
c Department of Emergency Medicine Washington University in St. Louis School of Medicine St. Louis, MO

Document Type: Article in Press
Source: Scopus
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Dydak, U.a b , Criswell, S.R.c d 
Imaging modalities for manganese toxicity
(2015) Issues in Toxicology, 2015-January (22), pp. 477-512. 

a School of Health Sciences, 550 Stadium Mall Drive, Purdue University, West Lafayette, IN, United States
b Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d American Parkinson Disease Association Advanced Center for Parkinson Research, St. Louis, MO, United States

Document Type: Article
Source: Scopus
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Cairns, N.J.a b c , Perrin, R.J.a c , Franklin, E.E.a b , Carter, D.a c , Vincent, B.a c , Xie, M.a b , Bateman, R.J.a b , Benzinger, T.a d , Friedrichsen, K.d , Brooks, W.S.f g , Halliday, G.M.f g , Mclean, C.h , Ghetti, B.e , Morris, J.C.a b c 
Neuropathologic assessment of participants in two multi-center longitudinal observational studies: The Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)
(2015) Neuropathology, 35 (4), pp. 390-400. 

DOI: 10.1111/neup.12205

a Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
f Neuroscience Research Australia, Sydney, NSW, Australia
g Department of Medicine, University of New South Wales, Sydney, NSW, Australia
h Florey Institute of Neuroscience and Mental Health, University of MelbourneVIC, Australia

Abstract
It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (eight), Australia (three), UK (one) and Germany (two). By 2014, 41 ADNI and 24 DIAN autopsies (involving nine participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final "gold standard" neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared. © 2015 Japanese Society of Neuropathology.

Author Keywords
Autosomal dominant Alzheimer disease;  Late-onset Alzheimer disease;  Neuropathologic diagnostic criteria;  Neuropathologic heat map;  PET-PiB amyloid imaging

Document Type: Article
Source: Scopus
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Grant, J.D.a , Waldron, M.a b , Sartor, C.E.a c , Scherrer, J.F.d , Duncan, A.E.a e , Mccutcheon, V.a , Haber, J.R.f , Jacob, T.f , Heath, A.C.a , Bucholz, K.a 
Parental Separation and Offspring Alcohol Involvement: Findings from Offspring of Alcoholic and Drug Dependent Twin Fathers
(2015) Alcoholism: Clinical and Experimental Research, 39 (7), pp. 1166-1173. 

DOI: 10.1111/acer.12766

a Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MI, United States
b Department of Counseling and Educational Psychology, Indiana University School of Education, Bloomington, IN, United States
c Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
d Department of Family and Community Medicine, Saint Louis University, St. Louis, MI, United States
e George Warren Brown School of Social Work, Washington University, St. Louis, MI, United States
f Palo Alto Department of Veterans Affairs Medical Center, Palo Alto, CA, United States

Abstract
Background: We examined associations between parental separation during childhood and offspring alcohol involvement, adjusting for genetic and environmental risks specific to parental alcohol (AD) and cannabis/other illicit drug dependence (DD). Methods: The sample consisted of 1,828 offspring of male twins from the Vietnam Era Twin (VET) Registry, who completed a telephone diagnostic interview. Cox proportional hazards regression analyses were conducted predicting onset of first use, transition from first use to first AD symptom, and transition from first use to AD diagnosis from paternal and avuncular AD and DD history, parental separation, and offspring and family background characteristics. Paternal/avuncular DD/AD was based on the DSM-III-R; offspring and maternal AD were based on DSM-IV criteria. Results: Paternal DD/AD predicted increased offspring risk for all transitions, with genetic effects suggested on rate of transitioning to AD diagnosis. Parental separation was predictive of increased risk for early alcohol use, but a reduced rate of transition to both AD symptom onset and onset of AD. No interactions between separation and familial risk (indexed by paternal or avuncular DD/AD) were found. Conclusions: Findings highlight the contribution of both parental separation and paternal substance dependence in predicting timing of offspring alcohol initiation and problems across adolescence into early adulthood. © 2015 by the Research Society on Alcoholism.

Author Keywords
Alcohol Involvement;  Offspring of Twins;  Parental Alcohol Dependence;  Parental Drug Dependence;  Parental Separation or Divorce

Document Type: Article
Source: Scopus
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Park, A.M.a , Patil, R.D.a b , Paniello, R.C.a 
Prevention of post-traumatic reinnervation with microtubule inhibitors
(2015) Laryngoscope, . Article in Press. 

DOI: 10.1002/lary.25258

a Department of Otolaryngology-Head and Neck Surgery at the Washington University School of MedicineSt. Louis, MO, and the St. Louis V.A. Medical CenterSt. Louis, Missouri U.S.A
b Department of OtolaryngologyUniversity of CincinnatiCincinnati, Ohio U.S.A

Abstract
Objectives/Hypothesis: Functional recovery after a recurrent laryngeal nerve or facial nerve injury may be impaired due to aberrant reinnervation. Previous work in a rat peripheral nerve injury model found vincristine to be a potent inhibitor of reinnervation, and it has since been used to effectively block neural regeneration in other animal models. However, vincristine's narrow therapeutic index may limit its utility; therefore, another microtubule inhibitor, paclitaxel, which has a higher therapeutic index, was tested. Study Design: Animal (rat) study. Methods: After controlled injury to the rat posterior tibial (PT) nerve, the gastrocnemius/soleus complex was injected with saline (control, n=14), vincristine (n=30), or paclitaxel (n=20). Injections without a crush injury were performed using saline (n=5) or paclitaxel (n=9). The functional recovery (FR) of the PT nerve was assessed using walking track analysis. Results: At 6 weeks, controls had already recovered to baseline (FR=1.0), whereas the paclitaxel group had FR=0.724±0.064 and the vincristine group had FR=0.709±0.078. At 6 months, the paclitaxel rats had FR=0.798±0.167 and the vincristine rats had FR=0.754±0.240. These differences were significantly different from baseline, but the two agents were not different from each other. Paclitaxel did not affect the FR in the absence of a nerve injury. Conclusions: Intramuscular paclitaxel and vincristine both significantly inhibit regeneration of the PT nerve after crush injury for at least 6 months. Potential clinical uses of inhibition of reinnervation are discussed. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
Laryngeal nerve;  Larynx;  Neural regeneration;  Neurotoxin;  Paclitaxel;  Unilateral vocal fold paralysis;  Vincristine

Document Type: Article in Press
Source: Scopus
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Oeding, K., Valente, M.
The effect of a high upper input limiting level on word recognition in noise, sound quality preferences, and subjective ratings of real-world performance
(2015) Journal of the American Academy of Audiology, 26 (6), pp. 547-562. 

DOI: 10.3766/jaaa.14051

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

Abstract
Background: One important factor that plays a role in front-end processing is the analog-to-digital converter within current hearing aids. The average input dynamic range of hearing aids is 96 dB SPL with an upper input limiting level (UILL) of 95-105 dB SPL. The UILL of standard hearing aids could distort loud signals, such as loud speech or music, which have root-mean-square values of 90 and 105 dB SPL with crest factors of 12 dB SPL to 14-20 dB SPL, respectively. This indicates that these loud sounds could create a distorted signal for patients when the input limiting level is reached. Purpose: To examine if significant differences in word recognition in noise, sound quality preferences, and subjective ratings of real-world performance exist between conventional and high UILL hearing aids. Research Design: Words in noise and sound quality preferences were assessed using recordings on a Knowles Electronic Manikin for Acoustic Research with conventional and high UILL hearing aids, different microphone modes, and listening conditions. Participants wore the hearing aids for 2 mo and completed questionnaires on subjective performance. Study Sample: Ten adults with bilateral slight to moderately severe sensorineural hearing loss were recruited. Results: A four-factor repeated-measures analysis of variance (ANOVA) revealed significant differences between the conventional and high UILL across microphone modes and listening conditions for words in noise [F<inf>(2, 18)</inf> = 6.0; p < 0.05]. A three-factor repeated-measures ANOVA for sound quality preferences revealed a significant difference only for presentation level [F<inf>(1, 9)</inf> = 81.0; p < 0.001]. A one-factor ANOVA did not reveal significant differences between the conventional and high UILL on subjective ratings of real-world performance. Conclusions: Word recognition and sound quality preferences revealed significant differences between the conventional and high UILL; however, there were no differences in subjective ratings of real-world performance. One participant preferred the conventional UILL, two the high UILL, and seven thought performance was equal, which may be due to the listening environments participants encountered, as evidenced by datalogging. © 2015, American Academy of Audiology. All rights reserved.

Author Keywords
Analog-to-digital converter;  Hearing aid;  Sound quality;  Speech recognition;  Upper input limiting level

Document Type: Article
Source: Scopus
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Andrich, K.a b , Bieschke, J.a 
The effect of (-)-epigallo-catechin-(3)-gallate on amyloidogenic proteins suggests a common mechanism
(2015) Advances in Experimental Medicine and Biology, 863, pp. 139-161. 

DOI: 10.1007/978-3-319-18365-7_7

a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
b Max Delbrück Center for Molecular Medicine, Berlin, Germany

Abstract
Studies on the interaction of the green tea polyphenol (-)- Epigallocatechin-3-gallate (EGCG) with fourteen disease-related amyloid polypeptides and prions Huntingtin, Amyloid-beta, alpha-Synuclein, islet amyloid polypeptide (IAPP), Sup35, NM25 and NM4, tau, MSP2, semen-derived enhancer of virus infection (SEVI), immunoglobulin light chains, beta-microglobulin, prion protein (PrP) and Insulin, have yielded a variety of experimental observations. Here, we analyze whether these observations could be explained by a common mechanism and give a broad overview of the published experimental data on the actions of EGCG. Firstly, we look at the influence of EGCG on aggregate toxicity, morphology, seeding competence, stability and conformational changes. Secondly, we screened publications elucidating the biochemical mechanism of EGCG intervention, notably the effect of EGCG on aggregation kinetics, oligomeric aggregation intermediates, and its binding mode to polypeptides. We hypothesize that the experimental results may be reconciled in a common mechanism, in which EGCG binds to cross-beta sheet aggregation intermediates. The relative position of these species in the energy profile of the amyloid cascade would determine the net effect of EGCG on aggregation and disaggregation of amyloid fibrils. © Springer International Publishing Switzerland 2015.

Author Keywords
Aggregation;  Amyloid polypeptides;  Epigallocathechin-3-gallate (EGCG);  Fibrils

Document Type: Article
Source: Scopus
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Razafsky, D.a , Wirtz, D.b , Hodzic, D.a 
Nuclear envelope in nuclear positioning and cell migration
(2014) Advances in Experimental Medicine and Biology, 773, pp. 471-490. 

DOI: 10.1007/978-1-4899-8032-8_21

a Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
b Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles St., Baltimore MD 21218, United States

Abstract
Hauling and anchoring the nucleus within immobile or motile cells, tissues, and/or syncytia represents a major challenge. In the past 15 years, Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) have emerged as evolutionary-conserved molecular devices that span the nuclear envelope and provide interacting interfaces for cytoskeletal networks and molecular motors to the nuclear envelope. Here, we review the molecular composition of LINC complexes and focus on how their genetic alteration in vivo has provided a wealth of information related to the relevance of nuclear positioning during tissue development and homeostasis with a special emphasis on the central nervous system. As it may be relevant for metastasis in a range of cancers, the involvement of LINC complexes in migration of nonneuronal cells via its interaction with the perinuclear actin cap will also be developed. © 2014 Springer Science+Business Media New York.

Author Keywords
Actin cap;  Cell motility;  Interkinetic nuclear migration;  KASH domain;  LINC complexes;  Nesprin;  Neuronal migration;  Nuclear anchorage;  Nuclear lamina;  Retina;  Skeletal muscle;  SUN domain;  Sun protein

Document Type: Article
Source: Scopus

July 14, 2015

Documents



Sundaram, G.S.M.a b , Dhavale, D.d , Prior, J.L.a b , Sivapackiam, J.a b , Laforest, R.b , Kotzbauer, P.d , Sharma, V.a b c d
Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer’s disease
(2015) EJNMMI Research, 5 (1), art. no. 33, 13 p. 

DOI: 10.1186/s13550-015-0112-4

a ICCE Institute, Molecular Imaging Center, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, United States
c Department of Biomedical Engineering, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, United States

Abstract
Background: PET radiopharmaceuticals capable of imaging β-amyloid (Aβ) plaque burden in the brain could offer highly valuable diagnostic tools for clinical studies of Alzheimer’s disease. To further supplement existing armamentarium of FDA-approved agents as well as those under development, and to correlate multiphoton-imaging data reported earlier, herein, we describe preclinical validation of a PET tracer. Methods: A novel PET radiopharmaceutical (18F-7B) was synthesized and characterized. To assess its affinity for Aβ, binding assays with Aβ<inf>1-42</inf> fibrils, Alzheimer’s disease (AD) homogenates, and autoradiography studies and their IHC correlations were performed. For assessing its overall pharmacokinetic profiles in general and its ability to cross the blood-brain barrier (BBB) in particular, biodistribution studies in normal mice were performed. Finally, for evaluating potential for 18F-7B to serve as a targeted Aβ probe, the microPET/CT imaging was performed in age-matched amyloid precursor protein/presenilin-1 (APP/PS1) mice and wild-type (WT) counterparts. Results: The radiotracer 18F-7B shows saturable binding to autopsy-confirmed AD homogenates (K<inf>d</inf> = 17.7 nM) and Aβ<inf>1-42</inf> fibrils (K<inf>d</inf> = 61 nM). Preliminary autoradiography studies show binding of 18F-7B to cortical Aβ plaques in autopsy-confirmed AD tissue sections, inhibition of that binding by unlabeled counterpart 7A-indicating specificity, and a good correlation of tracer binding with Aβ immunostaining. The agent indicates high initial penetration into brains (7.23 ± 0.47%ID/g; 5 min) of normal mice, thus indicating a 5-min/120-min brain uptake clearance ratio of 4.7, a benchmark value (>4) consistent with the ability of agents to traverse the BBB to enable PET brain imaging. Additionally, 18F-7B demonstrates the presence of parental species in human serum. Preliminary microPET/CT imaging demonstrates significantly higher retention of 18F-7B in brains of transgenic mice compared with their WT counterparts, consistent with expected binding of the radiotracer to Aβ plaques, present in APP/PS1 mice, compared with their age-matched WT counterparts lacking those Aβ aggregates. Conclusions: These data offer a platform scaffold conducive to further optimization for developing new PET tracers to study Aβ pathophysiology in vitro and in vivo. © 2015, Sundaram et al.

Author Keywords
Alzheimer’s disease;  PET imaging;  Radiopharmaceuticals;  β-amyloid (Aβ)


Document Type: Article
Source: Scopus



Li, B.-W., Rush, A.C., Weil, G.J.
Expression of five acetylcholine receptor subunit genes in Brugia malayi adult worms
(2015) International Journal for Parasitology: Drugs and Drug Resistance, 5 (3), pp. 100-109. 

DOI: 10.1016/j.ijpddr.2015.04.003

Infectious Diseases Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Acetylcholine receptors (AChRs) are required for body movement in parasitic nematodes and are targets of "classical" anthelmintic drugs such as levamisole and pyrantel and of newer drugs such as tribendimidine and derquantel. While neurotransmission explains the effects of these drugs on nematode movement, their effects on parasite reproduction are unexplained. The levamisole AChR type (L-AChRs) in Caenorhabditis elegans is comprised of five subunits: Cel-UNC-29, Cel-UNC-38, Cel-UNC-63, Cel-LEV-1 and Cel-LEV-8. The genome of the filarial parasite Brugia malayi contains nine AChRs subunits including orthologues of Cel-unc-29, Cel-unc-38, and Cel-unc-63. We performed in situ hybridization with RNA probes to localize the expression of five AChR genes (Bm1_35890-. Bma-unc-29, Bm1_20330-. Bma-unc-38, Bm1_38195-. Bma-unc-63, Bm1_48815-. Bma-acr-26 and Bm1_40515-. Bma-acr-12) in B.malayi adult worms. Four of these genes had similar expression patterns with signals in body muscle, developing embryos, spermatogonia, uterine wall adjacent to stretched microfilariae, wall of Vas deferens, and lateral cord. Three L-AChR subunit genes (. Bma-unc-29, Bma-unc-38 and Bma-unc-63) were expressed in body muscle, which is a known target of levamisole. Bma-acr-12 was co-expressed with these levamisole subunit genes in muscle, and this suggests that its protein product may form receptors with other alpha subunits. Bma-acr-26 was expressed in male muscle but not in female muscle. Strong expression signals of these genes in early embryos and gametes in uterus and testis suggest that AChRs may have a role in nervous system development of embryogenesis and spermatogenesis. This would be consistent with embryotoxic effects of drugs that target these receptors in filarial worms. Our data show that the expression of these receptor genes is tightly regulated with regard to localization in adult worms and developmental stage in embryos and gametes. These results may help to explain the broad effects of drugs that target AChRs in filarial worms. © 2015 The Authors.

Author Keywords
Acetylcholine receptors;  Anthelmintic;  Brugia malayi;  Filarioideae;  In situ hybridization;  Reproduction


Document Type: Article
Source: Scopus



Chatterjee, A.R.a , Derdeyn, C.P.b
Stenting in Intracranial Stenosis: Current Controversies and Future Directions
(2015) Current Atherosclerosis Reports, 17 (8), art. no. 48, 9 p. 

DOI: 10.1007/s11883-015-0527-4

a Department of Radiology, Medical University of South Carolina, Suite 210, 96 Jonathan Lucas St., Charleston, SC, United States
b Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., Campus Box 8131, Saint Louis, MO, United States

Abstract
Angioplasty and stenting for intracranial atherosclerotic stenosis (ICAS) are a last resort for patients with high-grade intracranial stenosis with multiple ischemic events unresponsive to medical therapy. Medical management, consisting of aggressive risk factor control and dual antiplatelet therapy, is superior to angioplasty and stenting for the prevention of future stroke. Future studies of angioplasty and stenting in this population are important, as the stroke risk on medical therapy is 12 % at 1 year and post-procedure stroke rates are similar to rates with medical treatment. There are many issues that will need to be resolved for stenting to offer any benefit, however. Procedural risks of hemorrhagic and ischemic stroke are unacceptably high. High-risk subgroups, potentially based on hemodynamic factors, will need to be identified for future interventional trials. Nevertheless, it is still reasonable to consider angioplasty and stenting for selected patients with multiple recurrent events despite aggressive medical management, but benefits are unclear at this time. © 2015, Springer Science+Business Media New York.

Author Keywords
Angioplasty;  Cerebral atherosclerosis;  Endovascular;  Humans;  Intracranial atherosclerotic disease;  Ischemic stroke;  Stenosis;  Stenting


Document Type: Review
Source: Scopus



Vila, P.M., Lieu, J.E.C.
Asymmetric and unilateral hearing loss in children
(2015) Cell and Tissue Research, 361 (1), pp. 271-278. 

DOI: 10.1007/s00441-015-2208-6

Department of Otolaryngology - Head & Neck Surgery, Washington University School of Medicine, St. Louis, Mo., United States

Abstract
Asymmetric and unilateral hearing losses in children have traditionally been underappreciated, but health care practitioners are now beginning to understand their effect on development and the underlying pathophysiologic mechanisms. The common wisdom among medical and educational professionals has been that at least one normal-hearing or near-normal-hearing ear was sufficient for typical speech and language development in children. The objective of this review is to illustrate, to the non-otolaryngologist, the consequences of asymmetric and unilateral hearing loss in children on developmental and educational outcomes. Etiology, detection, and management are also discussed. Lastly, implications for further research are considered. © 2015, Springer-Verlag Berlin Heidelberg.

Author Keywords
Asymmetric hearing loss;  Children;  Unilateral hearing loss


Document Type: Review
Source: Scopus



Ren, L.a , Dhaka, A.b , Cao, Y.-Q.a
Function and postnatal changes of dural afferent fibers expressing TRPM8 channels
(2015) Molecular Pain, 11 (1), art. no. 37, . 

DOI: 10.1186/s12990-015-0043-0

a Washington University School of Medicine, Washington University Pain Center, Department of Anesthesiology, St. Louis, MO, United States
b University of Washington, Department of Biological Structure, Neurobiology and Behavior Graduate Program, Seattle, WA, United States

Abstract
Background: Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-expressing dural afferent fibers as well as the function of dural TRPM8 channels in mice. Results: First, we quantified the density and the number of axonal branches of TRPM8-expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from one TRPM8 allele between postnatal day 2 (P2) to adulthood. The number of axonal branches on individual dural EGFP-positive fibers was decreased by 30% between P2 and P11. The density of dural EGFP-positive fibers was subsequently reduced by 50% between P16 and P21. Conversely, the density and the number of branches of axons expressing calcitonin gene-related peptide remained stable in postnatal mouse dura. The density of TRPM8-expressing fibers innervating the mouse cornea epithelium was significantly increased from P2 to adulthood. Next, we tested the function of dural TRPM8 channels in adult mice and found that TRPM8 agonist menthol effectively inhibited the nocifensive behavior evoked by dural application of inflammatory mediators. Conclusions: Our results indicate that the TRPM8-expressing dural afferent fibers undergo cell- and target tissue-specific axonal pruning during postnatal development. Activation of dural TRPM8 channels decreases meningeal irritation-evoked nocifensive behavior in adult mice. This provides a framework to further explore the role of postnatal changes of TRPM8-expressing dural afferents in the pathophysiology of pediatric and adult migraine. © 2015 Ren et al.

Author Keywords
CGRP;  Dural afferent fibers;  Headache;  Migraine;  TRPM8


Document Type: Article
Source: Scopus



Ren, L.a , Dhaka, A.b , Cao, Y.-Q.a
Function and postnatal changes of dural afferent fibers expressing TRPM8 channels
(2015) Molecular Pain, . Article in Press. 

DOI: 10.1186/s12990-015-0043-0

a Washington University School of Medicine, Washington University Pain Center and Department of Anesthesiology, St. Louis, MO, 63110 USA
b University of Washington, Department of Biological Structure, Neurobiology and Behavior Graduate Program, Seattle, WA, 98195 USA

Abstract
Background: Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-expressing dural afferent fibers as well as the function of dural TRPM8 channels in mice. Results: First, we quantified the density and the number of axonal branches of TRPM8-expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from one TRPM8 allele between postnatal day 2 (P2) to adulthood. The number of axonal branches on individual dural EGFP-positive fibers was decreased by 30% between P2 and P11. The density of dural EGFP-positive fibers was subsequently reduced by 50% between P16 and P21. Conversely, the density and the number of branches of axons expressing calcitonin gene-related peptide remained stable in postnatal mouse dura. The density of TRPM8-expressing fibers innervating the mouse cornea epithelium was significantly increased from P2 to adulthood. Next, we tested the function of dural TRPM8 channels in adult mice and found that TRPM8 agonist menthol effectively inhibited the nocifensive behavior evoked by dural application of inflammatory mediators. Conclusions: Our results indicate that the TRPM8-expressing dural afferent fibers undergo cell- and target tissue-specific axonal pruning during postnatal development. Activation of dural TRPM8 channels decreases meningeal irritation-evoked nocifensive behavior in adult mice. This provides a framework to further explore the role of postnatal changes of TRPM8-expressing dural afferents in the pathophysiology of pediatric and adult migraine. © 2015 Ren et al.

Author Keywords
CGRP;  Dural afferent fibers;  Headache;  Migraine;  TRPM8


Document Type: Article in Press
Source: Scopus



Carr, D.B.a , O’Neill, D.b
Mobility and safety issues in drivers with dementia
(2015) International Psychogeriatrics, 10 p. Article in Press. 

DOI: 10.1017/S104161021500085X

a Division of Geriatrics and Nutritional Science, Department of Medicine and Neurology, Washington University in St. Louis, 660 Euclid Dr. St. Louis, MO 63110, USA
b Tallaght Hospital and Trinity College Dublin, Trinity Centre for Health Sciences, Tallaght Hospital, Dublin 24, Ireland

Abstract
Although automobiles remain the mobility method of choice for older adults, late-life cognitive impairment and progressive dementia will eventually impair the ability to meet transport needs of many. There is, however, no commonly utilized method of assessing dementia severity in relation to driving, no consensus on the specific types of assessments that should be applied to older drivers with cognitive impairment, and no gold standard for determining driving fitness or approaching loss of mobility and subsequent counseling. Yet, clinicians are often called upon by patients, their families, health professionals, and driver licensing authorities to assess their patients’ fitness-to-drive and to make recommendations about driving privileges. We summarize the literature on dementia and driving, discuss evidenced-based assessments of fitness-to-drive, and outline the important ethical and legal concerns. We address the role of physician assessment, referral to neuropsychology, functional screens, dementia severity tools, driving evaluation clinics, and driver licensing authority referrals that may assist clinicians with an evaluation. Finally, we discuss mobility counseling (e.g. exploration of transportation alternatives) since health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance our patients’ social connectedness and quality of life, while meeting their psychological and medical needs and maintaining personal and public safety. Copyright © International Psychogeriatric Association 2015

Author Keywords
Alzheimer’s disease;  assessment;  automobile;  cognitive impairment;  dementia;  driving;  older adult;  transportation


Document Type: Article in Press
Source: Scopus



Chung, Y.S.a , Barch, D.b
Anhedonia is associated with reduced incentive cue related activation in the basal ganglia
(2015) Cognitive, Affective and Behavioral Neuroscience, 19 p. Article in Press. 

DOI: 10.3758/s13415-015-0366-3

a Department of Psychology, Washington University, St. Louis, MO, United States
b Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, MO, United States

Abstract
Research has shown that reward incentives improve cognitive control in motivationally salient situations. Much previous work in this domain has focused on incentive cue-related activity in a number of brain regions, including the dorsolateral prefrontal cortex (DLPFC) and striatum. However, the more sustained changes in functional brain activity during task contexts with incentives have been relatively less explored. Here, we examined both the cue-related and sustained effects of rewards (i.e., monetary incentives) on cognitive control, with a particular focus on the roles of the DLPFC and striatum, using a mixed state–item design. We investigated whether variability in a reward-related trait (i.e., anhedonia) would modulate the sustained and/or the cue-related transient aspects of motivated cognitive control. Twenty-seven healthy individuals performed a modified response conflict task (Padmala & Pessoa, Journal of Cognitive Neuroscience, 23, 3419–3432, 2011) during scanning, in which participants were asked to categorize images as either houses or buildings with either congruent or incongruent overlaid words. Participants performed a baseline condition without knowledge of monetary incentives, followed by reward blocks with monetary incentives on some cued trials (reward cues) for fast and correct responses. We replicated previous work by showing increases in both sustained activity during reward versus baseline blocks and transient. cue-related activity in bilateral DLPFC and the basal ganglia. Importantly, healthy individuals with higher anhedonia showed less of an increase in trial-by-trial activity as a function of reward in the lateral globus pallidus. Together, our results suggest that reduced hedonic experience may be related to abnormality of reward cue-related activity in the basal ganglia. © 2015 Psychonomic Society, Inc.

Author Keywords
Cognitive control;  Emotion;  Mixed fMRI design;  Motivation;  Prefrontal cortex;  Reward


Document Type: Article in Press
Source: Scopus



Strickland, A.V.a , Schabhüttl, M.b , Offenbacher, H.c , Synofzik, M.d e , Hauser, N.S.f , Brunner-Krainz, M.g , Gruber-Sedlmayr, U.g , Moore, S.A.h , Windhager, R.b , Bender, B.i , Harms, M.j , Klebe, S.k , Young, P.l , Kennerson, M.m n , Garcia, A.S.M.a , Gonzalez, M.A.a , Züchner, S.a , Schule, R.a d e , Shy, M.E.o , Auer-Grumbach, M.b
Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1
(2015) Journal of Neurology, 11 p. Article in Press. 

DOI: 10.1007/s00415-015-7727-2

a Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
b Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, Vienna, Austria
c Department of Neurology, Hospital Knittelfeld, Knittelfeld, Austria
d Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
e German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
f Department of Medical Genetics, Children’s Hospital of Central California, Madera, CA, United States
g Division of General Pediatrics, Medical University Graz, Graz, Austria
h Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
i Magnetic Resonance Research Group, Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany
j Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, United States
k Department of Neurology, University Hospital Wuerzburg, Würzburg, Germany
l Department of Sleep Medicine and Neuromuscular Disorders, University of Munster, Munster, Germany
m Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia
n Molecular Medicine Laboratory, Concord Hospital, Sydney, Australia
o Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States

Abstract
Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot–Marie–Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways. © 2015 Springer-Verlag Berlin Heidelberg

Author Keywords
DYNC1H1;  Epilepsy;  Gastric volvulus;  Peripheral neuropathy;  Spastic paraplegia;  Spinal muscular atrophy


Document Type: Article in Press
Source: Scopus



Cheng, X.a , Marcus, D.b , Van Horn, J.D.c , Luo, Q.d , Mattay, V.S.a , Weinberger, D.R.a
Going beyond the current neuroinformatics infrastructure
(2015) Frontiers in Neuroinformatics, 9 (JUNE), art. no. 15, 3 p. 

DOI: 10.3389/fninf.2015.00015

a Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Laboratory of Neuro Imaging, Department of Neurology, Institute of Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, United States
d Center for Military Psychiatry and Neuroscience Research, Walter Reed Army Research Institute, Silver Spring, MD, United States
 

Author Keywords
Data Sharing;  Informatics;  Infrastructure;  Neuroinformatics;  Neuroscience


Document Type: Editorial
Source: Scopus



Zenga, J.a , Kreisel, D.b , Kushnir, V.M.c , Rich, J.T.a
Management of cervical esophageal and hypopharyngeal perforations
(2015) American Journal of Otolaryngology - Head and Neck Medicine and Surgery, . Article in Press. 

DOI: 10.1016/j.amjoto.2015.06.001

a Department of Otolaryngology Head and Neck Surgery, Washington University in St. Louis, Saint Louis, MO, USA
b Division of Cardiothoracic Surgery, Washington University in St. Louis, Saint Louis, MO, USA
c Division of Gastroenterology, Washington University School of Medicine, St Louis, MO, USA

Abstract
Purpose: Evidence is limited for outcomes of surgical versus conservative management for patients with cervical esophageal or hypopharyngeal perforations. Methods: Patients with cervical esophageal or hypopharyngeal perforations treated between 1994 and 2014 were identified using an institutional database. Outcomes were compared between patients who underwent operative drainage and those who had conservative management with broad-spectrum antibiotics and withholding oral intake. Results: Twenty-eight patients were identified with hypopharyngeal or cervical esophageal perforations, mostly due to iatrogenic (nasogastric tube placement, endoscopy, endotracheal intubation) injuries (68%). Fourteen were treated initially with conservative management and 14 with initial surgery. Six patients failed conservative treatment and two patients failed surgical treatment. Patients managed conservatively who had eaten between injury and diagnosis (p = 0.003), those who had 24. hours or more between the time of injury and diagnosis (p = 0.026), and those who showed signs of systemic toxicity (p = 0.001) were significantly more likely to fail conservative treatment and require surgery. No variables were significant for treatment failure in the surgical group. Of the 20 patients who ultimately underwent a surgical procedure, two required a second procedure. Conclusion: Patients who have eaten between the time of perforation and diagnosis, have 24. hours or more between injury and diagnosis, and those that show signs of systemic toxicity are at higher risk of failing conservative management and surgical drainage should be considered. For patients without these risk factors, a trial of conservative management can be attempted. © 2015.
 


Document Type: Article in Press
Source: Scopus



Tu, Z.a , Zhang, X.a , Jin, H.a , Yue, X.a , Padakanti, P.K.a , Yu, L.a , Liu, H.a , Flores, H.P.b , Kaneshige, K.c , Parsons, S.M.c , Perlmutter, J.S.a b
Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter
(2015) Bioorganic and Medicinal Chemistry, . Article in Press. 

DOI: 10.1016/j.bmc.2015.05.058

a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA
b Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA
c Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA

Abstract
Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogs; the minus enantiomer, (-)-18a displayed high potency (VAChT K <inf>i</inf> =0.59±0.06nM) and high selectivity for VAChT versus σ receptors (>10,000-fold). The radiosynthesis of (-)-[18F]18a was accomplished by a two-step procedure with 30-40% radiochemical yield. Preliminary biodistribution studies of (-)-[18F]18a in adult male Sprague-Dawley rats at 5, 30, 60 and 120min post-injection (p.i.) were promising. The total brain uptake of (-)-[18F]18a was 0.684%ID/g at 5min p.i. and by 120min p.i. slowly washed out to 0.409 %ID/g; evaluation of regional brain uptake showed stable levels of ~0.800 %ID/g from 5 to 120min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[18F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a ~90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[18F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[18F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects. © 2015 Elsevier Ltd.

Author Keywords
F-18;  PET tracer;  Striatum;  VAChT;  Vesamicol


Document Type: Article in Press
Source: Scopus



Li, F., Guo, C.J., Huang, C.-C., Yu, G., Brown, S.M., Xu, S., Liu, Q.
Transient receptor potential A1 activation prolongs isoflurane induction latency and impairs respiratory function in mice
(2015) Anesthesiology, 122 (4), pp. 768-775. 

DOI: 10.1097/ALN.0000000000000607

From the Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri (F.L., C.J.G., C.-C.H., G.Y., Q.L.); Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China (F.L., S.X.); School of Basic Medical Sciences, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China (G.Y.); and Departments of Pediatrics, Anesthesiology, and Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, Missouri (S.M.B.)

Abstract
BACKGROUND: Isoflurane is a potent volatile anesthetic; however, it evokes airway irritation and neurogenic constriction through transient receptor potential (TRP) A1 channels and sensitizes TRPV1 channels, which colocalizes with TRPA1 in most of the vagal C-fibers innervating the airway. However, little is known about the precise effects of these two channels on the respiratory function during isoflurane anesthesia.

METHODS: By using a rodent behavioral model and whole-body plethysmograph, the authors examined the response of Trpa1 and Trpv1 mice to isoflurane anesthesia and monitored their respiratory functions during anesthesia.

RESULTS: This study showed that Trpa1 mice (n = 9), but not Trpv1 mice (n = 11), displayed a shortened induction latency compared with wild-type mice (n = 10) during isoflurane anesthesia (33 ± 2.0 s in wild-type and 33 ± 3.8 s in Trpv1 vs. 17 ± 1.8 in Trpa1 at 2.2 minimum alveolar concentrations). By contrast, their response to the nonpungent volatile anesthetic sevoflurane is indistinguishable from wild-type mice (24 ± 3.6 s in wild-type vs. 26 ± 1.0 s in Trpa1 at 2.4 minimum alveolar concentrations). The authors discovered that Trpa1 mice inhaled more anesthetic but maintained better respiratory function. Further respiration pattern analysis revealed that isoflurane triggered nociceptive reflexes and led to prolonged resting time between breaths during isoflurane induction as well as decreased dynamic pulmonary compliance, an indicator of airway constriction, throughout isoflurane anesthesia in wild-type and Trpv1 mice, but not in Trpa1 mice.

CONCLUSION: Activation of TRPA1 by isoflurane negatively affects anesthetic induction latency by altering respiratory patterns and impairing pulmonary compliance.
 


Document Type: Article
Source: Scopus



Duncan, R.P.a b , Leddy, A.L.c , Cavanaugh, J.T.d , Dibble, L.E.e , Ellis, T.D.f , Ford, M.P.g , Foreman, K.B.e , Earhart, G.M.a b h
Balance differences in people with Parkinson disease with and without freezing of gait
(2015) Gait and Posture, . Article in Press. 

DOI: 10.1016/j.gaitpost.2015.06.007

a Washington University School of Medicine in Saint Louis, Program in Physical Therapy, St. Louis, MO, United States
b Washington University School of Medicine in Saint Louis, Department of Neurology, St. Louis, MO, United States
c Rehabilitation Hospital of the Pacific, Department of Physical Therapy, Honolulu, HI, United States
d University of New England, Department of Physical Therapy, Portland, ME, United States
e University of Utah, Department of Physical Therapy, Salt Lake City, UT, United States
f Boston University, Department of Physical Therapy and Athletic Training, Boston, MA, United States
g Samford University, Department of Physical Therapy, Birmingham, AL, United States
h Washington University School of Medicine in Saint Louis, Department of Anatomy and Neurobiology, St. Louis, MO, United States

Abstract
Background: Freezing of gait (FOG) is a relatively common and remarkably disabling impairment associated with Parkinson disease (PD). Laboratory-based measures indicate that individuals with FOG (PD + FOG) have greater balance deficits than those without FOG (PD. -FOG). Whether such differences also can be detected using clinical balance tests has not been investigated. We sought to determine if balance and specific aspects of balance, measured using Balance Evaluation Systems Test (BESTest), differs between PD + FOG and PD. -FOG. Furthermore, we aimed to determine if time-efficient clinical balance measures (i.e. Mini-BESTest, Berg Balance Scale (BBS)) could detect balance differences between PD + FOG and PD. -FOG. Methods: Balance of 78 individuals with PD, grouped as either PD + FOG (n = 32) or PD. -FOG (n = 46), was measured using the BESTest, Mini-BESTest, and BBS. Between-groups comparisons were conducted for these measures and for the six sections of the BESTest using analysis of covariance. A PD composite score was used as a covariate. Results: Controlling for motor sign severity, PD duration, and age, PD + FOG had worse balance than PD. -FOG when measured using the BESTest (p = 0.008, F = 7.35) and Mini-BESTest (p = 0.002, F = 10.37), but not the BBS (p = 0.27, F = 1.26). BESTest section differences were noted between PD + FOG and PD. -FOG for reactive postural responses (p <. 0.001, F = 14.42) and stability in gait (p = 0.003, F = 9.18). Conclusions: The BESTest and Mini-BESTest, which specifically assessed reactive postural responses and stability in gait, were more likely than the BBS to detect differences in balance between PD + FOG and PD. -FOG. Because it is more time efficient to administer, the Mini-BESTest may be the preferred tool for assessing balance deficits associated with FOG. © 2015 Elsevier B.V.

Author Keywords
Balance;  BESTest;  Freezing of gait;  Mini-BESTest;  Parkinson disease


Document Type: Article in Press
Source: Scopus



Santello, M.a , Lang, C.E.b
Are movement disorders and sensorimotor injuries pathologic synergies? When normal multi-joint movement synergies become pathologic
(2015) Frontiers in Human Neuroscience, 8 (JAN), art. no. 1050, 13 p. 

DOI: 10.3389/fnhum.2014.01050

a Neural Control of Movement Laboratory, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States
b Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MT, United States

Abstract
The intact nervous system has an exquisite ability to modulate the activity of multiple muscles acting at one or more joints to produce an enormous range of actions. Seemingly simple tasks, such as reaching for an object or walking, in fact rely on very complex spatial and temporal patterns of muscle activations. Neurological disorders such as stroke and focal dystonia affect the ability to coordinate multi-joint movements. This article reviews the state of the art of research of muscle synergies in the intact and damaged nervous system, their implications for recovery and rehabilitation, and proposes avenues for research aimed at restoring the nervous system’s ability to control movement. © 2015 Santello and Lang.

Author Keywords
Carpal tunnel syndrome;  Coordination;  Degrees of freedom;  Dystonia;  Stroke


Document Type: Article
Source: Scopus



Levinson, C.A.a , Rodebaugh, T.L.a , Fewell, L.b , Kass, A.E.c , Riley, E.N.a , Stark, L.b , McCallum, K.b , Lenze, E.J.c
D-cycloserine facilitation of exposure therapy improves weight regain in patients with anorexia nervosa: A pilot randomized controlled trial
(2015) Journal of Clinical Psychiatry, 76 (6), pp. e787-e793. 

DOI: 10.4088/JCP.14m09299

a Department of Psychology, Washington University in St Louis, St Louis, MO, United States
b McCallum Place Treatment Facility, St Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Objective: Exposure therapy in anorexia nervosa has preliminarily been shown to be effective for increasing food intake. D-Cycloserine is a glutamatergic N-methyld-aspartate receptor agonist that has been shown to facilitate the benefits of exposure therapy for anxiety disorders by enhancing the emotional learning in the exposures; therefore, we examined D-cycloserine- facilitation of exposure therapy to increase body mass index (BMI) in patients with anorexia nervosa. Method: Participants (N = 36) with anorexia nervosa (diagnosed via DSM-IV) were recruited from a partial hospitalization eating disorder clinic between February 2013 and November 2013. Participants were randomly assigned to receive exposure therapy plus D-cycloserine (n = 20) or placebo (n = 16). Participants completed psychoeducation and 4 sessions of exposure therapy, with medication (D-cycloserine vs placebo) given prior to the first 3 exposure sessions. They also completed a 1-month follow-up. Results: As hypothesized, participants in the D-cycloserine group showed a significantly greater increase in BMI than those in the placebo group (Wilk Λ = 0.86, F<inf>3,32</inf> = 2.20, P = .043, η<inf>p</inf>2 = 0.12). D-Cycloserine participants gained 3 pounds relative to 0.5 pounds in the placebo group. Both groups experienced significantly decreased anxiety over the course of therapy (Wilk Λ = 0.80, F<inf>3,32</inf> = 3.32, P = .023, η<inf>p</inf>2 = 0.20). Conclusions: This study preliminarily demonstrates that D-cycloserine facilitates exposure therapy for anorexia nervosa, leading to increased weight gain. A potential mechanism is that participants who receive D-cycloserine may generalize learning from within-session exposures to food intake during other similar meals, resulting in sustained increases in BMI. Further research is needed to confirm these findings and test the putative mechanism that generalized learning from exposure therapy can increase BMI and stabilize a healthy weight. Trial Registration: ClinicalTrials.gov identifier: NCT01996644. © Copyright 2015 Physicians Postgraduate Press, Inc.
 


Document Type: Article
Source: Scopus



O’Brien, D.E.a , Alter, B.J.a , Satomoto, M.a , Morgan, C.D.a , Davidson, S.a , Vogt, S.K.a , Norman, M.E.a , Gereau, G.B.a , Demaro, J.A., IIIa , Landreth, G.E.b , Golden, J.P.a , Gereau, R.W.a
ERK2 alone drives inflammatory pain but cooperates with ERK1 in sensory neuron survival
(2015) Journal of Neuroscience, 35 (25), pp. 9491-9507. 

DOI: 10.1523/JNEUROSCI.4404-14.2015

a Washington University Pain Center, Department of Anesthesiology, St. Louis, MO, United States
b Neuroscience Department, Case Western Reserve University, Cleveland, OH, United States

Abstract
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are highly homologous yet distinct components of signal transduction pathways known to regulate cell survival and function. Recent evidence indicates an isoform-specific role for ERK2 in pain processing and peripheral sensitization. However, the function of ERK2 in primary sensory neurons has not been directly tested. To dissect the isoform-specific function of ERK2 in sensory neurons, we used mice with Cre-loxP-mediated deletion of ERK2 in Na<inf>v</inf>1.8+ sensory neurons that are predominantly nociceptors. We find that ERK2, unlike ERK1, is required for peripheral sensitization and cold sensation. We also demonstrate that ERK2, but not ERK1, is required to preserve epidermal innervation in a subset of peptidergic neurons. Additionally, deletion of both ERK isoforms in Na<inf>v</inf>1.8+sensory neurons leads to neuron loss not observed with deletion of either isoform alone, demonstrating functional redundancy in the maintenance of sensory neuron survival. Thus, ERK1 and ERK2 exhibit both functionally distinct and redundant roles in sensory neurons. © 2015 the authors.

Author Keywords
ERK;  MAP kinase;  MEK;  Nociception;  Pain;  Sensory neuron


Document Type: Article
Source: Scopus



Day, G.S.a b , Munoz, D.G.c
Fanning the Flames in Anti-N-methyl-D-aspartate Receptor Encephalitis
(2015) International Journal of Gynecological Pathology, 34 (4), pp. 401-402. 

DOI: 10.1097/PGP.0000000000000186

a Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Division of Pathology, Department of Laboratory Medicine, Saint Michael's Hospital, Toronto, ON, Canada
 
 


Document Type: Letter
Source: Scopus



Lucey, B.P., Holtzman, D.M.
How amyloid, sleep and memory connect
(2015) Nature Neuroscience, 18 (7), pp. 933-934. 

DOI: 10.1038/nn.4048

Department of Neurology, Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
 
 


Document Type: Short Survey
Source: Scopus



McConathy, J.a , Sheline, Y.I.b
Imaging biomarkers associated with cognitive decline: A review
(2015) Biological Psychiatry, 77 (8), pp. 685-692. 

DOI: 10.1016/j.biopsych.2014.08.024

a Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States

Abstract
In evaluating disease changes, it is critical to have measurements that are sensitive, specific, and reliable. Cognitive decline, particularly in the context of Alzheimer's disease, is an area that has attracted numerous recent studies, and the proposed biomarkers used in these investigations need to be validated. In this review, we highlight studies with important implications about the role of imaging biomarkers in cognitive decline and dementia as well as in distinguishing preclinical dementia before evidence of cognitive decline. Structural changes determined on cross-sectional and longitudinal magnetic resonance imaging provide early prediction of dementia, particularly when combined with other measures. Molecular imaging using positron emission tomography and single photon emission computed tomography tracers quantify the presence or activity of receptors, transporters, enzymes, metabolic pathways, and proteins. The newest developments in molecular imaging are described, and methods are compared. Distinguishing features of imaging biomarkers among dementias and the spectrum of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease are described. Appropriate use criteria for positron emission tomography with amyloid tracers are delineated. Although these efforts are still in the early phase of development, there is great promise for further development in structural magnetic resonance imaging and positron emission tomography technologies. © 2015 Society of Biological Psychiatry.

Author Keywords
Amyloid;  Biomarkers;  Dementia;  Florbetaben;  Flutemetamol;  PET


Document Type: Article
Source: Scopus



Rensing, N., Han, L., Wong, M.
Intermittent dosing of rapamycin maintains antiepileptogenic effects in a mouse model of tuberous sclerosis complex
(2015) Epilepsia, . Article in Press. 

DOI: 10.1111/epi.13031

Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis, Missouri U.S.A

Abstract
Objective: Inhibitors of the mechanistic target of rapamycin (mTOR) pathway have antiepileptogenic effects in preventing epilepsy and pathologic and molecular mechanisms of epileptogenesis in mouse models of tuberous sclerosis complex (TSC). However, long-term treatment with mTOR inhibitors may be required to maintain efficacy and potentially has chronic side effects, such as immunosuppression. Attempts to minimize drug exposure will facilitate translational efforts to develop mTOR inhibitors as antiepileptogenic agents for patients with TSC. In this study, we tested intermittent dosing paradigms of mTOR inhibitors for antiepileptogenic properties in a TSC mouse model. Methods: Western blot analysis of phosphorylation of S6 protein was used to assess the dose- and time-dependence of mTOR inhibition by rapamycin in control mice and conditional knockout mice with inactivation of the Tsc1 gene in glial fibrillary acidic protein (GFAP)-expressing cells (Tsc1GFAPCKO mice). Based on the Western blot studies, different dosing paradigms of rapamycin starting at postnatal day 21 were tested for their ability to prevent epilepsy or pathologic abnormalities in Tsc1GFAPCKO mice: 4 days of rapamycin only (4-∞), 4 days on-24 days off (4-24), and 4 days on-10 days off (4-10). Results: mTOR activity was inhibited by rapamycin in a dose-dependent fashion and recovered to baseline by about 10 days after the last rapamycin dose. The 4-10 and 4-24 dosing paradigms almost completely prevented epilepsy and the 4-10 paradigm inhibited glial proliferation and megalencephaly in Tsc1GFAPCKO mice. Significance: Intermittent dosing of rapamycin, with drug holidays of more than 3 weeks, maintains significant antiepileptogenic properties in mouse models of TSC. These findings have important translational applications in developing mTOR inhibitors as antiepileptogenic agents in TSC patients by minimizing drug exposure and potential side effects. © 2015 International League Against Epilepsy.

Author Keywords
Epilepsy;  Mechanistic target of rapamycin;  Mice;  Rapamycin;  Seizure


Document Type: Article in Press
Source: Scopus



Kanekura, K.a b , Ma, X.c , Murphy, J.T.c , Zhu, L.J.d , Diwan, A.c e , Urano, F.a f
IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions
(2015) Science Signaling, 8 (382), art. no. ra62, . 

DOI: 10.1126/scisignal.aaa0341

a Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University, St. Louis, MO, United States
b Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
c Division of Cardiology, Department of Medicine, Washington University, St. Louis, MO, United States
d Prog. in Molec., Cell and Cancer Biolo., Molecu. Medic., and Bioinfor. and I.B., University of Massachusetts, Medical School, Worcester, MA, United States
e John Cochran VA Medical Center, St. Louis, MO, United States
f Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
The endoplasmic reticulum (ER) has emerged as a critical regulator of cell survival. IRE1 is a trans-membrane protein with kinase and RNase activities that is localized to the ER and that promotes resistance to ER stress. We showed a mechanism by which IRE1 conferred protection against ER stress-mediated cell death. IRE1 signaling prevented ER membrane permeabilization mediated by Bax and Bak and cell death in cells experiencing ER stress. Suppression of IRE1 signaling triggered by its kinase activity led to the accumulation of the BH3 domain-containing protein Bnip3, which in turn triggered the oligomerization of Bax and Bak in the ER membrane and ER membrane permeabi-lization. Consequently, in response to ER stress, cells deficient in IRE1 were susceptible to leakage of ER contents, which was associated with the accumulation of calcium in mitochondria, oxidative stress in the cytosol, and ultimately cell death. Our results reveal a role for IRE1 in preventing a cell death-initializing step that emanates from the ER and provide a potential target for treating diseases characterized by ER stress, including diabetes and Wolfram syndrome.
 


Document Type: Article
Source: Scopus



Sommers, M.S.
Listening comprehension in middle-aged adults
(2015) American Journal of Audiology, 24 (2), pp. 88-90. 

DOI: 10.1044/2015_AJA-14-0060

Washington University, St. Louis, MO, United States

Abstract
Purpose: The purpose of this summary is to examine changes in listening comprehension across the adult lifespan and to identify factors associated with individual differences in listening comprehension. Method: In this article, the author reports on both cross-sectional and longitudinal changes in listening comprehension. Conclusions: Despite significant declines in both sensory and cognitive abilities, listening comprehension remains relatively unchanged in middle-aged listeners (between the ages of 40 and 60 years) compared with young listeners. These results are discussed with respect to possible compensatory factors that maintain listening comprehension despite impaired hearing and reduced cognitive capacities. © 2015 American Speech-Language-Hearing Association.
 


Document Type: Article
Source: Scopus



Lockhart, E.M., Ben Abdallah, A., Tuuli, M.G., Leighton, B.L.
Obstructive Sleep Apnea in Pregnancy
(2015) Obstetrics and Gynecology, 126 (1), pp. 93-102. 

DOI: 10.1097/AOG.0000000000000848

Departments of Anesthesiology and Obstetrics and Gynecology, Washington University School of Medicine, 660 S. Euclid, Box 8054, St. Louis, MO, United States

Abstract
Objective: To estimate the predictive ability of current obstructive sleep apnea (OSA) screening tools and the individual questions in these tools at identifying pregnant women who have OSA. Methods: A total of 293 third-trimester patients were enrolled between 2010 and 2012, and 248 patients had sleep monitor results. Recruited participants completed a questionnaire consisting of six OSA screening tools and overnight portable sleep monitoring. Predictive ability of the screening tools for OSA compared with results of the diagnosis from overnight sleep monitoring was estimated using the area under receiver operating characteristic curves. Results: Two hundred eighteen (88%) of the patients were OSA-negative, and 30 patients (12%) were OSA-positive based on sleep monitoring results. Compared with OSA-negative patients, OSA-positive patients had greater body mass indices and neck circumferences as well as significantly higher rates of hypertension (chronic and gestational), pregestational diabetes mellitus, asthma, and preeclampsia. The overall predictive ability of the screening tools for OSA was modest (area under receiver operating characteristic curves 0.62-0.695). However, individual components of the questionnaire were strongly associated with OSA. Conclusion: We found that none of the studied OSA screening tools accurately detected OSA in pregnant women in the third trimester. We have identified proposed elements of a new screening tool based on promising components from several tools that may more accurately detect patients with OSA. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
 


Document Type: Article
Source: Scopus



Pita-Thomas, W.a b , Steketee, M.B.a c , Moysidis, S.N.a , Thakor, K.a , Hampton, B.a , Goldberg, J.L.a d
Promoting filopodial elongation in neurons by membrane-bound magnetic nanoparticles
(2015) Nanomedicine: Nanotechnology, Biology, and Medicine, 11 (3), pp. 559-567. 

DOI: 10.1016/j.nano.2014.11.011

a Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States
b Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
c Department of Ophthalmology and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Ophthalmology, Shiley Eye Center, UC San Diego, San Diego, CA, United States

Abstract
Filopodia are 5-10. μm long processes that elongate by actin polymerization, and promote axon growth and guidance by exerting mechanical tension and by molecular signaling. Although axons elongate in response to mechanical tension, the structural and functional effects of tension specifically applied to growth cone filopodia are unknown. Here we developed a strategy to apply tension specifically to retinal ganglion cell (RGC) growth cone filopodia through surface-functionalized, membrane-targeted superparamagnetic iron oxide nanoparticles (SPIONs). When magnetic fields were applied to surface-bound SPIONs, RGC filopodia elongated directionally, contained polymerized actin filaments, and generated retrograde forces, behaving as bona fide filopodia. Data presented here support the premise that mechanical tension induces filopodia growth but counter the hypothesis that filopodial tension directly promotes growth cone advance. Future applications of these approaches may be used to induce sustained forces on multiple filopodia or other subcellular microstructures to study axon growth or cell migration. © 2015 Elsevier Inc.

Author Keywords
Axon growth;  Filopodia;  Mechanical tension;  Nanoparticles


Document Type: Article
Source: Scopus



Valnegri, P.a b , Puram, S.V.b c , Bonni, A.a b
Regulation of dendrite morphogenesis by extrinsic cues
(2015) Trends in Neurosciences, 38 (7), pp. 439-447. 

DOI: 10.1016/j.tins.2015.05.003

a Department of Anatomy and Neurobiology, Washington University in St Louis School of Medicine, St Louis, MO, United States
b Department of Neurobiology, Harvard Medical School, Boston, MA, United States
c Department of Otolaryngology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA, United States

Abstract
Dendrites play a central role in the integration and flow of information in the nervous system. The morphogenesis and maturation of dendrites is hence an essential step in the establishment of neuronal connectivity. Recent studies have uncovered crucial functions for extrinsic cues in the development of dendrites. We review the contribution of secreted polypeptide growth factors, contact-mediated proteins, and neuronal activity in distinct phases of dendrite development. We also highlight how extrinsic cues influence local and global intracellular mechanisms of dendrite morphogenesis. Finally, we discuss how these studies have advanced our understanding of neuronal connectivity and have shed light on the pathogenesis of neurodevelopmental disorders. © 2015 Elsevier Ltd.

Author Keywords
Calcium signaling;  Contact-mediated regulators;  Dendrite morphogenesis;  Neuronal activity;  Secreted polypeptide growth factors


Document Type: Review
Source: Scopus



Knauert, M.P.a , Haspel, J.A.b , Pisani, M.A.a
Sleep Loss and Circadian Rhythm Disruption in the Intensive Care Unit
(2015) Clinics in Chest Medicine, . Article in Press. 

DOI: 10.1016/j.ccm.2015.05.008

a Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC-441 South, PO Box208057, New Haven, CT 06520-8057, USA
b Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA

Abstract
Critical illness is associated with profound sleep disruption. Causality is diverse and includes physiologic, psychological, and environmental factors. There are limited pharmacologic interventions available to treat sleep disturbances in critical illness; however, multidisciplinary strategies that alter the intensive care unit (ICU) environment and cluster care delivery have shown promise in sleep and circadian promotion and delirium reduction. With the appropriate administrative support and involvement of diverse ICU stakeholders, effective strategies could be created, implemented, and maintained to improve sleep disruption in critically ill patients. © 2015 Elsevier Inc.

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


Document Type: Article in Press
Source: Scopus



Gordon, B.A.a b , Zacks, J.M.a c , Blazey, T.d , Benzinger, T.L.S.a b d e , Morris, J.C.b f , Fagan, A.M.b f g , Holtzman, D.M.b d f g , Balota, D.A.b c
Task-evoked fMRI changes in attention networks are associated with preclinical Alzheimer's disease biomarkers
(2015) Neurobiology of Aging, 36 (5), pp. 1771-1779. 

DOI: 10.1016/j.neurobiolaging.2015.01.019

a Department of Radiology, Washington University in St Louis, St Louis, MO, United States
b Knight Alzheimer's Disease Research Center, Washington University in St Louis, St Louis, MO, United States
c Department of Psychology, Washington University in St Louis, St Louis, MO, United States
d Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO, United States
e Department of Neurological Surgery, Washington University in St Louis, St Louis, MO, United States
f Department of Neurology, Washington University in St Louis, St Louis, MO, United States
g The Hope Center for Neurodegenerative Disorders, Washington University in St Louis, St Louis, MO, United States

Abstract
There is a growing emphasis on examining preclinical levels of Alzheimer's disease (AD)-related pathology in the absence of cognitive impairment. Previous work examining biomarkers has focused almost exclusively on memory, although there is mounting evidence that attention also declines early in disease progression. In the current experiment, 2 attentional control tasks were used to examine alterations in task-evoked functional magnetic resonance imaging data related to biomarkers of AD pathology. Seventy-one cognitively normal individuals (females= 44, mean age= 63.5 years) performed 2 attention-demanding cognitive tasks in a design that modeled both trial- and task-level functional magnetic resonance imaging changes. Biomarkers included amyloid β<inf>42</inf>, tau, and phosphorylated tau measured from cerebrospinal fluid and positron emission tomography measures of amyloid deposition. Both tasks elicited widespread patterns of activation and deactivation associated with large task-level manipulations of attention. Importantly, results from both tasks indicated that higher levels of tau and phosphorylated tau pathologies were associated with block-level overactivations of attentional control areas. This suggests early alteration in attentional control with rising levels of AD pathology. © 2015 Elsevier Inc.

Author Keywords
Alzheimer;  Alzheimer's disease;  Amyloid;  Attention;  Biomarkers;  Dementia;  FMRI;  Ptau;  Tau


Document Type: Article
Source: Scopus



Miller, J.B.a , Heitsch, L.b , Siket, M.S.c , Schrock, J.W.d , Wira, C.R.e , Lewandowski, C.a , Madsen, T.E.c , Merck, L.H.c , Wright, D.W.f
The Emergency Medicine Debate on tPA for Stroke: What Is Best for Our Patients? Efficacy in the First Three Hours
(2015) Academic Emergency Medicine, . Article in Press. 

DOI: 10.1111/acem.12712

a Department of Emergency Medicine Henry Ford Hospital Detroit, MI
b Department of Emergency Medicine Washington University School of Medicine St. Louis, MO
c Department of Emergency Medicine Alpert Medical School of Brown University Providence, RI
d Department of Emergency Medicine Case Western Reserve University School of Medicine Cleveland, OH
e Department of Emergency Medicine Yale School of Medicine New Haven, CT
f Department of Emergency Medicine Emory University Atlanta, GA
 
 


Document Type: Article in Press
Source: Scopus



Zhu, C.a , Herrmann, U.S.a , Li, B.a , Abakumova, I.a , Moos, R.a , Schwarz, P.a , Rushing, E.J.a , Colonna, M.b , Aguzzi, A.a
Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains
(2015) Neurobiology of Aging, 36 (5), pp. 1994-2003. 

DOI: 10.1016/j.neurobiolaging.2015.02.019

a Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2-/- mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. © 2015 Elsevier Inc.

Author Keywords
Microglial activation;  Neuroinflammation;  Pathogenesis;  Prion disease;  TREM2


Document Type: Article
Source: Scopus



Sorensen, C.J.a , Johnson, M.B.b , Callaghan, J.P.c , George, S.Z.d , Van Dillen, L.R.a
Validity of a Paradigm for Low Back Pain Symptom Development During Prolonged Standing
(2015) Clinical Journal of Pain, 31 (7), pp. 652-659. 

DOI: 10.1097/AJP.0000000000000148

a Program in Physical Therapy, Washington University School of Medicine in St. Louis, Campus Box 8502, 4444 Forest Park Blvd, Saint Louis, MO, United States
b Integrated Motion Studio, Austin, TX, United States
c Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada
d Department of Physical Therapy, Center for Pain Research and Behavioral Health, University of Florida, Gainesville, FL, United States

Abstract
Objectives: Examine the validity of an induced pain paradigm in which people stand while performing simulated light work tasks (standing paradigm). Materials and Methods: Initially, people with low back pain (LBP) reported the quality and location of their typical symptoms on a body pain diagram. Then, people with LBP and back-healthy people stood for 2 hours and reported the intensity, quality, and location of symptoms at baseline and every 15 minutes. Quality and location of typical symptoms of people with LBP were compared with their symptoms during standing. Back-healthy people were separated into pain developers (PDs) and nonpain developers. Symptom quality and location were compared between people with LBP and PDs. Results: There were no differences in the quality and location of typical symptoms and symptoms during standing in people with LBP (P > 0.05). Three symptom descriptors were used by > 30% of people with LBP to describe typical symptoms. Only 2 people with LBP used these descriptors to describe typical symptoms but not during standing. There were no differences in the quality and location of symptoms reported in standing between people with LBP and PDs (P > 0.05). Four symptom descriptors were used by > 30% of participants with LBP during standing. There were no symptoms reported by PDs that were not reported by people with LBP. Discussion: This study provides evidence that symptoms experienced during the standing paradigm are similar to symptoms experienced by people with LBP and, thus, provides support for the validity of the paradigm. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
induced pain paradigm;  low back pain;  prolonged standing


Document Type: Article
Source: Scopus