Scopus weekly reports:
May 29, 2013
May 22, 2013
May 15, 2013
May 1, 2013
May 29, 2013
Bryant, L.a , Coffey, A.a , Povinelli, D.J.b , Pruett, J.R.c
Theory of Mind experience sampling in typical adults
(2013) Consciousness and Cognition, 22 (3), pp. 697-707.
a Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
b Department of Biology, University of Louisiana, 104 University Circle, Lafayette, LA 70504, United States
c Department of Psychiatry, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
We explored the frequency with which typical adults make Theory of Mind (ToM) attributions, and under what circumstances these attributions occur. We used an experience sampling method to query 30 typical adults about their everyday thoughts. Participants carried a Personal Data Assistant (PDA) that prompted them to categorize their thoughts as Action, Mental State, or Miscellaneous at approximately 30 pseudo-random times during a continuous 10-h period. Additionally, participants noted the direction of their thought (self versus other) and degree of socializing (with people versus alone) at the time of inquiry. We were interested in the relative frequency of ToM (mental state attributions) and how prominent they were in immediate social exchanges. Analyses of multiple choice answers suggest that typical adults: (1) spend more time thinking about actions than mental states and miscellaneous things, (2) exhibit a higher degree of own- versus other-directed thought when alone, and (3) make mental state attributions more frequently when not interacting (offline) than while interacting with others (online). A significant 3-way interaction between thought type, direction of thought, and socializing emerged because action but not mental state thoughts about others occurred more frequently when participants were interacting with people versus when alone; whereas there was an increase in the frequency of both action and mental state attributions about the self when participants were alone as opposed to socializing. A secondary analysis of coded free text responses supports findings 1-3. The results of this study help to create a more naturalistic picture of ToM use in everyday life and the method shows promise for future study of typical and atypical thought processes. © 2013 Elsevier Inc.
Experience sampling; Folk psychology; Social cognition; Theory of Mind
Document Type: Article
Persky, S.a , Kaphingst, K.A.b , Allen Jr., V.C.c , Senay, I.d
Effects of patient-provider race concordance and smoking status on lung cancer risk perception accuracy among African-Americans
(2013) Annals of Behavioral Medicine, 45 (3), pp. 308-317. Cited 1 time.
a Social and Behavioral Research Branch, National Human Genome Research Institute, 31 Center Drive, Bethesda, MD 20892, United States
b Washington University in St. Louis, St. Louis, MO, United States
c University of California, Los Angeles, Los Angeles, CA, United States
d Zirve University, Gaziantep, Turkey
Background: Communication of lung cancer risk information between providers and African-American patients occurs in a context marked by race-based health disparities. Purpose: A controlled experiment assessed whether perceived physician race influenced African-American patients' (n = 127) risk perception accuracy following the provision of objective lung cancer risk information. Methods: Participants interacted with a virtual reality-based, simulated physician who provided personalized cancer risk information. Results: Participants who interacted with a racially discordant virtual doctor were less accurate in their risk perceptions at post-test than those who interacted with a concordant virtual doctor, F(1,94) = 4.02, p =.048. This effect was amplified among current smokers. Effects were not mediated by trust in the provider, engagement with the health care system, or attention during the encounter. Conclusions: The current study demonstrates that African-American patients' perceptions of a doctor's race are sufficient to independently impact their processing of lung cancer risk information. © 2013 The Society of Behavioral Medicine (outside the USA).
Lung cancer; Race concordance; Risk perception; Smoking; Virtual reality
Gaffrey, M.S., Barch, D.M., Singer, J., Shenoy, R., Luby, J.L.
Disrupted Amygdala Reactivity in Depressed 4- to 6-Year-Old Children
(2013) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press.
Washington University, St. Louis
Objective: Disrupted amygdala activity in depressed adolescents and adults while viewing facial expressions of emotion has been reported. However, few data are available to inform the developmental nature of this phenomenon, an issue that studies of the earliest known forms of depression might elucidate. The current study addressed this question by examining functional brain activity and its relationships to emotion regulation in depressed 4- to 6-year-old children and their healthy peers. Method: A total of 54 medication-naive 4- to 6-year-olds (23 depressed and 31 healthy) participated in a case-control study using functional magnetic resonance imaging (fMRI). Imaging data were used to compare functional brain activity in children with and without depression during emotion face processing. Results: A right-lateralized pattern of elevated amygdala, thalamus, inferior frontal gyrus, and angular gyrus activity during face processing was found in depressed 4- to 6-year-olds. In addition, relationships between increased amygdala activity during face processing and disruptions in parent-reported emotion regulation and negative affect were found. No between-group differences specific to emotion face type were identified. Conclusion: To our knowledge, this is the earliest evidence of alterations in functional brain activity in depression using fMRI. Results suggest that, similar to findings in older depressed groups, depression at this age is associated with disrupted amygdala functioning during face processing. The findings also raise the intriguing possibility that disrupted amygdala function is a depression-related biomarker that spans development. Additional studies will be needed to clarify whether the current findings are a precursor to or a consequence of very early childhood depression. © 2013 American Academy of Child and Adolescent Psychiatry.
amygdala; depression; face processing; functional magnetic resonance imaging (fMRI); preschool depression
Document Type: Article in Press
Barch, D.M.a b c , Bustillo, J.d , Gaebel, W.e , Gur, R.f g h , Heckers, S.i , Malaspina, D.j k , Owen, M.J.l m , Schultz, S.n , Tandon, R.o , Tsuang, M.p q r s t , Van Os, J.u v , Carpenter, W.w
Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: Relevance to DSM-5
(2013) Schizophrenia Research, . Article in Press.
a Department of Psychology, Washington University, St. Louis, MO, USA
b Department of Psychiatry, Washington University, St. Louis, MO, USA
c Department of Radiology, Washington University, St. Louis, MO, USA
d Department of Psychiatry, University of New Mexico, Albuquerque, NM, USA
e Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany
f Department of Psychiatry, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
g Department of Neurology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
h Department of Radiology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
i Department of Psychiatry, Vanderbilt University, Nashville, TN, USA
j Department of Psychiatry, New York University, New York, NY, USA
k New York State Office of Mental Health, Creedmoor Psychiatric Center, Queens, NY, USA
l MRC Centre for Neuropsychiatric Genetics, Cardiff University, Cardiff, Wales, United Kingdom
m Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales, United Kingdom
n Department of Psychiatry, University of Iowa School of Medicine, Iowa City, IA, USA
o Department of Psychiatry, University of Florida Medical School, Gainesville, FL, USA
p Center for Behavioral Genomics, University of California San Diego, San Diego, CA, USA
q Department of Psychiatry, University of California San Diego, San Diego, CA, USA
r Institute of Genomic Medicine, University of California San Diego, San Diego, CA, USA
s Veterans Affairs San Diego Health Care System, San Diego, CA, USA
t Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard School of Public Health, Boston, MA, USA
u Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, The Netherlands
v King's College London, King's Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, United Kingdom
w Department of Psychiatry, Maryland Psychiatric Research Center, Baltimore, MD, USA
Work on the causes and treatment of schizophrenia and other psychotic disorders has long recognized the heterogeneity of the symptoms that can be displayed by individuals with these illnesses. Further, researchers have increasingly emphasized the ways in which the severity of different symptoms of this illness can vary across individuals, and have provided evidence that the severity of such symptoms can predict other important aspects of the illness, such as the degree of cognitive and/or neurobiological deficits. Additionally, research has increasingly emphasized that the boundaries between nosological entities may not be categorical and that the comorbidity of disorders may reflect impairments in common dimensions of genetic variation, human behavior and neurobiological function. As such, it is critical to focus on a dimensional approach to the assessment of symptoms and clinically relevant phenomena in psychosis, so as to increase attention to and understanding of the causes and consequences of such variation. In the current article, we review the logic and justification for including dimensional assessment of clinical symptoms in the evaluation of psychosis in the Fifth Edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5). © 2013.
Cognition; Diagnosis; Dimensions; DSM-5; Psychosis; Schizoaffective
Moore, R.P.a , Wester, T.a , Sunder, R.a , Schrock, C.a , Park, T.S.b
Peri-operative pain management in children with cerebral palsy: Comparative efficacy of epidural vs systemic analgesia protocols
(2013) Paediatric Anaesthesia, . Article in Press.
a Division of Pediatric Anesthesiology Department of Anesthesiology Washington University in St. Louis School of Medicine St. Louis, MO USA
b Division of Pediatric Neurosurgery Department of Neurosurgery Washington University in St. Louis School of Medicine St. Louis, MO USA
Summary: Introduction: Selective Dorsal Rhizotomy (SDR) is the only surgical intervention with class I evidence supporting permanent reduction in spasticity for children with cerebral palsy (Paediatr Anaesth, 12, 2002, 296; Neurosurg Focus, 21, 2006, e2). Postoperatively, adequate analgesia can be difficult to achieve (J Neurosurg, 105, 2006, 8; Childs Nerv Syst, 17, 2001, 556; Pediatr Neurosurg, 43, 2007, 107; Anesth Analg, 79, 1994, 340; Reg Anesth Pain Med, 24, 1999, 438; Pediatr Anesth, 19, 2009, 1213). This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac. This regimen was compared to a protocol utilizing systemic fentanyl and diazepam. Methods: Following IRB approval, 31 patients receiving epidural analgesia were compared with 41 patients who received systemic analgesia. All surgeries were performed by one surgeon with standardized anesthetic and nursing care. Studied outcomes included: pain scores; episodes of severe pain; nausea, itching; oxygen desaturation; and ICU admission. Data were analyzed using Mann-Whitney U-test, CHI square, and Fisher exact test where indicated with P < 0.05 considered significant. Results: Studied groups had similar demographics, biometrics and disease burdens. Patients in the epidural group had statistically and clinically significant reductions in peak recorded pain scores for each 4-h period in the first 24 postoperative hours. Severe pain (score >5) was markedly reduced in the epidural group with 9% of epidural patients vs. 68% of systemic patients experiencing at least one episode. Fewer epidural patients experienced oxygen desaturation during the first two postoperative days (6.5% vs. 41%, 6.5% vs. 39%). Conclusion: Epidural analgesia resulted in substantial improvements in pain control and safety. The data supports the superiority of a multimodal analgesia approach centered on epidural analgesia. A similar protocol should be considered following simple laminectomies or procedures associated with lower-extremity muscle spasm. © 2013 John Wiley & Sons Ltd.
Acute; Drugs; Local anesthetics; Neurological disease; Neurosurgery; Pain; Regional
Levinson, C.A., Langer, J.K., Rodebaugh, T.L.
Reactivity to Exclusion Prospectively Predicts Social Anxiety Symptoms in Young Adults
(2013) Behavior Therapy, . Article in Press.
Washington University in St. Louis
Peer victimization leads to negative outcomes such as increased anxiety and depression. The prospective relationship between peer victimization and social anxiety in children and adolescents is well established, and adults with social anxiety disorder (SAD) are more likely than individuals with other anxiety disorders to report a history of teasing. However, a crucial bridge between these findings (peer victimization in young adults) is missing. We manipulated perceptions of peer exclusion in a young adult sample (N = 108) using the Cyberball Ostracism Task. Reactivity to exclusion prospectively predicted social anxiety symptoms at a 2-month follow-up, whereas self-reported teasing during high school and current relational victimization did not. This research suggests that reactions to peer victimization may be a worthwhile target for clinical interventions in young adults. Targeting how young adults react to stressful social interactions such as exclusion may help prevent the development of SAD. Future research should test if reactivity to exclusion plays a role in the relationship between other disorders (e.g., depression) and peer victimization. © 2013.
Cyberball; exclusion; peer victimization; social anxiety
Guo, K., Zhegalova, N., Achilefu, S., Berezin, M.Y.
Bloodstain age analysis: Toward solid state fluorescent lifetime measurements
(2013) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 8572, art. no. 857214, .
Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
One of the most pressing unsolved challenges in forensic science is the determination of time since deposition (TSD) of bloodstains at crime scenes. Despite a number of high profile cases over the past couple hundred years involving controversy over TSD methods, no reliable quantitative method has been established. We present here an approach that has yet to be explored by forensic scientist: measuring the fluorescence lifetime of solid-state blood. Such a method would allow for on-site measurements of bloodstains utilizing the appropriate device, and would allow for rapid results returned in real-time to investigators. © 2013 Copyright SPIE.
albumin; analysis; blood; forensics; tryptophan
Document Type: Conference Paper
Mcdonald, C.M.a , Henricson, E.K.a , Abresch, R.T.a , Han, J.J.a , Escolar, D.M.b , Florence, J.M.c , Duong, T.d , Arrieta, A.d , Clemens, P.R.e , Hoffman, E.P.d f , Cnaan, A.d g , V. Vishwanathanh , S. Chidambaranathanh , W. Douglas Biggari , Jean K. Mahj , Mar Tuliniusk , Robert Leshnerl , Carolina Tesi-Rochal , Andrew Kornbergm , Monique Ryanm , Yoram Nevon , Alberto Dubrovskyo , Nancy Kuntzp , Sherilyn Driscollp , Anne Connollyq , Alan Pestronkq , Jean Teasleyr , Tulio Bertorinis , Kathryn Northt , Hanna Kolskiu , Jose Carlov , Ksenija Gorniw , Timothy Lotzex , John Dayy
The cooperative international neuromuscular research group duchenne natural history study-a longitudinal investigation in the era of glucocorticoid therapy: Design of protocol and the methods used
(2013) Muscle and Nerve, . Article in Press.
a Department of Physical Medicine and RehabilitationSchool of MedicineUniversity of CaliforniaDavis, 4860 Y Street, Suite 3850Sacramento, California95817USA
b Department of NeurologyKennedy Krieger InstituteBaltimore, MarylandUSA
c Department of NeurologyWashington UniversitySt. Louis, MissouriUSA
d Center for Genetic Medicine ResearchChildren's National Medical CenterWashington, DC USA
e Department of NeurologyUniversity of Pittsburgh and Department of Veterans Affairs Medical CenterPittsburgh, PennsylvaniaUSA
f Department of Integrative Systems BiologyGeorge Washington UniversityWashington, DCUSA
g Departments of Pediatrics, Epidemiology, and BiostatisticsGeorge Washington UniversityWashington, DCUSA
h Sundaram Medical Foundation and Apollo Children's Hospital
i Holland Bloorview Kids Rehabilitation Hospital
j Alberta Children's Hospital
k Queen Sylvia Children's Hospital
l Children's National Medical Center
m Royal Children's Hospital
n Hadassah Hebrew University Hospital
o Instituto de Neurosciencias Fundacion Favaloro
p Mayo Clinic
q Washington University, St. Louis
r Children's Hospital of Virginia
s University of Tennessee, Memphis
t Children's Hospital of Westmead
u University of Alberta
v University of Puerto Rico
w University of Pavia and Niguarda Ca' Granda Hospital
x Texas Children's Hospital
y University of Minnesota
Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. Methods: The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments. Results: Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). Conclusions: Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. © 2013 Wiley Periodicals, Inc.
Adolescent; Adult; Child/preschool; Follow-up study; Health status; Human; Locomotion; Male; Muscle strength/physiology; Muscular dystrophies/classification; Muscular dystrophies/Duchenne/physiopathology; Muscular dystrophies/therapy; Phenotype; Quality of life/psychology; Respiratory function test
Mechelli, R.ao , Umeton, R.ao , Policano, C.ao , Annibali, V.ao , Coarelli, G.ao , Ricigliano, V.A.G.ao , Vittori, D.ao , Fornasiero, A.ao , Buscarinu, M.C.ao , Romano, S.ao , Salvetti, M.ao , Ristori, G.ao , Sawcer, S.a ao , Hellenthal, G.b ao , Pirinen, M.b ao , Spencer, C.C.A.b ao , Patsopoulos, N.A.c e ao , Moutsianas, L.f ao , Dilthey, A.f ao , Su, Z.b ao , Freeman, C.b ao , Hunt, S.E.g ao , Edkins, S.g ao , Gray, E.g ao , Booth, D.R.h ao , Potter, S.C.g ao , Goris, A.i ao , Band, G.b ao , Oturai, A.B.j ao , Strange, A.b ao , Saarela, J.k ao , Bellenguez, C.b ao , Fontaine, B.l ao , Gillman, M.g ao , Hemmer, B.mao , Gwilliam, R.g ao , Zipp, F.n o ao , Jayakumar, A.g ao , Martin, R.p ao , Leslie, S.q ao , Hawkins, S.r ao , Giannoulatou, E.b ao , D'alfonso, S.s ao , Blackburn, H.g ao , Boneschi, F.M.t ao , Liddle, J.g ao , Harbo, H.F.u v ao , Perez, M.L.g ao , Spurkland, A.w ao , Waller, M.J.g ao , Mycko, M.P.x ao , Ricketts, M.g ao , Comabella, M.y ao , Hammond, N.g ao , Kockum, I.z ao , McCann, O.T.g ao , Ban, M.a ao , Whittaker, P.g ao , Kemppinen, A.a ao , Weston, P.g ao , Hawkins, C.aaao , Widaa, S.g ao , Zajicek, J.ab ao , Dronov, S.g ao , Robertson, N.ac ao , Bumpstead, S.J.g ao , Barcellos, L.F.ad ae ao , Ravindrarajah, R.g ao , Abraham, R.aa ao , Alfredsson, L.af ao , Ardlie, K.d ao , Aubin, C.d ao , Baker, A.a ao , Baker, K.acao , Baranzini, S.E.ag ao , Bergamaschi, L.s ao , Bergamaschi, R.ah ao , Bernstein, A.ae ao , Berthele, A.m ao , Boggild, M.ai ao , Bradfield, J.P.aj ao , Brassat, D.ak ao , Broadley, S.A.al ao , Buck, D.m ao , Butzkueven, H.am ao ap , Capra, R.aoaq , Carroll, W.M.ao ar , Cavalla, P.ao as , Celius, E.G.u ao , Cepok, S.m ao , Chiavacci, R.aj ao , Clerget-Darpoux, F.ao at , Clysters, K.i ao , Comi, G.t ao , Cossburn, M.ac ao , Cournu-Rebeix, I.l ao , Cox, M.B.ao au , Cozen, W.ao av , Cree, B.A.C.ag ao , Cross, A.H.ao aw , Cusi, D.ao ax , Daly, M.J.d ao ay az , Davis, E.ao ba , de Bakker, P.I.W.c d ao bb bc , Debouverie, M.ao bd , D'hooghe, M.B.ao be , Dixon, K.ao ba , Dobosi, R.i ao , Dubois, B.i ao , Ellinghaus, D.ao bf , Elovaara, I.ao bg bh , Esposito, F.t ao , Fontenille, C.l ao , Foote, S.ao bi , Franke, A.ao bf , Galimberti, D.ao bj , Ghezzi, A.ao bk , Glessner, J.aj ao , Gomez, R.ag ao , Gout, O.ao bl , Graham, C.ao bm , Grant, S.F.A.aj ao bn bo , Guerini, F.R.ao bp, Hakonarson, H.aj ao bn bo , Hall, P.ao bq , Hamsten, A.ao br , Hartung, H.-P.ao bs , Heard, R.N.h ao , Heath, S.ao bt , Hobart, J.ab ao , Hoshi, M.m ao , Infante-Duarte, C.ao bu , Ingram, G.ac ao , Ingram, W.ab ao , Islam, T.ao av , Jagodic, M.zao , Kabesch, M.ao bv , Kermode, A.G.ao ar , Kilpatrick, T.J.am an ao bw , Kim, C.aj ao , Klopp, N.ao bx , Koivisto, K.ao by , Larsson, M.ao br , Lathrop, M.ao bt , Lechner-Scott, J.S.ao au bz , Leone, M.A.ao ca , Leppä, V.k ao cb , Liljedahl, U.ao cc , Bomfim, I.L.z ao , Lincoln, R.R.ag ao , Link, J.z ao , Liu, J.ao cd , Lorentzen, Å.R.v ao ce , Lupoli, S.ao ax cf , Macciardi, F.aoax cg , Mack, T.ao av , Marriott, M.am an ao , Martinelli, V.t ao , Mason, D.ao ch , McCauley, J.L.ao ci , Mentch, F.aj ao , Mero, I.-L.u ao ce , Mihalova, T.aa ao , Montalban, X.y ao , Mottershead, J.ao cj ck , Myhr, K.-M.ao cl cm , Naldi, P.ao ca , Ollier, W.ao ba , Page, A.ao cn , Palotie, A.g k ao co cp , Pelletier, J.ao cq , Piccio, L.ao aw , Pickersgill, T.ac ao , Piehl, F.z ao , Pobywajlo, S.e ao , Quach, H.L.ad ao , Ramsay, P.P.ad ao , Reunanen, M.ao cr , Reynolds, R.ao cs , Rioux, J.D.ao ct , Rodegher, M.t ao , Roesner, S.p ao , Rubio, J.P.am ao , Rückert, I.-M.ao bx , Salvi, E.ao ax cv , Santaniello, A.ag ao , Schaefer, C.A.ae ao , Schreiber, S.ao bf cw , Schulze, C.ao cx , Scott, R.J.ao au , Sellebjerg, F.j ao , Selmaj, K.W.x ao , Sexton, D.ao cy , Shen, L.ae ao , Simms-Acuna, B.ae ao , Skidmore, S.a ao , Sleiman, P.M.A.aj ao bn , Smestad, C.u ao , Sørensen, P.S.j ao , Søndergaard, H.B.j ao , Stankovich, J.ao bi , Strange, R.C.aa ao , Sulonen, A.-M.k ao cb , Sundqvist, E.z ao , Syvänen, A.-C.ao cc , Taddeo, F.ao cv , Taylor, B.ao bi , Blackwell, J.M.ao cz da , Tienari, P.ao db , Bramon, E.ao dc , Tourbah, A.ao dd , Brown, M.A.ao de , Tronczynska, E.x ao , Casas, J.P.ao df , Tubridy, N.an ao dg , Corvin, A.ao dh , Vickery, J.ab ao , Jankowski, J.ao di , Villoslada, P.ao dj , Markus, H.S.ao dk , Wang, K.aj ao bn , Mathew, C.G.ao dl , Wason, J.ao dm , Palmer, C.N.A.ao dn , Wichmann, H.-E.ao bx do dp , Plomin, R.ao dq , Willoughby, E.ao dr , Rautanen, A.b ao , Winkelmann, J.m ao ds dt , Wittig, M.ao bf du , Trembath, R.C.ao dl , Yaouanq, J.ao dv , Viswanathan, A.C.ao dw , Zhang, H.aj ao bn , Wood, N.W.ao dx , Zuvich, R.ao cy , Deloukas, P.g ao , Langford, C.g ao , Duncanson, A.ao dy , Oksenberg, J.R.ag ao , Pericak-Vance, M.A.ao ci , Haines, J.L.ao cy , Olsson, T.z ao , Hillert, J.z ao , Ivinson, A.J.ao ay dz , De Jager, P.L.d e ao ay , Peltonen, L.g k ao cb co cp , Stewart, G.J.h ao , Hafler, D.A.d ao cu , Hauser, S.L.ag ao , McVean, G.b ao , Donnelly, P.b f ao , Compston, A.a ao
A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis
(2013) PLoS ONE, 8 (5), art. no. e63300, .
a University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, United Kingdom
b Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, United Kingdom
c Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
d Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, United States
e Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA, United States
f Dept Statistics, University of Oxford, Oxford, United Kingdom
g Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
h Westmead Millennium Institute, University of Sydney, Australia
i Laboratory for Neuroimmunology, Section of Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium
j Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
k Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
l INSERM UMR S 975 CRICM, UPMC, Département de neurologie Pitié-Salpêtrière, AP-HP, Paris, France
m Department of Neurology, Klinikum Rechts der Isar der Technischen Universität, Munich, Germany
n Department of Neurology, University Medicine Mainz, Johannes Gutenberg University Mainz, Mainz, Germany
o Max Delbrueck Center for Molecular Medicine, Berlin, Germany
p Institute for Neuroimmunology and Clinical MS Research (inims), Centre for Molecular Neurobiology, Hamburg, Germany
q Department of Clinical Pharmacology, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom
r Queen's University Belfast, University Road, Belfast, Northern Ireland, United Kingdom
s Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
t Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
u Department of Neurology, Oslo University Hospital, Oslo, Norway
v Department of Neurology, University of Oslo, Oslo, Norway
w Institute of Basal Medical Sciences, University of Oslo, Oslo, Norway
x Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, Poland
y Clinical Neuroinmunology Unit, Multiple Sclerosis Center of Catalonia (CEM-Cat), Vall d'Hebron University Hospital, Barcelona, Spain
z Department of Clinical Neurosciences, Centre for Molecular Medicine CMM, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden
aa Keele University Medical School, Stoke-on-Trent, United Kingdom
ab Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth, Clinical Neurology Research Group, Tamar Science Park, Plymouth, United Kingdom
ac Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, United Kingdom
ad Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, United States
ae Kaiser Permanente Northern California Division of Research, CA, United States
af Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
ag Department of Neurology, University of California San Francisco, San Francisco, CA, United States
ah Neurological Institute C. Mondino, IRCCS, Pavia, Italy
ai The Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
aj Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
ak INSERM U 563 et Pôle Neurosciences, Hopital Purpan, Toulouse, France
al School of Medicine, Griffith University, Australia
am Florey Neuroscience Institutes, University of Melbourne, Victoria, Australia
an Royal Melbourne Hospital, Parkville, VIC, Australia
ao Centre for Experimental Neurological Therapies, S. Andrea Hospital-site, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University, Rome, Italy
ap Department of Medicine, RMH Cluster, University of Melbourne, Victoria, Australia
aq Multiple Sclerosis Centre, Department of Neurology, Ospedali Civili di Brescia, Brescia, Italy
ar Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Australia
as Department of Neurosciences, University of Turin, A.O.U. San Giovanni Battista, Turin, Italy
at INSERM U535, Univ Paris-Sud, Villejuif, France
au University of Newcastle, University Drive, Callaghan NSW, Australia
av Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
aw Department of Neurology, Washington University, St Louis MO, United States
ax Department of Medicine, Surgery and Dentistry, AO San Paolo, University of Milan, c/o Filarete Foundation, Milano, Italy
ay Harvard Medical School, Boston, MA, United States
az Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States
ba The UK DNA Banking Network, Centre for Integrated Genomic Medical Research, University of Manchester, United Kingdom
bb Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
bc Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
bd Service de Neurologie, Hôpital Central, Nancy, France
be National Multiple Sclerosis Center, Melsbroek, Belgium
bf Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
bg Department of Neurology, Tampere University Hospital, Tampere, Finland
bh University of Tampere, Medical School, Tampere, Finland
bi Menzies Research Institute, Hobart, TAS, Australia
bj Department of Neurological Sciences, Centro Dino Ferrari, University of Milan, Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
bk Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Gallarate (VA), Italy
bl Service de Neurologie, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
bm Belfast Health and Social Care Trust, City Hospital, Belfast, Northern Ireland, United Kingdom
bn Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
bo Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
bp Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS, S. Maria Nascente, Milan, Italy
bq Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
br Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden
bs Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany
bt Centre National de Genotypage, Evry Cedex, France
bu Experimental and Clinical Research Center, Charité - Universitä tsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany
bv Clinic for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Germany
bw Centre for Neuroscience, University of Melbourne, Victoria, Australia
bx Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Munich, Germany
by Seinäjoki Central Hospital, Seinäjoki, Finland
bz Hunter Medical Research Institute, John Hunter Hospital, Lookout Road, New Lambton NSW, Australia
ca SCDU Neurology, Maggiore della Carità Hospital, Novara, Italy
cb Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland
cc Molecular Medicine, Department of Medical Sciences, Uppsala University, Univeristy Hospital, Entrance 70, 3rd Floor, Res Dept 2, Uppsala, Sweden
cd Human Genetics and Cancer Biology, Genome Institute of Singapore, Singapore
ce Institute of Immunology, Oslo University Hospital, Oslo, Norway
cf Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy
cg Dept of Psychiatry and Human Behavior, University of California, Irvine (UCI), Irvine CA, United States
ch Christchurch School of Medicine, University of Otago, Christchurch, New Zealand
ci John P. Hussman Institute for Human Genomics, The Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, United States
cj Greater Manchester Centre for Clinical Neurosciences, Hope Hospital, Salford, United Kingdom
ck The Department of Neurology, Dunedin Public Hospital, Otago, New Zealand
cl The Multiple Sclerosis National Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway
cm Department of Clinical Medicine, University of Bergen, Bergen, Norway
cn Plymouth Hospitals NHS Trust, Department of Neurology, Derriford Hospital, Plymouth, United Kingdom
co Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
cp Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
cq Pôle Neurosciences Cliniques, Service de Neurologie, Hôpital de la Timone, Marseille, France
cr Department Neurology, Oulu University Hospital, Oulu, Finland
cs UK MS Tissue Bank, Wolfson Neuroscience Laboratories, Imperial College London, Hammersmith Hospital, London, United Kingdom
ct Université de Montréal and Montreal Heart Institute, Research Center, Montreal, QC, Canada
cu Department of Neurology and Immunology, Yale University Medical School, New Haven, CT, United States
cv KOS Genetic Srl, Milan, Italy
cw Department of General Internal Medicine, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
cx Systems Biology and Protein-Protein Interaction, Center for Molecular Neurobiology, Hamburg, Germany
cy Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, United States
cz Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Australia
da Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
db Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland
dc Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London, United Kingdom
dd Service de Neurologie et Faculté de Médecine de Reims, Université de Reims Champagne-Ardenne, Reims, France
de University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia
df Dept Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
dg St. Vincent's University Hospital, Dublin, Ireland
dh Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
di Centre for Gastroenterology, Bart's and the London School of Medicine and Dentistry, London, United Kingdom
dj Department of Neurosciences, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, Spain
dk Clinical Neurosciences, St George's University of London, London, United Kingdom
dl Dept Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom
dm Medical Research Council Biostatistics Unit, Robinson Way, Cambridge, United Kingdom
dn Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
do Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
dp Klinikum Grosshadern, Munich, Germany
dq King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London, United Kingdom
dr Department of Neurology, Auckland City Hospital, Grafton Road, Auckland, New Zealand
ds Institut für Humangenetik, Technische Universität München, Germany
dt Institut für Humangenetik, Helmholtz Zentrum München, Germany
du Popgen Biobank, Christian-Albrechts University Kiel, Kiel, Germany
dv Pôle Recherche et Santé Publique, CHU Pontchaillou, Rennes, France
dw NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, UCL Institute of Ophthalmology, London, United Kingdom
dx Dept Molecular Neuroscience, Institute of Neurology, Queen Square, London, United Kingdom
dy Molecular and Physiological Sciences, The Wellcome Trust, London, United Kingdom
dz Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, United States
Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.
Wanda, P.A., Fine, M.S., Weeks, H.M., Gross, A.M., MacY, J.L., Thoroughman, K.A.
Brevity of haptic force perturbations induces heightened adaptive sensitivity
(2013) Experimental Brain Research, 226 (3), pp. 407-420.
Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, One Brookings Drive, St. Louis, MO 63130, United States
We have exposed human participants to both full-movement and pulsatile viscous force perturbations to study the effect of force duration on the incremental transformation of sensation into adaptation. Traditional views of movement biomechanics could suggest that pulsatile forces would largely be attenuated as stiffness and viscosity act as a natural low-pass filter. Sensory transduction, however, tends to react to changes in stimuli and therefore could underlie heightened sensitivity to briefer, pulsatile forces. Here, participants adapted within perturbation duration conditions in a manner proportionate to sensed force and positional errors. Across perturbation conditions, we found participants had greater adaptive sensitivity when experiencing pulsatile forces rather than full-movement forces. In a follow-up experiment, we employed error-clamped, force channel trials to determine changes in predictive force generation. We found that while participants learned to closely compensate for the amplitude and breadth of full-movement forces, they exhibited a persistent mismatch in amplitude and breadth between adapted motor output and experienced pulsatile forces. This mismatch could generate higher salience of error signals that contribute to heightened sensitivity to pulsatile forces. © 2013 Springer-Verlag Berlin Heidelberg.
Force channels; Haptic environments; Human motor adaptation; Motor control; Trial-by-trial learning
Zayas, L.E.a , McMillen, J.C.b , Lee, M.Y.c , Books, S.J.d
Challenges to quality assurance and improvement efforts in behavioral health organizations: A qualitative assessment
(2013) Administration and Policy in Mental Health and Mental Health Services Research, 40 (3), pp. 190-198.
a School of Social Work, Arizona State University, 411 N. Central Ave., Phoenix, AZ 85004-0689, United States
b School of Social Services Administration, University of Chicago, Chicago, IL, United States
c School of Social Work, Tulane University, New Orleans, LA, United States
d School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
Behavioral health organizations have been increasingly required to implement plans to monitor and improve service quality. This qualitative study explores challenges that quality assurance and improvement (QA/I) personnel experience in performing their job in those practice settings. Sixteen QA/I personnel from different agencies in St. Louis, Missouri, U.S.A., were interviewed face-to-face using a semi-structured instrument to capture challenges and a questionnaire to capture participant and agency characteristics. Data analysis followed a grounded theory approach. Challenges involved agency resources, agency buy-in, personnel training, competing demands, shifting standards, authority, and research capacity. Further research is needed to assess these challenges given expected outcomes. © 2011 Springer Science+Business Media, LLC.
Behavioral health services; Qualitative methods; Quality assurance; Quality improvement
Xu, X.a , Nehorai, A.a , Dougherty, J.b
Cell type specific analysis of human transcriptome data
(2012) Proceedings - IEEE International Workshop on Genomic Signal Processing and Statistics, art. no. 6507737, pp. 99-100.
a Preston M. Green Department of Electrical and Systems Engineering, Washington University, St. Louis, MO 63130, United States
b Department of Genetics, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63130, United States
The central nervous system (CNS) is composed of hundreds of distinct cell types, each expressing different subsets of genes from the genome. High throughput gene expression analysis of complex tissues like the CNS from patients and controls is a common method to screen for potentially pathological molecular mechanisms of psychiatric disease. One mechanism by which gene expression might be seen to vary across samples would be alterations in the cellular composition of the tissue. While there are a few gene 'markers' from literature for each cell type, their expression patterns vary significantly resulting in poor sensitivity and specificity. Here, we propose a method utilizing prior information from cell specific transcriptome profiling experiments in mice and co-expression network analysis to select cell type specific gene markers, and further to analytically detect changing cellular composition in human tissues. Our method successfully detects changes in cellularity over time that roughly correspond to known epochs of human brain development. © 2012 IEEE.
May 22, 2013
Etzel, J.A.a , Zacks, J.M.b , Braver, T.S.a
Searchlight analysis: Promise, pitfalls, and potential
(2013) NeuroImage, 78, pp. 261-269.
a Cognitive Control and Psychopathology Lab., Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
b Dynamic Cognition Laboratory, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
Document Type: Note
Levinson, C.A.a d , Rodebaugh, T.L.a , White, E.K.b , Menatti, A.R.c , Weeks, J.W.d , Iacovino, J.M.a , Warren, C.S.b
Social appearance anxiety, perfectionism, and fear of negative evaluation: Distinct or shared risk factors for social anxiety and eating disorders?
(2013) Appetite, 67, pp. 125-133.
a Washington University, St. Louis, United States
b University of Nevada, Las Vegas, United States
c Ohio University, Athens, OH, United States
d Department of Psychology, Washington University, St. Louis, MO 63130, United States
Social anxiety and eating disorders are highly comorbid. Social appearance anxiety (i.e., fear of negative evaluation of one's appearance), general fear of negative evaluation, and perfectionism have each been proposed as risk factors for both social anxiety disorder and the eating disorders. However, no research to date has examined all three factors simultaneously. Using structural equation modeling in two diverse samples (N=236; N=136) we tested a model in which each of these risk factors were uniquely associated with social anxiety and eating disorder symptoms. We found support for social appearance anxiety as a shared risk factor between social anxiety and eating disorder symptoms, whereas fear of negative evaluation was a risk factor only for social anxiety symptoms. Despite significant zero-order relationships, two facets of perfectionism (high standards and maladaptive perfectionism) did not emerge as a risk factor for either disorder when all constructs were considered. These results were maintained when gender, body mass index, trait negative affect, and depression were included in the model. It is possible that treating negative appearance evaluation fears may reduce both eating disorder and social anxiety symptoms. © 2013 Elsevier Ltd.
Eating disorders; Fear of negative evaluation; Perfectionism; Social anxiety; Social appearance anxiety; Structural equation modeling
Document Type: Article
Wilfley, D.E.a , Agras, W.S.b , Taylor, C.B.b
Reducing the burden of eating disorders: A model for population-based prevention and treatment for university and college campuses
(2013) International Journal of Eating Disorders, 46 (5), pp. 529-532.
a Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, Saint Louis, MO 63110, United States
b Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, United States
Population-based models aim to improve treatment delivery for symptomatic individuals and decrease the number of individuals requiring care. The proposed model has the potential to increase early intervention, reduce costs, and maximize capacity to serve the entire student body, resulting in improvements in students' overall health and well being, self image, academic performance, and quality of life. Although there is preliminary support for this approach, a programmatic line of research to better inform model implementation including long-term effectiveness and cost-effectiveness is needed. Successful implementation has potential for rapid dissemination to reach the 20 million students enrolled in US colleges and universities. Copyright © 2013 Wiley Periodicals, Inc.
Bandt, S.K.a , Werner, N.b , Dines, J.c , Rashid, S.b , Eisenman, L.N.b , Hogan, R.E.b , Leuthardt, E.C.a , Dowling, J.a
Trans-middle temporal gyrus selective amygdalohippocampectomy for medically intractable mesial temporal lobe epilepsy in adults: Seizure response rates, complications, and neuropsychological outcomes
(2013) Epilepsy and Behavior, 28 (1), pp. 17-21.
a Washington University, School of Medicine, Department of Neurological Surgery, St. Louis, MO, United States
b Washington University, School of Medicine, Department of Neurology, St. Louis, MO, United States
c Washington University, School of Medicine, St. Louis, MO, United States
Objective: Selective amygdalohippocampectomy (AHC) has evolved to encompass a variety of techniques to resect the mesial temporal lobe. To date, there have been few large-scale evaluations of trans-middle temporal gyrus selective AHC. The authors examine a large series of patients who have undergone the trans-middle temporal gyrus AHC and assess its clinical and neuropsychological impact. Methods: A series of 76 adult patients underwent selective AHC via the trans-middle temporal gyrus approach over a 10-year period, 19 of whom underwent pre- and postoperative neuropsychological evaluations. Results: Favorable seizure response rates were achieved (92% Engel class I or II), with very low surgical morbidity and no mortality. Postoperative neuropsychological assessment revealed a decline in verbal memory for the left AHC group. No postoperative memory decline was identified for the right AHC group, but rather some improvements were noted within this group. Conclusions: The trans-middle temporal gyrus selective AHC is a safe and effective choice for management of medically refractory epilepsy in adults. © 2013 Elsevier Inc.
Epilepsy; Neuropsychological outcomes; Selective amygdalohippocampectomy; Temporal stem
Levinson, C.A.a , Rodebaugh, T.L.a , Menatti, A.R.b , Weeks, J.W.b
Development and validation of the social exercise and anxiety measure (SEAM): Assessing fears, avoidance, and importance of social exercise
(2013) Journal of Psychopathology and Behavioral Assessment, 35 (2), pp. 244-253.
a Washington University in St. Louis, St. Louis, MO, United States
b Ohio University, Athens, OH, United States
In two studies (N = 416; N = 118) examining responses from undergraduates, we developed the Social Exercise and Anxiety Measure (SEAM) and tested its factorial, convergent, and divergent validity. Our results demonstrate that the SEAM exhibits an excellent three factor structure consisting of the following subscales: Social Exercise Self-efficacy, Gym Avoidance, and Exercise Importance. In both studies, Social Exercise Self-efficacy correlated negatively, and Gym Avoidance correlated positively with social interaction anxiety, fear of scrutiny, and fear of negative evaluation. Exercise Importance correlated positively with frequency of exercise and frequency of public exercise. Implications for the mental and physical health of individuals with high levels of social anxiety are discussed. © 2012 Springer Science+Business Media New York.
Anxiety; Assessment; Exercise; Self-efficacy; Social anxiety
Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations
(2013) Experimental Neurology, 244, pp. 22-26.
Department of Neurology, The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
Focal cortical dysplasia (FCD) and other localized malformations of cortical development represent common causes of intractable pediatric epilepsy. Insights into the cellular and molecular pathogenesis of focal cortical malformations may reveal information about associated mechanisms of epileptogenesis and suggest new therapies for seizures caused by these developmental lesions. In animal models and human studies of FCD and the related disease of Tuberous Sclerosis Complex (TSC), the mammalian target of rapamycin (mTOR) pathway has been implicated in mediating cellular and molecular changes leading to the formation of the cortical malformations and the expression of epilepsy. The use of mTOR inhibitors may represent a rational therapeutic strategy for treating or even preventing epilepsy due to FCD and TSC. © 2011 Elsevier Inc.
Epilepsy; Malformation of cortical development; Seizure; Tuberous sclerosis complex
Document Type: Review
Li, Q.a , Yan, H.a , Ding, T.-B.b , Han, J.a , Shui, Y.-B.c , Beebe, D.C.c
Oxidative responses induced by pharmacologic vitreolysis and/or long-term hyperoxia treatment in rat lenses
(2013) Current Eye Research, 38 (6), pp. 639-648.
a Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
b Department of Microbiology, Fourth Military Medical University, Xi'an, China
c Department of Ophthalmology and Visual Sciences, Washington University, Saint Louis, MO, United States
Purpose: The aim of the study was to investigate the protective effects of intact vitreous gel on the lens after pharmacologic vitreolysis and hyperoxia exposure in rats in vivo. Methods: Eyes of Sprague-Dawley rats were induced to posterior vitreous detachment (PVD) by pharmacologic vitreolysis, and the rats with and without PVD were treated with hyperoxia 3h per day for 5 months. Lens transparency was monitored by a slit-lamp biomicroscope. A series of biochemical measurements were made in extracts of the lens cortex and nucleus. Ascorbate levels were measured in the aqueous and vitreous humors. Results: No significant differences in lens transparency or morphology were observed in all groups, and no significant biochemical changes were observed in the cortex or nucleus of lenses of the PVD group. In the lens nucleus, the values of water-soluble protein concentration in PVD+hyperoxia group were lower than that of the PVD group. The levels of water-soluble proteins, glutathione (GSH) and ascorbate decreased in the hyperoxia group with an intact vitreous body. Vitreolysis enhanced the effect of hyperoxia, decreasing soluble protein, GSH and ascorbate below the levels seen in eyes with vitreolysis alone. The levels of antioxidants and soluble proteins were lower in the lens nucleus, and the effects of vitreolysis plus hyperoxia were more significant in the nucleus. Hyperoxia and hyperoxia plus vitreolysis reduced catalase activity and increased oxidized GSH to a greater extent in the lens cortex, although these treatments increased protein-GSH mixed disulfides in both regions. Long-term hyperoxia also lowered ascorbate levels in the vitreous and aqueous humors, an effect that was enhanced by vitreolysis. Conclusions: Exposure to excess molecular oxygen produces significant oxidative damage to the lens, especially the lens nucleus. These effects were enhanced by pharmacologic vitreolysis, indicating that intact vitreous gel protects the lens from oxidative damage. © 2013 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Cataract; Hyperoxia; Oxidative stress; Pharmacologic vitreolysis; Posterior vitreous detachment
Yaghi, S.a , Moore, P.b , Ray, B.a , Keyrouz, S.G.c
Predictors of tracheostomy in patients with spontaneous intracerebral hemorrhage
(2013) Clinical Neurology and Neurosurgery, 115 (6), pp. 695-698.
a Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, United States
b Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Background: One third of patients with intracerebral hemorrhage (ICH) require mechanical ventilation; in most, tracheostomy may be necessary. Limited data exist about predictors of tracheostomy in ICH. The aim of our study is to identify predictors of tracheostomy in ICH. Methods: We reviewed medical records of patients seen in our institution between 2005 and 2009, using ICD-9 codes for ICH, for admission clinical and radiological parameters. A stepwise logistic regression model was used to identify tracheostomy predictors. Results: Ninety patients with ICH were included in the analysis, eleven of which required tracheostomy. Patients requiring a tracheostomy were more likely to have a large hematoma volume (≥30 mL) (63.4% vs. 29.1%, p = 0.037), intraventricular hemorrhage (81.8% vs. 27.8%, p < 0.0001), hydrocephalus (81.8% vs. 8.8%, p < 0.0001), admission GCS < 8 (81.8% vs. 5.1%, p < 0.0001), intubation ≥ 14 days (54.5% vs. 1.27%, p < 0.0001) and pneumonia (63.6% vs. 17.7%, p = 0.003). Stepwise logistic regression yielded admission GCS (OR = 80.55, p = 0.0003) and intubation days (OR = 87.49, p < 0.006) as most important predictors. Conclusion: We could potentially predict the need for tracheostomy early in the course of ICH based on the admission GCS score; duration of intubation is another predictor for tracheostomy. Early tracheostomy could decrease the time, and therefore risks of prolonged endotracheal intubation and length of hospital stay. © 2012 Elsevier B.V. All rights reserved.
Endotracheal intubation; GCS; Hydrocephalus; Intracerebral hemorrhage; Intraventricular hemorrhage; Tracheostomy
Nguyen, T.-V.a , McCracken, J.d , Ducharme, S.a , Botteron, K.N.e , Mahabir, M.b , Johnson, W.f , Israel, M.c , Evans, A.C.a , Karama, S.a c
Testosterone-related cortical maturation across childhood and adolescence
(2013) Cerebral Cortex, 23 (6), pp. 1424-1432.
a McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
b Integrated Graduate Program in Neuroscience, McGill University, Montreal, QC H3A 2B4, Canada
c Douglas Mental Health University Institute, McGill University, Montreal, QC H3A 2B4, Canada
d Department of Child Psychiatry, University of California in Los Angeles, Los Angeles, CA 90024, United States
e Department of Child Psychiatry and Radiology, School of Medicine, Washington University, St Louis, MO 63130, United States
f Department of Psychology, Edinburgh University, Edinburgh EH8 9AD, United Kingdom
Neuroendocrine theories of brain development hold testosterone as the predominant factor mediating sex-specific cortical growth and the ensuing lateralization of hemispheric function. However, studies to date have focussed on prenatal testosterone rather than pubertal changes in testosterone. Yet, animal studies have shown a high density of androgen-sensitive receptors in multiple key cortical areas, and puberty is known to coincide with both a significant rise in testosterone and the emergence of behavioral sex differences, suggesting peripubertal influences of testosterone on brain development. Here, we used linear mixed models to examine sex-specific cortical maturation associated with changes in testosterone levels in a longitudinal sample of developmentally healthy children and adolescents. A significant "sex by age by testosterone" interaction on cortical thickness (CTh) involving widespread areas of the developing brain was found. Testosterone levels were associated with CTh changes in regions of the left hemisphere in males and of the right hemisphere in females. In both sexes, the relationship between testosterone and CTh varied across the age span. These findings show the association between testosterone and CTh to be complex, highly dynamic, and to vary, depending on sex and age; they also suggest sex-related hemispheric lateralization effects of testosterone in humans. © 2012 The Author.
androgens; brain development; gray matter; puberty; sex
Klebe, S.a b c d e f g , Golmard, J.L.h , Nalls, M.A.i , Saad, M.j k au , Singleton, A.B.i , Bras, J.M.l , Hardy, J.l bf , Simon-Sanchez, J.i m av , Heutink, P.m av , Kuhlenbäumer, G.n , Charfi, R.o p , Klein, C.q , Hagenah, J.q , Gasser, T.r s aw ax , Wurster, I.r s , Lesage, S.a b c aq ay az ba , Lorenz, D.t cv , Deuschl, G.t cc , Durif, F.u , Pollak, P.v cz , Damier, P.w bz , Tison, F.x di , Durr, A.a b c d ay az ba cf , Amouyel, P.y z aa be bf , Lambert, J.C.y z aa , Tzourio, C.ab ac , Maubaret, C.ad , Charbonnier-Beaupel, F.a b c , Tahiri, K.a b c , Vidailhet, M.b c f ae , Martinez, M.j k au , Brice, A.a b c d f ay az ba cf , Corvol, J.C.a b c e o , Agid, Y.af , Anheim, M.ag , Bonnet, A.-M.af , Borg, M.ah , Brice, A.af ag , Broussolle, E.ai , Corvol, J.-C.aj , Damier, Ph.ak , Destée, A.al , Durr, A.ag , Durif, F.am , Klebe, S.ag , Lohmann, E.ag , Martinez, M.an , Penet, C.ao , Pollak, P.v , Krack, P.v , Rascol, O.ap , Tison, F.x , Tranchant, C.aq , Vérin, M.ar , Viallet, F.as , Vidailhet, M.af , Nalls, M.A.i , Plagnol, V.at , Bras, J.M.l , Hernandez, D.G.i l , Sharma, M.au , Sheerin, U.-M.l , Schulte, C.aw ax , Sveinbjörnsdóttir, S.bb bc bd , Arepalli, S.i , Band, G.bg , Vukcevic, D.bg , Barker, R.A.bh , Bellinguez, C.bg , Ben-Shlomo, Y.bi , Berendse, H.W.bj , Berg, D.aw ax , Bhatia, K.bk , De Bie, R.M.A.bl , Biffi, A.bm bn bo , Bloem, B.bp , Bochdanovits, Z.av , Bonin, M.bq , Brockmann, K.aw ax , Brooks, J.i , Burn, D.J.br , Charlesworth, G.l , Chen, H.bs , Chinnery, P.F.bt , Chong, S.i , Clarke, C.E.bu bv , Cookson, M.R.i , Cooper, J.M.bw , Corvol, J.C.bp bq br bx , Counsell, C.by , Dartigues, J.F.ca , Deloukas, P.cb , Dexter, D.T.cd , Van Dijk, K.D.bj , Dillman, A.i , Durif, F.ce , Edkins, S.cb , Evans, J.R.cg , Foltynie, T.ch , Freeman, C.bg , Gao, J.bs , Gardner, M.l , Gibbs, R.i l , Goate, A.ci , Gray, E.cb , Guerreiro, R.l , Gústafsson, O.cj , Harris, C.by , Hellenthal, G.bg , Van Hilten, J.J.ck , Hofman, A.cl , Hollenbeck, A.cm , Holton, J.cn , Hu, M.co , Huang, X.cp , Huber, H.aw ax , Hudson, G.bt , Hunt, S.E.cb , Huttenlocher, J.cj , Illig, T.cq , Jónsson, P.V.cr , Langford, C.cg , Lees, A.cn , Lichtner, P.cs , Limousin, P.ct , Lopez, G.cu , McNeill, A.bw , Moorby, C.bu , Moore, M.i , Morris, H.cw , Morrison, K.E.bu cx , Mudanohwo, E.cy , O'Sullivan, S.S.cn , Pearson, J.cw , Pearson, R.bg , Perlmutter, J.S.ci , Pétursson, H.bq cj , Pirinen, M.bg , Post, B.bp cb , Ravina, B.da , Revesz, T.cn , Riess, O.bq , Rivadeneira, F.cl db , Rizzu, P.av , Ryten, M.l , Sawcer, S.dc , Schapira, A.bw , Scheffer, H.dd , Shaw, K.cn , Shoulson, I.de , Sidransky, E.cu , De Silva, R.l , Smith, C.df , Spencer, C.C.A.bg , Stefánsson, H.cj , Steinberg, S.cj , Stockton, J.D.bu , Strange, A.bg , Su, Z.bg , Talbot, K.dg , Tanner, C.M.dh , Tashakkori-Ghanbaria, A.cb , Trabzuni, D.l , Traynor, B.J.i , Uitterlinden, A.G.cl db , Vandrovcova, J.l , Velseboer, D.bl , Marie Vidailhetay az ba , Walker, R.df , Van De Warrenburg, B.bp , Weale, M.E.dj dk , Wickremaratchi, M.dk , Williams, N.cx , Williams-Gray, C.H.bh , Winder-Rhodes, S.dk dl , Stefánsson, K.cj , Wood, N.W.l be , Singleton, A.B.i
The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
(2013) Journal of Neurology, Neurosurgery and Psychiatry, 84 (6), pp. 666-673.
a INSERM, UMR-S975, CR-ICM, Paris, France
b UPMC University Paris 06, UMR-S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France
c CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France
d Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogéné tique, Hôpital de la Pitié-Salpêtrière, Paris, France
e INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France
f Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France
g Department of Neurology, University Hospital Würzburg, Würzburg, Germany
h Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Hôpital de la Pitié-Salpêtrière, Paris, France
i Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
j INSERM U1043, CPTP, Toulouse, France
k Paul Sabatier University, Toulouse, France
l Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
m Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands
n Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany
o Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France
p Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Tunis, Tunisia
q Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
r Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
s Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
t Department of Neurology, UKS-H, Campus Kiel, Christian-Albrechts-University, Kiel, Germany
u Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France
v CHU de Grenoble, Department of Neurology, Grenoble, France
w CHU de Nantes, Centre d'Investigation Clinique, Nantes, France
x Hôpital Haut-Lévêque, Department of Neurology, Pessac, France
y INSERM, U744, Lille, France
z Institut Pasteur de Lille, Lille, France
aa Université Lille-Nord de France, Lille, France
ab Université Pierre et Marie Curie-Paris 6, ER4-UPMC Modélisation en Recherche Clinique, Hôpital Pitié-Salpêtrière, Paris, France
ac INSERM UMR-S708, Neuroépidémiologie, Paris, France
ad INSERM U897, Université Bordeaux Ségalen, Bordeaux, France
ae Movement Disorders and Basal Ganglia: Pathophysiology and Experimental Therapeutics, INSERM, UMR-S975, Paris, France
af AP-HP, Hôpital de la Pitié-Salpêtrière, Department of Neurology, 75013 Paris, France
ag Hôpital de la Pitié-Salpêtrière, Département de Génétique et Cytogéné tique, Centre de Génétique Moléculaire et Chromosomique, 75013 Paris, France
ah Service de Neurologie, Hôpital Pasteur, Nice, France
ai University of Lyon, Hospices Civils de Lyon, Neurological Hospital, Lyon, France
aj INSERM, Centre d'Investigation Clinique CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France
ak CHU Nantes, CIC0004, Department of Neurology, Nantes, France
al University Lille-Nord de France, CHRU de Lille, Neurologie, Hôpital Roger Salengro, Lille Cedex, France
am Hôpital Gabriel Montpied, Department of Neurology, Clermont-Ferrand, France
an INSERM U563, CPTP, Toulouse, France
ao INSERM, U975, 75013 Paris, France
ap Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France
aq Department of Neurology, Hôpital Civil, Strasbourg, France
ar Service de Neurologie, Hôpital Pontchaillou, CHU de Rennes, Rennes, France
as Service de Neurologie, CHU la Timone, Marseille, France
at UCL Genetics Institute, Gower Place, London, WC1E 6BT, United Kingdom
au INSERM UMR 1043, CPTP, Toulouse, France
av Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, Netherlands
aw Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany
ax DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
ay INSERM, UMR-S975 (Formerly UMR-S679), Paris, France
az Université Pierre et Marie Curie-Paris, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR-S975, Paris, France
ba CNRS, UMR 7225, Paris, France
bb Department of Neurology, Landspítali University Hospital, Reykjavík, Iceland
bc Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, United Kingdom
bd Queen Mary College, University of London, London, United Kingdom
be 51INSERM U744, Lille, France
bf Institut Pasteur de Lille, Université de Lille Nord, Lille, France
bg Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7LJ, United Kingdom
bh Department of Neurology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 2QQ, United Kingdom
bi Department of Social Medicine, Bristol University, United Kingdom
bj Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands
bk Department of Motor Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
bl Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
bm Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, United States
bn Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States
bo Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02139, United States
bp Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
bq Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany
br Newcastle University Clinical Ageing Research Unit, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom
bs Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, North Carolina, United States
bt Neurology M4104, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom
bu School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
bv Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Dudley Road, Birmingham B18 7QH, United Kingdom
bw Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom
bx INSERM CIC-9503, Hôpital Pitié-Salpêtrière, Paris, France
by University of Aberdeen, Division of Applied Health Sciences, Population Health Section, Polwarth building, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
bz CHU Nantes, CIC0004, Service de Neurologie, Nantes, France
ca INSERM U897, Université Victor Segalen, Bordeaux, France
cb Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom
cc Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität Kiel, Kiel, Germany
cd Parkinson's Disease Research Group, Faculty of Medicine, Imperial College London, Du Cane Road, W12 0NN London, United Kingdom
ce Service de Neurologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France
cf AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
cg Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB22PY, United Kingdom
ch Institute of Neurology, University College London, London, United Kingdom
ci Department of Psychiatry, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
cj DeCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
ck Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
cl Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
cm AARP, Washington DC, United States\
cn Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, United Kingdom
co Department of Clinical Neurology, West Wing, Level 3, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, United Kingdom
cp Departments of Neurology, Radiology, Neurosurgery, Pharmacology, Kinesiology and Bioengineering, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA, United
cq Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany
cr Department of Geriatrics, Landspítali University Hospital, Reykjavík, Iceland
cs Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany
ct Institute of Neurology, Sobell Department, Unit of Functional Neurosurgery, Queen Square, London, United Kingdom
cu Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, United States
cv Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-Universität Kiel, Kiel, Germany
cw MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, CF14 4XN, United Kingdom
cx Neurosciences Department, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, United Kingdom
cy Neurogenetics Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
cz Service de Neurologie, CHU de Grenoble, Grenoble, France
da Translational Neurology, Biogen Idec, 14 Cambridge Center, Bio 6, Cambridge, MA, United States
db Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
dc University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom
dd Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
de Department of Neurology, University of Rochester, Rochester, NY 14620, United States
df Department of Pathology, Wilkie Building, Teviot Place, Edinburgh, EH8 9AG, United Kingdom
dg University of Oxford, Department of Clinical Neurology, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
dh Clinical Research Department, Parkinson's Institute and Clinical Center, Sunnyvale, CA, United States
di Service de Neurologie, Hôpital Haut-Lévêque, Pessac, France
dj King's College London, Department of Medical and Molecular Genetics, London SE1 9RT, United Kingdom
dk Department of Neurology, Cardiff University, Cardiff, United Kingdom
dl Department of Psychiatry and Medical Research Council, Wellcome Trust Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, United Kingdom
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls ( p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
Novak, C.B.a g , Anastakis, D.J.a , Beaton, D.E.b , Mackinnon, S.E.c , Katz, J.d e f
Validity of the Patient Specific Functional Scale in patients following upper extremity nerve injury
(2013) Hand, 8 (2), pp. 132-138.
a Toronto Western Hospital Hand Centre, Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, ON, Canada
b Mobility Program Clinical Research Unit, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
c Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychology, York University, Toronto, ON, Canada
e Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, ON, Canada
f Department of Anesthesia, University of Toronto, Toronto, ON, Canada
g University of Toronto, TWH Hand Centre, 399 Bathurst Street, EW 2-422, Toronto, ON, M5T 2S8, Canada
Purpose: This study evaluated the validity of the Patient Specific Functional Scale (PSFS) in patients with upper extremity nerve injury. Methods: Following Research Ethics Boards (REB) approval, we included English-speaking adults, with greater than 6 months after an upper extremity nerve injury. Patient reported questionnaires included: PSFS, 36-item short-form health survey (SF-36), Disabilities of the Arm, Shoulder and Hand (DASH), McGill Pain Questionnaire, Pain Catastrophizing Scale (PCS) and Pain Disability Index (PDI). Statistical analyses evaluated the relationships among the outcome measures and the independent variables (age, gender, nerve injured, time since injury, work status, worker's compensation/litigation). Linear regression was used to evaluate the variables that predicted the PSFS. Results: There were 157 patients (53 women, 104 men); median time since injury of 14 months. The mean ± SD scores were: PSFS 3.1 ± 2.3, DASH 44 ± 22, PCS 16 ± 15, pain intensity 4.2 ± 3.0, pain rating index 13 ± 11, PDI 28.3 ± 17.6 and SF-36 component scores physical (41.8 ± 8.7) mental (45.9 ± 12.6). There were moderate correlations between the PSFS and the DASH, and the SF-36 physical role domain. The PSFS was significantly lower in brachial plexus injuries. The final model explained 20.7 % of the variance and independent variables were DASH, nerve injured and age. Conclusion: This study provides evidence of construct validity of the PSFS for patients with upper extremity nerve injury. The PSFS is a valid method to assess functional limitations identified by the individual and can be completed in a shorter period of time than the DASH. © 2013 American Association for Hand Surgery.
Nerve injury; Outcome; Self-report function; Upper extremity; Validity
Lafranzo, N.A., Maurer, J.A.
Arsonic acid self-assembled monolayers protect oxide surfaces from micronewton nanomechanical forces
(2013) Advanced Functional Materials, 23 (19), pp. 2415-2421.
Washington University in St. Louis, Department of Chemistry, Center for Materials Innovation, One Brookings Drive, Saint Louis, MO 63130, United States
The development of new surface coatings is critical for combating wear and increasing the device lifetime in microelectromechanical systems (MEMS). Here, a class of arsonic acid self-assembled monolayers (SAMs) is reported that form readily on oxide substrates including silicon oxide, borosilicate glass, and titanium oxide. Monolayers are easily prepared using a straightforward soaking technique, which is amenable to large-scale commercial applications. Monolayer formation on borosilicate glass and titanium oxide is characterized using infrared spectroscopy. Monolayers on borosilicate glass, native silicon oxide and titanium oxide are evaluated with contact angle measurements, as well as wear measurements using nanoscratching experiments. On titanium oxide and borosilicate glass, monolayers prepared from hexadecylarsonic acid provide significantly greater surface protection than surfaces reacted under similar conditions with hexadecylphosphonic acid, a common modifying agent for oxide substrates. Hexadecylarsonic acid self-assembled monolayers are prepared on glass, silicon oxide, and titanium oxide via a straight-forward soaking method. These monolayers protect the substrates from micronewton mechanical forces applied in scanning probe microscopy nanoscratching experiments. Compared to hexadecylphosphonic acid, the arsonate shows increased reactivity and greater protection of the substrate from mechanical stress. This system shows excellent potential as a microelectromechanical systems (MEMS) lubricant. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
nanoscratching; nanotribology; organoarsonate; self-assembled monolayers; wear
Bloch, C.a , Hill, P.M.b , Chen, K.L.a , Saito, A.c , Klein, E.E.a
Startup of the Kling Center for proton therapy
(2013) AIP Conference Proceedings, 1525, pp. 314-318.
a Washington University, School of Medicine, 4921 Parkview Place, St. Louis, MO 63110, United States
b Univeristy of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, United States
c Gunma University, Heavy Ion Medical Center, 3-39-22 Showa-Machi, Maebashi 371-8511, Gunma, Japan
In November of 2011 Mevion Medical Systems (formerly Still River Systems) delivered the Mevion S250 proton therapy system accelerator to the Kling Center for Proton Therapy at the Siteman Cancer Center in Saint Louis. The Mevion system is unique, with an in-room gantry-mounted superconducting synchrocyclotron. This is the first true single-room proton therapy system and it has a greatly reduced size as well as cost. A month after its arrival, the installation was complete and the superconducting magnet was ramped up to full current (∼2000 amperes). In March of 2012, full energy beam (250 MeV) was extracted and radiation surveys were performed to verify the shielding. Once that was shown to be sufficient, Mevion began fine-tuning the system to provide a highly isocentric beam from the 50 ton system. In June of 2012 the field-shaping system (energy degraders, contoured scatterers and range modulators) were installed and measurements of the clinical beam properties commenced. Monte Carlo simulations (MCNPX) have been performed for the system and validated with beam measurements done at the factory. These simulations have been used for a preliminary commissioning of our treatment planning system. Additionally, predictions of the neutron background have been made and validated with factory measurements. Final commissioning of the treatment planning system and verification of the neutron background will be accomplished with measurements made later in 2012. Based on current progress, patient treatments are scheduled to begin in late 2012. Beam and radiation background data will be presented. © 2013 AIP Publishing LLC.
Proton radiation therapy; Superconducting synchrocyclotron
Document Type: Conference Paper
Slattery, E., White, A.J., Gauthier, M., Linscott, L., Hirose, K.
Tolosa-Hunt syndrome masquerading as Gradenigo syndrome in a teenager
(2013) International Journal of Pediatric Otorhinolaryngology, . Article in Press.
Departments of Otolaryngology, Radiology and Pediatrics, Washington University, 660 South Euclid Avenue, Campus Box 8115, St. Louis MO 63110, USA
Tolosa-Hunt syndrome is an idiopathic chronic granulomatous inflammatory process commonly involving the cavernous sinus and the orbit . Symptoms include unilateral eye pain, ophthalmoplegia, headache, and facial pain in the distribution of the upper divisions of the trigeminal nerve and are highly responsive to steroid therapy. Gradenigo syndrome describes extension of a middle ear infection to the petrous apex, with trigeminal pain and ophthalmoplegia, typically responsive to antibiotics and often surgical drainage. We report a case of a 17 year-old girl with apparent Gradenigo syndrome, presenting with unilateral eye pain, abducens palsy, headache, hearing loss and serous otitis media, who was ultimately diagnosed with Tolosa-Hunt syndrome. © 2013 Elsevier Ireland Ltd. All rights reserved.
Gradenigo; Ophthalmoplegia; Otitis media; Tolosa-Hunt
Document Type: Article in Press
Verghese, P.B.a b c , Castellano, J.M.a b c , Garai, K.b c d , Wang, Y.b e , Jiang, H.a b c , Shah, A.a b c , Bu, G.f , Frieden, C.b c d , Holtzman, D.M.a b c
ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (19), pp. E1807-E1816.
a Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
c Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
d Departments of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
e Departments of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
Apolipoprotein E gene (APOE) alleles may shift the onset of Alzheimer's disease (AD) through apoE protein isoforms changing the probability of amyloid-β (Aβ) accumulation. It has been proposed that differential physical interactions of apoE isoforms with soluble Aβ (sAβ) in brain fluids influence the metabolism of Aβ, providing a mechanism to account for how APOE influences AD risk. In contrast, we provide clear evidence that apoE and sAβ interactions occur minimally in solution and in the cerebrospinal fluid of human subjects, producing apoE3 and apoE4 isoforms as assessed by multiple biochemical and analytical techniques. Despite minimal extracellular interactions with sAβ in fluid, we find that apoE isoforms regulate the metabolism of sAβ by astrocytes and in the interstitial fluid of mice that received apoE infusions during brain Aβ microdialysis. We find that a significant portion of apoE and sAβ compete for the low-density lipoprotein receptor-related protein 1 (LRP1)-dependent cellular uptake pathway in astrocytes, providing a mechanism to account for apoE's regulation of sAβ metabolism despite minimal evidence of direct interactions in extracellular fluids.We propose that apoE influences sAβ metabolism not through direct binding to sAβ in solution but through its actions with other interacting receptors/transporters and cell surfaces. These results provide an alternative frame work for the mechanistic explanations on how apoE isoforms influence the risk of AD pathogenesis.
Cholesterol efflux; Neurodegeneration
Wu, B.a , Novelli, J.a g , Jiang, D.b , Dailey, H.A.c d , Landmann, F.e , Ford, L.f , Taylor, M.J.f , Carlow, C.K.S.a , Kumar, S.a , Foster, J.M.a , Slatko, B.E.a
Interdomain lateral gene transfer of an essential ferrochelatase gene in human parasitic nematodes
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (19), pp. 7748-7753.
a Division of Molecular Parasitology, New England Biolabs, Inc., Ipswich, MA 01938, United States
b Infectious Diseases Division, Developmental Biology Department, Washington University School of Medicine, St. Louis, MO 63110, United States
c Biomedical and Health Sciences Institute, Department of Microbiology, Athens, GA 30602, United States
d Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, United States
e Molecular Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, United States
f Parasitology Department, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom
g Synthon B.V., 6503 GN, Nijmegen, Netherlands
Lateral gene transfer events between bacteria and animals highlight an avenue for evolutionary genomic loss/gain of function. Herein, we report functional lateral gene transfer in animal parasitic nematodes. Members of the Nematoda are heme auxotrophs, lacking the ability to synthesize heme; however, the human filarial parasite Brugia malayi has acquired a bacterial gene encoding ferrochelatase (BmFeCH), the terminal step in heme biosynthesis. BmFeCH, encoded by a 9-exon gene, is a mitochondrial-targeted, functional ferrochelatase based on enzyme assays, complementation, and inhibitor studies. Homologs have been identified in several filariae and a nonfilarial nematode. RNAi and ex vivo inhibitor experiments indicate that BmFeCH is essential for viability, validating it as a potential target for filariasis control.
Nochajski, T.H.a , Stasiewicz, P.R.b , Patterson, D.A.c
Depression, readiness for change, and treatment among court-mandated DUI offenders
(2013) Journal of Dual Diagnosis, 9 (2), pp. 139-148.
a School of Social Work, University at Buffalo, 660 Baldy Hall, Amherst, NY 14260, United States
b Research Institute on Addictions, Buffalo, NY, United States
c Brown School, Washington University, St. Louis, MO, United States
Objective: The current study is part of a larger study that was designed to evaluate the impact of brief interventions on subsequent alcohol and drug use in individuals convicted of driving under the influence (DUI). This element considers the interaction of depression levels with treatment on subsequent substance use and problems related to substance use. Methods: Subjects were referred to the Research Institute on Addictions from various courts in the Western New York area for clinical evaluation and treatment referral, if further treatment was indicated. A total of 765 individuals were referred to the program, with 549 agreeing to participate. Participants were assessed at baseline using a number of different measures, with depression and readiness to change among them. A follow-up assessment took place 18 to 24 months following the baseline, with subsequent treatment experiences being one of the primary measures of interest for this study. A total of 443 participants were successfully interviewed at follow-up. Results: The high depression group had greater readiness to change and a greater likelihood of entering treatment than the low depression group (p's <.001). ANCOVAs showed depression by treatment interactions for drug problem severity, drug use, DUI risk, alcohol expectancies, abstinence self-efficacy, and psychiatric distress (all p's <.05). Furthermore, the treated high depression group made the largest positive gains across all outcomes (all p's <.01). Conclusions: The readiness to change, treatment entry, and ANCOVA results all support the approach of Wells-Parker et al. (2006) that depression may be a strong indicator of DUI offenders readiness to change their substance use behavior. © 2013 Taylor and Francis Group, LLC.
depression; DUI; impaired driving; readiness to change; treatment outcome
Holden, L.K.a , Finley, C.C.a b , Firszt, J.B.a , Holden, T.A.a , Brenner, C.a , Potts, L.G.a , Gotter, B.D.a , Vanderhoof, S.S.a , Mispagel, K.a , Heydebrand, G.c , Skinner, M.W.a
Factors affecting open-set word recognition in adults with cochlear implants
(2013) Ear and Hearing, 34 (3), pp. 342-360.
a Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Advanced Bionics LLC, Valencia, CA, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
OBJECTIVE: A great deal of variability exists in the speech-recognition abilities of postlingually deaf adult cochlear implant (CI) recipients. A number of previous studies have shown that duration of deafness is a primary factor affecting CI outcomes; however, there is little agreement regarding other factors that may affect performance. The objective of the present study was to determine the source of variability in CI outcomes by examining three main factors, biographic/audiologic information, electrode position within the cochlea, and cognitive abilities in a group of newly implanted CI recipients. DESIGN:: Participants were 114 postlingually deaf adults with either the Cochlear or Advanced Bionics CI systems. Biographic/audiologic information, aided sentence-recognition scores, a high resolution temporal bone CT scan and cognitive measures were obtained before implantation. Monosyllabic word recognition scores were obtained during numerous test intervals from 2 weeks to 2 years after initial activation of the CI. Electrode position within the cochlea was determined by three-dimensional reconstruction of pre- and postimplant CT scans. Participants' word scores over 2 years were fit with a logistic curve to predict word score as a function of time and to highlight 4-word recognition metrics (CNC initial score, CNC final score, rise time to 90% of CNC final score, and CNC difference score). RESULTS:: Participants were divided into six outcome groups based on the percentile ranking of their CNC final score, that is, participants in the bottom 10% were in group 1; those in the top 10% were in group 6. Across outcome groups, significant relationships from low to high performance were identified. Biographic/audiologic factors of age at implantation, duration of hearing loss, duration of hearing aid use, and duration of severe-to-profound hearing loss were significantly and inversely related to performance as were frequency modulated tone, sound-field threshold levels obtained with the CI. That is, the higher-performing outcome groups were younger in age at the time of implantation, had shorter duration of severe-to-profound hearing loss, and had lower CI sound-field threshold levels. Significant inverse relationships across outcome groups were also observed for electrode position, specifically the percentage of electrodes in scala vestibuli as opposed to scala tympani and depth of insertion of the electrode array. In addition, positioning of electrode arrays closer to the modiolar wall was positively correlated with outcome. Cognitive ability was significantly and positively related to outcome; however, age at implantation and cognition were highly correlated. After controlling for age, cognition was no longer a factor affecting outcomes. CONCLUSION:: There are a number of factors that limit CI outcomes. They can act singularly or collectively to restrict an individual's performance and to varying degrees. The highest performing CI recipients are those with the least number of limiting factors. Knowledge of when and how these factors affect performance can favorably influence counseling, device fitting, and rehabilitation for individual patients and can contribute to improved device design and application. © 2013 by Lippincott Williams & Wilkins.
Prather, A.A.a b d , Bogdan, R.c , Hariri, A.R.d
Impact of sleep quality on amygdala reactivity, negative affect, and perceived stress
(2013) Psychosomatic Medicine, 75 (4), pp. 350-358.
a Department of Psychiatry, University of California, San Francisco, CA, United States
b Robert Wood Johnson Foundation Health, Society Scholars Program, University of California, Berkeley, CA, United States
c BRAIN Lab, Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, NC, United States
OBJECTIVE: Research demonstrates a negative impact of sleep disturbance on mood and affect; however, the biological mechanisms mediating these links are poorly understood. Amygdala reactivity to negative stimuli has emerged as one potential pathway. Here, we investigate the influence of self-reported sleep quality on associations between threat-related amygdala reactivity and measures of negative affect and perceived stress. METHODS: Analyses on data from 299 participants (125 men, 50.5% white, mean [standard deviation] age = 19.6 [1.3] years) who completed the Duke Neurogenetics Study were conducted. Participants completed several self-report measures of negative affect and perceived stress. Threat-related (i.e., angry and fearful facial expressions) amygdala reactivity was assayed using blood oxygen level-dependent functional magnetic resonance imaging. Global sleep quality was assessed using the Pittsburgh Sleep Quality Index. RESULTS: Amygdala reactivity to fearful facial expressions predicted greater depressive symptoms and higher perceived stress in poor (β values = 0.18-1.86, p values < .05) but not good sleepers (β values = -0.13 to -0.01, p values > .05). In sex-specific analyses, men reporting poorer global sleep quality showed a significant association between amygdala reactivity and levels of depression and perceived stress (β values = 0.29-0.44, p values < .05). In contrast, no significant associations were observed in men reporting good global sleep quality or in women, irrespective of sleep quality. CONCLUSIONS: This study provides novel evidence that self-reported sleep quality moderates the relationships between amygdala reactivity, negative affect, and perceived stress, particularly among men. Copyright © 2013 by the American Psychosomatic Society.
Amygdala; depression; negative affect; sleep; stress
Rao, R.C.a b , Blinder, K.J.a b , Smith, B.T.a b , Shah, G.K.a b
Internal limiting membrane peeling for primary rhegmatogenous retinal detachment repair
(2013) Ophthalmology, 120 (5), pp. 1102-1103.e2.
a Retina Institute, St. Louis, MO, United States
b Washington University, School of Medicine, Department of Ophthalmology and Visual Sciences, St. Louis, MO, United States
Jiang, T.a , Perry, A.b , Dacey Jr., R.G.c , Zipfel, G.J.c d , Derdeyn, C.P.a c d
Intracranial atherosclerotic disease associated with moyamoya collateral formation: Histopathological findings - Case report
(2013) Journal of Neurosurgery, 118 (5), pp. 1030-1034.
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Atherosclerotic disease has been suspected as a cause of moyamoya disease in some patients but has not, to the authors' knowledge, been confirmed by pathological studies. The authors present the histopathological findings in a patient with moyamoya collateral formation associated with atherosclerotic occlusive disease of the distal internal carotid artery (ICA). Typical atheromatous changes were evident in the distal ICA and proximal middle cerebral artery. In addition, intimal thickening, fibrosis, and abnormal internal elastic lamina were present in these vessels. These findings are common in moyamoya but not in atherosclerotic disease. Proliferation and enlargement of the lenticulostriate arteries in the basal ganglia was also identified. Moyamoya phenomenon secondary to atherosclerotic disease has similar histopathological features to idiopathic moyamoya phenomenon, both in the affected large basal arteries and lenticulostriate collaterals. These findings support the hypothesis advanced by Peerless that moyamoya is a 2-step process involving an obliterative vasculopathy of the terminal ICA and a secondary proliferative response. ©AANS, 2013.
Atherosclerosis; Histopathological study; Lenticulostriate artery; Moyamoya disease; Stroke; Vascular disorders; Vasculopathy
Fritz, B.A.a , Rao, P.a , Mashour, G.A.b , Abdallah, A.B.a , Burnside, B.A.a , Jacobsohn, E.c , Zhang, L.a , Avidan, M.S.a
Postoperative recovery with bispectral index versus anesthetic concentration-guided protocols
(2013) Anesthesiology, 118 (5), pp. 1113-1122.
a Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
c Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MN, Canada
Background: Use of the bispectral index (BIS) monitor has been suggested to decrease excessive anesthetic drug administration, leading to improved recovery from general anesthesia. The purpose of this substudy of the B-Unawareand BAG-RECALL trials was to assess whether a BIS-based anesthetic protocol was superior to an end-tidal anesthetic concentration-based protocol in decreasing recovery time and postoperative complications. Methods: Patients at high risk for awareness were randomized to either BIS-guided or end-tidal anesthetic concentration-guided general anesthesia in the original trials. Outcomes included time to postanesthesia care unit discharge readiness, time to achieve a postoperative Aldrete score of 9-10, intensive care unit length of stay, postoperative nausea and vomiting, and severe postoperative pain. Univariate Cox regression and chi-square tests were used for statistical analyses. Results: The BIS cohort was not superior in time to postanesthesia care unit discharge readiness (hazard ratio, 1.0; 95% CI, 1.0-1.1; n = 2,949), time to achieve an Aldrete score of 9-10 (hazard ratio, 1.2; 95% CI, 1.0-1.4; n = 706), intensive care unit length of stay (hazard ratio, 1.0; 95% CI, 0.9-1.1; n = 2,074), incidence of postoperative nausea and vomiting (absolute risk reduction,-0.5%; 95% CI,-5.8 to 4.8%; n = 789), or incidence of severe postoperative pain (absolute risk reduction, 4.4%; 95% CI,-2.3 to 11.1%; n = 759). Conclusions: In patients at high risk for awareness, the BIS-guided protocol is not superior to an anesthetic concentration-guided protocol in time needed for postoperative recovery or in the incidences of common postoperative complications. © 2013 the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology.
Ching, J.K., Weihl, C.C.
Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy
(2013) Autophagy, 9 (5), pp. 799-800.
Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS. © 2013 Landes Bioscience.
Autophagy; MTOR; Myopathy; Rapamycin; VCP
Baldo, G.a e , Wozniak, D.F.b , Ohlemiller, K.K.c , Zhang, Y.a , Giugliani, R.e , Ponder, K.P.a d
Retroviral-vector-mediated gene therapy to mucopolysaccharidosis i mice improves sensorimotor impairments and other behavioral deficits
(2013) Journal of Inherited Metabolic Disease, 36 (3), pp. 499-512.
a Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
e Gene Therapy Center, Hospital de Clinicas de Porto Alegre, Porto Alegre RS, Brazil
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to α-L-iduronidase (IDUA) deficiency that results in the accumulation of glycosaminoglycans (GAG). Systemic gene therapy to MPS I mice can reduce lysosomal storage in the brain, but few data are available regarding the effect upon behavioral function. We investigated the effect of gene therapy with a long-terminal-repeat (LTR)-intact retroviral vector or a self-inactivating (SIN) vector on behavioral function in MPS I mice. The LTR vector was injected intravenously to 6-week-old MPS I mice, and the SIN vector was given to neonatal or 6-week-old mice. Adult-LTR, neonatal-SIN, and adult-SIN-treated mice achieved serum IDUA activity of 235 ± 20 (84-fold normal), 127 ± 10, and 71 ± 7 U/ml, respectively. All groups had reduction in histochemical evidence of lysosomal storage in the brain, with the adult-LTR group showing the best response, while adult-LTR mice had reductions in lysosomal storage in the cristae of the vestibular system. Behavioral evaluation was performed at 8 months. Untreated MPS I mice had a markedly reduced ability to hold onto an inverted screen or climb down a pole. LTR-vector-treated mice had marked improvements on both of these tests, whereas neonatal-SIN mice showed improvement in the pole test. We conclude that both vectors can reduce brain disease in MPS I mice, with the LTR vector achieving higher serum IDUA levels and better correction. Vestibular abnormalities may contribute to mobility problems in patients with MPS I, and gene therapy may reduce symptoms. © 2012 SSIEM and Springer.
Ju, Y.-E.S.a , McLeland, J.S.a , Toedebusch, C.D.a , Xiong, C.b c , Fagan, A.M.a b d , Duntley, S.P.a , Morris, J.C.a b , Holtzman, D.M.a b d
Sleep quality and preclinical Alzheimer disease
(2013) JAMA Neurology, 70 (5), pp. 587-593. Cited 1 time.
a Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, United States
b Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
Importance: Sleep and circadian problems are very common in Alzheimer disease (AD). Recent animal studies suggest a bidirectional relationship between sleep and β-amyloid (Aβ), a key molecule involved in AD pathogenesis. Objective: To test whether Aβ deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep. Design: Cross-sectional study conducted from October 2010 to June 2012. Setting: General community volunteers at the Washington University Knight Alzheimer's Disease Research Center. Participants: Cognitively normal individuals (n=145) 45 years and older were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. Valid actigraphy data were recorded in 142. The majority (124 of 142) were recruited from the Adult Children Study, in which all were aged 45 to 75 years at baseline and 50% have a parental history of late-onset AD. The rest were recruited from a community volunteer cohort in which all were older than 60 years and healthy at baseline. Main Outcome Measures: Sleep was objectively measured using actigraphy for 2 weeks. Sleep efficiency, which is the percentage of time in bed spent asleep, was the primary measure of sleep quality. Total sleep time was the primary measure of sleep quantity. Cerebrospinal fluid Aβ42 levels were used to determine whether amyloid deposition was present or absent. Concurrent sleep diaries provided nap information. Results: Amyloid deposition, as assessed by Aβ42 levels, was present in 32 participants (22.5%). This group had worse sleep quality, as measured by sleep efficiency (80.4% vs 83.7%), compared with those without amyloid deposition, after correction for age, sex, and APOEaε4 allele carrier status (P = .04). In contrast, quantity of sleep was not significantly different between groups, as measured by total sleep time. Frequent napping, 3 or more days per week, was associated with amyloid deposition (31.2% vs 14.7%; P = .03). Conclusions and Relevance: Amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality but not with changes in sleep quantity. ©2013 American Medical Association. All rights reserved.
To BIS or not to BIS
(2013) Anesthesiology, 118 (5), p. 1234.
Washington University School of Medicine at Saint Louis, St. Louis, MO, United States
Document Type: Letter
Durrant, D.M., Robinette, M.L., Klein, R.S.
IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis.
(2013) The Journal of experimental medicine, 210 (3), pp. 503-516.
Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Infections of the central nervous system (CNS) with cytopathic viruses require efficient T cell responses to promote viral clearance, limit immunopathology, and enhance survival. We found that IL-1R1 is critical for effector T cell reactivation and limits inflammation within the CNS during murine West Nile virus (WNV) encephalitis. WNV-infected IL-1R1(-/-) mice display intact adaptive immunity in the periphery but succumb to WNV infection caused by loss of virologic control in the CNS with depressed local Th1 cytokine responses, despite parenchymal entry of virus-specific CD8(+) T cells. Ex vivo analysis of CD4(+) T cells from WNV-infected CNS of IL-1R1(-/-) mice revealed impaired effector responses, whereas CD8(+) T cells revealed no cell intrinsic defects in response to WNV antigen. WNV-infected, IL-1R1(-/-) mice also exhibited decreased activation of CNS CD11c(+)CD11b(-)CD103(+) and CD11c(+)CD11b(-)CD8α(+)Dec-205(+) cells with reduced up-regulation of the co-stimulatory molecules CD80, CD86, and CD68. Adoptive transfer of wild-type CD11c-EYFP(+) cells from WNV-infected CNS into WNV-infected IL-1R1(-/-) mice trafficked into the CNS restored T cell functions and improved survival from otherwise lethal infection. These data indicate that IL-1R1 signaling promotes virologic control during WNV infection specifically within the CNS via modulation of CD11c(+) cell-mediated T cell reactivation at this site.
Document Type: Article
May 15, 2013
Mui, A.C.a b , Glajchen, M.c , Chen, H.d , Sun, J.e
Developing an Older Adult Volunteer Program in a New York Chinese Community: An Evidence-Based Approach
(2013) Ageing International, 38 (2), pp. 108-121.
a Sau Po Centre on Ageing, University of Hong Kong, Hong Kong, China
b Columbia University School of Social Work, 1255 Amsterdam Ave, NY, NY, 10027, United States
c Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, First Avenue at 16th Street, NY, NY, 10003, United States
d Brown School of Social Work, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, United States
e Institute of Gerontology, Renmin University of China, 59, Zhongguancun Street, Haidian, Beijing, China
This study reports the results of a pilot volunteer project for older Chinese immigrants and documents benefits for both volunteers and caregiver recipients. Using a social marketing approach, the volunteer project was designed as a social model to promote better health among older Chinese immigrants in New York City. The packaging of this health promotion project as a volunteer program was based on a strengths perspective. In the program, 18 older Chinese immigrants were trained to provide support and referral to family caregivers of ill relatives in the Chinese community. At 6 months, outcomes were evaluated for both volunteers and caregivers. The older volunteers perceived benefits associated with volunteering, specifically, a greater sense of well-being and satisfaction with life. In addition, the majority of volunteers felt empowered by training and volunteering (100 %), felt the skills they learned improved communication with their own families (90 %), and reported physical and emotional health benefits (61 %). At the same time, caregivers reported stress reduction following volunteer support. Findings suggest that a volunteer program model may be an effective health promotion intervention for older Chinese immigrants. © 2012 The Author(s).
Chinese immigrants; Friendly callers; Older volunteers; Telephone assurance
Titus, J.B.d e , Lee, A.f , Kasasbeh, A.g , Thio, L.L.b , Stephenson, J.c , Steger-May, K.h , Limbrick, D.D.a , Smyth, M.D.a
Health-related quality of life before and after pediatric epilepsy surgery: The influence of seizure outcome on changes in physical functioning and social functioning
(2013) Epilepsy and Behavior, 27 (3), pp. 477-483.
a Department of Neurosurgery, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States
c Department of Psychology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States
d Pediatric Neuropsychology, Dell Children's Medical Center, Austin, TX, United States
e Department of Psychology, University of Texas at Austin, Austin, TX, United States
f Department of Neurosurgery, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, United States
g Department of Neuroscience, University of Arizona, Tucson, AZ, United States
h Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
Health-related quality of life (HRQOL) is an important outcome in pediatric epilepsy surgery, but there are few studies that utilize presurgical ratings to assess the effect of surgery on HRQOL. We collected parental ratings on the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire for 28 children who participated in neuropsychological assessment before and after epilepsy surgery. Our results revealed significant improvements in overall HRQOL after surgery, especially in physical and social activities. These changes were apparent despite generally unchanged intellectual and psychological functioning. Children with better seizure outcome had more improvement in HRQOL; however, improvements were not statistically different among children with Engel class I, II, and III outcomes. Our results suggest that children can experience significant improvements in HRQOL following epilepsy surgery even when neuropsychological functioning remains unchanged. Moreover, improvements in HRQOL appear evident in children who experience any worthwhile improvement in seizure control (Engel class III or better). © 2013 Elsevier Inc..
Behavior; Cognition; Epilepsy; Outcome; Pediatric; Quality of life; Seizures; Surgery
Armstrong, R.A.a , Hamilton, R.L.c , MacKenzie, I.R.A.b , Hedreen, J.d , Cairns, N.J.e f g
Laminar distribution of the pathological changes in sporadic frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy: A quantitative study using polynomial curve fitting
(2013) Neuropathology and Applied Neurobiology, 39 (4), pp. 335-347.
a Vision Sciences, Aston University, Birmingham, United Kingdom
b Department of Pathology, Vancouver General Hospital, Vancouver, Canada
c Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
d McLean Hospital, Harvard Brain Tissue Resource Center, Belmont, MA, United States
e Charles F. and Joanne Knight Alzheimer's Disease Research Center, United States
f Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
g Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
Aims: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. Results: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. Conclusions: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
Frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP); FTLD with ubiquitin-positive inclusions (FTLD-U); Laminar distribution; Neuronal cytoplasmic inclusions (NCI); Transactive response (TAR) DNA-binding protein of 43kDa (TDP-43)
Ledzewicz, U.a , Olumoye, O.a , Schättler, H.b
On optimal chemotherapy with a strongly targeted agent for a model of tumor-immune system interactions with generalized logistic growth
(2013) Mathematical Biosciences and Engineering, 10 (3), pp. 787-802.
a Dept. of Mathematics and Statistics, Southern Illinois University Edwardsville, Edwardsville, IL 62026-1653, United States
b Dept. of Electrical and Systems Engineering, Washington University, St. Louis, MO 63130-4899, United States
In this paper, a mathematical model for chemotherapy that takes tumor immune-system interactions into account is considered for a strongly targeted agent. We use a classical model originally formulated by Stepanova, but replace exponential tumor growth with a generalised logistic growth model function depending on a parameter v. This growth function interpolates between a Gompertzian model (in the limit v → 0) and an exponential model (in the limit v → ∞). The dynamics is multi-stable and equilibria and their stability will be investigated depending on the parameter v. Except for small values of v, the system has both an asymptotically stable microscopic (benign) equilibrium point and an asymptotically stable macroscopic (malignant) equilibrium point. The corresponding regions of attraction are separated by the stable manifold of a saddle. The optimal control problem of moving an initial condition that lies in the malignant region into the benign region is formulated and the structure of optimal singular controls is determined.
Generalized logistic growth; Optimal control; Targeted chemotherapy; Tumor immune system interactions
Derringer, J.a , Krueger, R.F.b , Dick, D.M.c , Agrawal, A.d , Bucholz, K.K.d , Foroud, T.e , Grucza, R.A.d , Hesselbrock, M.N.f , Hesselbrock, V.f , Kramer, J.g , Nurnberger, J.I.e , Schuckit, M.h , Bierut, L.J.d , Iacono, W.G.b , Mcgue, M.b
Measurement invariance of DSM-IV alcohol, marijuana and cocaine dependence between community-sampled and clinically overselected studies
(2013) Addiction, . Article in Press.
a University of Colorado Boulder, CO USA
b University of Minnesota Minneapolis, MN USA
c Virginia Commonwealth University Richmond, VA USA
d Washington University in St. Louis St Louis, MO USA
e Indiana University Indianapolis, IN USA
f University of Connecticut West Hartford, CT USA
g University of Iowa Iowa City, IA USA
h University of California San Diego, CA USA
Aims: To examine whether DSM-IV symptoms of substance dependence are psychometrically equivalent between existing community-sampled and clinically overselected studies. Participants: A total of 2476 adult twins born in Minnesota and 4121 unrelated adult participants from a case-control study of alcohol dependence. Measurements: Life-time DSM-IV alcohol, marijuana and cocaine dependence symptoms and ever use of each substance. Design: We fitted a hierarchical model to the data, in which ever use and dependence symptoms for each substance were indicators of alcohol, marijuana or cocaine dependence which were, in turn, indicators of a multi-substance dependence factor. We then tested the model for measurement invariance across participant groups, defined by study source and participant sex. Findings: The hierarchical model fitted well among males and females within each sample [comparative fit index (CFI)>0.96, Tucker-Lewis index (TLI)>0.95 and root mean square error of approximation (RMSEA)<0.04 for all], and a multi-group model demonstrated that model parameters were equivalent across sample- and sex-defined groups (ΔCFI=0.002 between constrained and unconstrained models). Differences between groups in symptom endorsement rates could be expressed solely as mean differences in the multi-substance dependence factor. Conclusions: Life-time substance dependence symptoms fitted a dimensional model well. Although clinically overselected participants endorsed more dependence symptoms, on average, than community-sampled participants, the pattern of symptom endorsement was similar across groups. From a measurement perspective, DSM-IV criteria are equally appropriate for describing substance dependence across different sampling methods. © 2013 Society for the Study of Addiction.
Item response theory; Sampling comparison; Sex differences; Substance dependence
Lai, C.W.J.a , Kolesnikov, A.V.c , Frederick, J.M.d , Blake, D.R.a , Jiang, L.d , Stewart, J.S.b , Chen, C.-K.f , Barrow, J.R.b , Baehr, W.d e g , Kefalov, V.J.c , Willardson, B.M.a
Phosducin-like protein 1 is essential for G-protein assembly and signaling in retinal rod photoreceptors
(2013) Journal of Neuroscience, 33 (18), pp. 7941-7951.
a Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, United States
b Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, United States
c Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, UT 84132, United States
e Department of Neurobiology and Anatomy, University of Utah Health Science Center, Salt Lake City, UT 84132, United States
f Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States
g Department of Biology, University of Utah, Salt Lake City, UT 84112, United States
G-protein β subunits perform essential neuronal functions as part of G-protein βγ and Gβ5-regulators of G-protein signaling (RGS) complexes. Both Gβγ and Gβ5-RGS are obligate dimers that are thought to require the assistance of the cytosolic chaperonin CCT and a cochaperone, phosducin-like protein 1 (PhLP1) for dimer formation. To test this hypothesis in vivo, we deleted the Phlp1 gene in mouse (Mus musculus) retinal rod photoreceptor cells and measured the effects on G-protein biogenesis and visual signal transduction. In the PhLP1-depleted rods, Gβγ dimer formation was decreased 50-fold, resulting in a >10-fold decrease in light sensitivity. Moreover, a 20-fold reduction in Gβ5 and RGS9-1 expression was also observed, causing a 15-fold delay in the shutoff of light responses. These findings conclusively demonstrate in vivo that PhLP1 is required for the folding and assembly of both Gβγ and Gβ5-RGS9. © 2013 the authors.
Nelson, E.C.a , Heath, A.C.a , Lynskey, M.T.b , Agrawal, A.a , Henders, A.K.c , Bowdler, L.M.c , Todorov, A.A.a , Madden, P.A.F.a , Moore, E.d , Degenhardt, L.e f , Martin, N.G.c , Montgomery, G.W.c
PTSD risk associated with a functional DRD2 polymorphism in heroin-dependent cases and controls is limited to amphetamine-dependent individuals
(2013) Addiction Biology, . Article in Press.
a Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
b Institute of Psychiatry King's College London UK
c Queensland Institute of Medical Research Brisbane Australia
d New South Wales Health Justice Health and Forensic Mental Health Network Pagewood Australia
e National Drug and Alcohol Research Centre University of New South Wales Sydney Australia
f Centre for Health Policy Programs and Economics School of Population Health University of Melbourne Carlton Australia
Posttraumatic stress disorder (PTSD), a pathologic response to severe stress, is a common co-morbid disorder in substance-dependent individuals. Evidence from twin studies suggests that PTSD is moderately heritable. Genetic association studies to date have reported a limited number of replicated findings. We conducted a candidate gene association study in trauma-exposed individuals within the Comorbidity and Trauma Study's sample (1343 heroin-dependent cases and 406 controls from economically disadvantaged neighborhoods). After data cleaning, the 1430 single nucleotide polymorphisms (SNPs) retained for analyses provided coverage of 72 candidate genes and included additional SNPs for which association was previously reported as well as 30 ancestry-informative markers. We found a functional DRD2 promoter polymorphism (rs12364283) to be most highly associated with PTSD liability [odds ratio (OR) 1.65 (1.27-2.15); P=1.58×10-4]; however, this association was not significant, with a stringent Bonferroni correction for multiple comparisons. The top hits include SNPs from other dopaminergic system genes: DRD2 DRD3, TH and DBH. Additional analyses revealed that the association involving rs12364283 is largely limited to amphetamine-dependent individuals. Substantial risk is observed in amphetamine-dependent individuals, with at least one copy of this SNP [OR 2.86 (1.92-4.27); P=2.6×10-7]. Further analyses do not support extensive mediation of PTSD risk via self-reported impulsivity (BIS total score). These findings suggest roles for impairment in inhibitory control in the pathophysiology of PTSD and raise questions about stimulant use in certain populations (e.g. those in combat). © 2013 Society for the Study of Addiction.
Amphetamine dependence; Association study; DRD2; PTSD
Babetto, E.a , Beirowski, B.b , Russler, EmilieV.a , Milbrandt, J.b c , DiAntonio, A.a c
The Phr1 Ubiquitin Ligase Promotes Injury-Induced Axon Self-Destruction
(2013) Cell Reports, . Article in Press.
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
Axon degeneration is an evolutionarily conserved process that drives the loss of damaged axons and is an early event in many neurological disorders, so it is important to identify the molecular constituents of this poorly understood mechanism. Here, we demonstrate that the Phr1 E3 ubiquitin ligase is a central component of this axon degeneration program. Loss of Phr1 results in prolonged survival of severed axons in both the peripheral and central nervous systems, as well as preservation of motor and sensory nerve terminals. Phr1 depletion increases the axonal level of the axon survival molecule nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and NMNAT2 is necessary for Phr1-dependent axon stability. The profound long-term protection of peripheral and central mammalian axons following Phr1 deletion suggests that pharmacological inhibition of Phr1 function may be an attractive therapeutic candidate for amelioration of axon loss in neurological disease. © 2013 The Authors.
Wilkins, C.H.a b c d , Roe, C.M.b e , Morris, J.C.b e , Galvin, J.E.b f
Mild Physical Impairment Predicts Future Diagnosis of Dementia of the Alzheimer's Type
(2013) Journal of the American Geriatrics Society, . Article in Press.
a Division of Geriatrics and Nutritional Science, Department of Internal MedicineWashington University School of Medicine St. Louis, Missouri
b Knight Alzheimer's Disease Research Center, Washington University School of Medicine St. Louis, Missouri
c Department of PsychiatryWashington University School of Medicine St. Louis, Missouri
d Department of SurgeryWashington University School of Medicine St. Louis, Missouri
e Department of Neurology Washington University School of Medicine St. Louis, Missouri
f Center of Excellence on Brain Aging New York University Langone Medical Center New York, New York
Objectives: To determine whether mildly impaired physical function (based on performance-based assessment) is associated with development of dementia of the Alzheimer's type (DAT) in cognitively normal older adults. Design: Longitudinal, observational study with yearly assessments of physical and cognitive function. Mean follow-up was 5 years. Setting: Knight Alzheimer's Disease Research Center at Washington University, St. Louis, Missouri. Participants: Four hundred thirty-five cognitively normal adults aged 60 and older participating in longitudinal studies of aging. Measurements: Survival analyses were used to examine whether scores on the 9-item Physical Performance Test (PPT) predicted time to DAT diagnosis. Cox proportional hazards models were used to examine associations between PPT total scores and time to cognitive impairment and DAT; as well as the association between time and these events, adjusting for and simultaneously testing the effects of age, sex, education, and presence of one or more apolipoprotein (APOE) ε4 alleles. Results: During the follow-up period, 81 participants developed DAT. Participants diagnosed with DAT were older (81.0 vs 74.2, P = .001) and had worse performance on the PPT (25.5 vs 28.1, P = .009) than those who remained cognitively normal. Time to DAT diagnosis was associated with PPT total score (hazard ratio (HR) = 0.89, 95% confidence interval (CI) = 0.86-0.93, P < .001) such that time to DAT diagnosis was longer for participants with higher physical performance scores. In the adjusted analysis, PPT score significantly predicted time to DAT diagnosis (HR = 0.94, 95% CI = 0.89-0.99, P = .02). Conclusion: Mild physical impairment in cognitively normal older adults is associated with subsequent development of DAT. Although the physical impairment may be sufficiently mild that it is recognized only using performance-based assessments, its presence may predate clinically detectable cognitive decline. © 2013, The American Geriatrics Society.
Dementia of Alzheimer's type; Frailty; Physical performance; Predictors
Zheng, Q., Nonet, M.L.
UNC-16/JIP3/sunday driver: A new cop on the organelle highway
(2013) Genetics, 194 (1), pp. 35-37.
Department of Anatomy and Neurobiology, Washington University Medical School, St. Louis, MO 63110, United States
Baumard, N.a , Boyer, P.b
Explaining moral religions
(2013) Trends in Cognitive Sciences, . Article in Press.
a Institute of Cognitive and Evolutionary Anthropology, Oxford and University of Pennsylvania, Philadelphia, PA, USA
b Washington University, St. Louis, MO, USA
Moralizing religions, unlike religions with morally indifferent gods or spirits, appeared only recently in some (but not all) large-scale human societies. A crucial feature of these new religions is their emphasis on proportionality (between deeds and supernatural rewards, between sins and penance, and in the formulation of the Golden Rule, according to which one should treat others as one would like others to treat oneself). Cognitive science models that account for many properties of religion can be extended to these religions. Recent models of evolved dispositions for fairness in cooperation suggest that proportionality-based morality is highly intuitive to human beings. The cultural success of moralizing movements, secular or religious, could be explained based on proportionality. © 2013 Elsevier Ltd. All rights reserved.
Henricson, E.K.a , Abresch, R.T.a , Cnaan, A.b c , Hu, F.b , Duong, T.b , Arrieta, A.b , Han, J.a , Escolar, D.M.d , Florence, J.M.e , Clemens, P.R.f , Hoffman, E.P.b g , Mcdonald, C.M.a , Vishwanathan, V.h , Chidambaranathan, S.h , Douglas Biggar, W.i , Mah, J.K.j , Tulinius, M.k , Leshner, R.l , Tesi-Rocha, C.l , Kornberg, A.m , Ryan, M.m , Nevo, Y.n , Dubrovsky, A.o , Kuntz, N.p , Driscoll, S.p , Connolly, A.q , Pestronk, A.q , Teasley, J.r , Bertorini, T.s , North, K.t , Kolski, H.u , Carlo, J.v , Gorni, K.w , Lotze, T.x , Day, J.y
The cooperative international neuromuscular research group Duchenne natural history study: Glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures
(2013) Muscle and Nerve, . Article in Press.
a Department of Physical Medicine and RehabilitationSchool of MedicineUniversity of CaliforniaDavis4860 Y StreetSuite 3850Sacramento California95817 USA
b Center for Genetic Medicine Research, Children's National Medical CenterWashington, DC USA
c Departments of Pediatrics, Epidemiology, and Biostatistics, George Washington UniversityWashington, DC USA
d Department of Neurology, Kennedy Krieger InstituteBaltimore, Maryland USA
e Department of Neurology, Washington UniversitySt. Louis, Missouri USA
f Department of Neurology, University of Pittsburgh and Department of Veterans Affairs Medical CenterPittsburgh, Pennsylvania USA
g Department of Integrative Systems Biology, George Washington UniversityWashington, DC USA
h Sunaram Medical Foundation and Apollo Children's Hospital
i Holland Bloorview Kids Rehabilitation Hospital
j Alberta Children's Hospital
k Queen Sylvia Children's Hospital
l Children's National Medical Center
m Royal Children's Hospital
n Hadassah Hebrew University Hospital
o Instituto de Neurosciencias Fundacion Favaloro
p Mayo Clinic
q Washington University, St. Louis
r Children's Hospital of Virginia
s University of Tennessee, Memphis
t Children's Hospital of Westmead
u University of Alberta
v University of Puerto Rico
w University of Pavia and Niguarda Ca'Granda Hospital
x Texas Children's Hospital
y University of Minnesota
Introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. Methods: The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2-28 years. A comprehensive battery of measures was obtained. Results: A novel composite functional "milestone" scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4±0.39 MMT unit/year, compared with -0.4±0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. Conclusions: In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy. © 2013 Wiley Periodicals, Inc.
Adolescent; Adult; Child/preschool; Follow-up studies; Health status; Humans; Locomotion; Male; Muscle strength/physiology; Muscular dystrophies/classification; Muscular dystrophies/Duchenne/physiopathology; Muscular dystrophies/therapy; Phenotype; Quality of life/psychology; Respiratory function tests
Willey, J.Z.a , Khatri, P.b , Khoury, J.C.g , Merino, J.G.h , Ford, A.L.c , Rost, N.S.i , Gonzales, N.R.d , Ali, L.K.e , Meyer, B.C.f , Broderick, J.P.b
Variability in the use of intravenous thrombolysis for mild stroke: Experience across the SPOTRIAS network
(2013) Journal of Stroke and Cerebrovascular Diseases, 22 (4), pp. 318-322.
a Department of Neurology, Columbia University, 710 West 168th Street, New York, NY 10032, United States
b Department of Neurology, University of Cincinnati, OH, United States
c Department of Neurology, Washington University, Saint Louis, MO, United States
d Department of Neurology, University of Texas-Houston, United States
e Department of Neurology, University of California, Los Angeles, United States
f Department of Neurology, University of California, San Diego, United States
g Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, OH, United States
h Section on Stroke Diagnostics and Therapeutics, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
i Stroke Division, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
Background: Current guidelines do not define the lower severity threshold for thrombolysis. In this study, we describe the variability of treatment of mild stroke patients across a network of academic stroke centers. Methods: Stroke centers within the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) prospectively collect data on patients treated with intravenous recombinant tissue plasminogen activator (IV rt-PA), including demographics, pretreatment National Institutes of Health Stroke Scale (NIHSS) scores, and in-hospital mortality. We examined the variability in proportion of total tissue plasminogen activator-treated patients in the NIHSS categories (0-3, 4-5, or ≥6) and associated outcomes. Results: A total of 2514 patients with reported NIHSS scores were treated with IV rt-PA between January 1, 2005 and December 31, 2009. The proportion of patients with mild stroke (NIHSS scores of 0-3) who were treated with IV rt-PA varied substantially across the centers (2.7-18.0%; P <.001). There were 5 deaths in the 256 treated with an NIHSS score of 0-3 (2.0%). The proportion of treated patients across the network with an NIHSS score of 0 to 3 increased from 4.8% in 2005 to 10.7% in 2009 (P =.001). Conclusions: There is substantial variability in the proportion of treated patients who have mild stroke across the SPOTRIAS centers, reflecting a paucity of data on how to best treat patients with mild stroke. Randomized trial data for this group of patients are needed to clarify the use of rt-PA in patients with the mildest strokes. © 2013 by National Stroke Association.
Mild stroke; stenosis
Li, L.a b , Hu, X.b , Preuss, T.M.c d , Glasser, M.F.e , Damen, F.W.f , Qiu, Y.g , Rilling, J.d h i j
Mapping putative hubs in human, chimpanzee and rhesus macaque connectomes via diffusion tractography
(2013) NeuroImage, . Article in Press.
a Marcus Autism Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
b Biomedical Imaging Technology Center, Emory University/Georgia Institute of Technology School of Medicine, Atlanta, GA, USA
c Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
d Center for Translational Social Neuroscience, Atlanta, GA, USA
e Department of Anatomy and Neurobiology, Washington University School of Medicine, MO, USA
f Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
g School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA
h Department of Anthropology, Emory University, Atlanta, GA, USA
i Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA
j Yerkes National Primate Center, Emory University, Atlanta, GA, USA
Mapping anatomical brain networks with graph-theoretic analysis of diffusion tractography has recently gained popularity, because of its presumed value in understanding brain function. However, this approach has seldom been used to compare brain connectomes across species, which may provide insights into brain evolution. Here, we employed a data-driven approach to compare interregional brain connections across three primate species: 1) the intensively studied rhesus macaque, 2) our closest living primate relative, the chimpanzee, and 3) humans. Specifically, we first used random parcellations and surface-based probabilistic diffusion tractography to derive the brain networks of the three species under various network densities and resolutions. We then compared the characteristics of the networks using graph-theoretic measures. In rhesus macaques, our tractography-defined hubs showed reasonable overlap with hubs previously identified using anterograde and retrograde tracer data. Across all three species, hubs were largely symmetric in the two hemispheres and were consistently identified in medial parietal, insular, retrosplenial cingulate and ventrolateral prefrontal cortices, suggesting a conserved structural architecture within these regions. However, species differences were observed in the inferior parietal cortex, polar and medial prefrontal cortices. The potential significance of these interspecies differences is discussed. © 2013 Elsevier Inc. All rights reserved.
Brain networks; Chimpanzee; Evolution; Graph theory; Human; Macaque; Parietal cortex; Prefrontal cortex; Random parcellation; Tracer
Vangberg, H.C.B.a , Eisemann, M.a , Waterloo, K.a , Richter, J.b , Rozsa, S.c , Cloninger, C.R.c
The Norwegian Junior Temperament and Character Inventory (JTCI): An assessment of its psychometric properties
(2013) Comprehensive Psychiatry, . Article in Press.
a University of Tromsø, Norway
b Centre for Child and Adolescent Mental Health, Eastern and Southern Norway, Oslo, Norway
c Center for Well-Being, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
The role of adolescent personality concerning mental health, well-being, self development, and academic performance is an interesting aspect that needs more attention. The use of the JTCI (Junior Temperament and Character Inventory) can contribute to more knowledge and a better understanding of a possible influence of personality in this context. The aim of this study was to assess the psychometric properties of the Norwegian version of the JTCI among an adolescent sample in terms of factor analysis, reliability and validity. The sample included 2075 subjects in the age from 15-18 years. We analyzed the factor structure, internal consistency, and validity of the measure. The Norwegian version of the JTCI was found to have good psychometric properties in terms of internal consistency, a reasonable factor structure and significant correlations with depression, self-esteem, and self-efficacy. However, further research on its differentiation of Harm Avoidance and Self-directedness is needed. The JTCI appears as a useful tool in addressing issues ranging from scholastic performance to developmental issues, mental health and well-being. © 2013 Elsevier Inc. All rights reserved.
Schwedt, T.J.a b , Schlaggar, B.L.a c d e , Mar, S.a d , Nolan, T.c , Coalson, R.S.a c , Nardos, B.a , Benzinger, T.c , Larson-Prior, L.J.c
Atypical resting-state functional connectivity of affective pain regions in chronic migraine
(2013) Headache, 53 (5), pp. 737-751. Cited 1 time.
a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States
Objective. - Chronic migraineurs (CM) have painful intolerances to somatosensory, visual, olfactory, and auditory stimuli during and between migraine attacks. These intolerances are suggestive of atypical affective responses to potentially noxious stimuli. We hypothesized that atypical resting-state functional connectivity (rs-fc) of affective pain-processing brain regions may associate with these intolerances. This study compared rs-fc of affective pain-processing regions in CM with controls. Methods. - Twelve minutes of resting-state blood oxygenation level-dependent data were collected from 20 interictal adult CM and 20 controls. Rs-fc between 5 affective regions (anterior cingulate cortex, right/left anterior insula, and right/left amygdala) with the rest of the brain was determined. Functional connections consistently differing between CM and controls were identified using summary analyses. Correlations between number of migraine years and the strengths of functional connections that consistently differed between CM and controls were calculated. Results. - Functional connections with affective pain regions that differed in CM and controls included regions in anterior insula, amygdala, pulvinar, mediodorsal thalamus, middle temporal cortex, and periaqueductal gray. There were significant correlations between the number of years with CM and functional connectivity strength between the anterior insula with mediodorsal thalamus and anterior insula with periaqueductal gray. Conclusion. - CM is associated with interictal atypical rs-fc of affective pain regions with pain-facilitating and pain-inhibiting regions that participate in sensory-discriminative, cognitive, and integrative domains of the pain experience. Atypical rs-fc with affective pain regions may relate to aberrant affective pain processing and atypical affective responses to painful stimuli characteristic of CM. © 2013 American Headache Society.
chronic migraine; functional connectivity; functional magnetic resonance imaging; headache; migraine; pain
Ellis, T.a , Boudreau, J.K.b , DeAngelis, T.R.c , Brown, L.E.c , Cavanaugh, J.T.d , Earhart, G.M.e , Ford, M.P.f , Foreman, K.B.g , Dibble, L.E.h
Barriers to exercise in people with parkinson disease
(2013) Physical Therapy, 93 (5), pp. 628-636.
a Department of Physical Therapy and Athletic Training, Sargent College of Health and Rehabilitation Sciences, Boston University, 635 Commonwealth Ave, Boston, MA 02215, United States
b Department of Physical Therapy and Athletic Training, Sargent College of Health and Rehabilitation Sciences, Boston University, and Braintree Rehabilitation Hospital, Braintree, MA, United States
c Department of Physical Therapy and Athletic Training, Sargent College of Health and Rehabilitation Sciences, Boston University, United States
d Department of Physical Therapy, University of New England, Portland, ME, United States
e Washington University in St Louis, St Louis, MO, United States
f Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, United States
g Department of Physical Therapy, University of Utah, Salt Lake City, UT, United States
h Department of Physical Therapy, University of Utah, United States
Background. Exercise is known to reduce disability and improve quality of life in people with Parkinson disease (PD). Although barriers to exercise have been studied in older adults, barriers in people with chronic progressive neurological diseases, such as PD, are not well defined. Objective. The purpose of this study was to identify perceived barriers to exercise in people with PD. Design. The study had a cross-sectional design. Methods. People who had PD, dwelled in the community, and were at stage 2.4 on the Hoehn and Yahr scale participated in this cross-sectional study (N=260; mean age=67.7 years). Participants were divided into an exercise group (n=164) and a nonexercise group (n=96). Participants self-administered the barriers subscale of the Physical Fitness and Exercise Activity Levels of Older Adults Scale, endorsing or denying specific barriers to exercise participation. Multivariate logistic regression analysis was used to examine the contribution of each barrier to exercise behavior, and odds ratios were reported. Results. Three barriers were retained in the multivariate regression model. The nonexercise group had significantly greater odds of endorsing low outcome expectation (ie, the participants did not expect to derive benefit from exercise) (odds ratio [OR]=3.93, 95% confidence interval [CI]=2.08-7.42), lack of time (OR=3.36, 95% CI=1.55-7.29), and fear of falling (OR=2.35, 95% CI=1.17-4.71) than the exercise group. Limitations. The cross-sectional nature of this study limited the ability to make causal inferences. Conclusions. Low outcome expectation from exercise, lack of time to exercise, and fear of falling appear to be important perceived barriers to engaging in exercise in people who have PD, are ambulatory, and dwell in the community. These may be important issues for physical therapists to target in people who have PD and do not exercise regularly. The efficacy of intervention strategies to facilitate exercise adherence in people with PD requires further investigation. © 2013 American Physical Therapy Association.
Mattsson, N.a b , Andreasson, U.a , Persson, S.a , Carrillo, M.C.c , Collins, S.d , Chalbot, S.e , Cutler, N.f , Dufour-Rainfray, D.g , Fagan, A.M.h , Heegaard, N.H.H.i , Robin Hsiung, G.-Y.j , Hyman, B.k , Iqbal, K.e , Lachno, D.R.l , Lleó, A.m , Lewczuk, P.n , Molinuevo, J.L.o , Parchi, P.p , Regeniter, A.q , Rissman, R.r , Rosenmann, H.s , Sancesario, G.t , Schröder, J.u , Shaw, L.M.v , Teunissen, C.E.w , Trojanowski, J.Q.v , Vanderstichele, H.x , Vandijck, M.y , Verbeek, M.M.z , Zetterberg, H.a aa , Blennow, K.a , Käser, S.A.ab
CSF biomarker variability in the Alzheimer's Association quality control program
(2013) Alzheimer's and Dementia, 9 (3), pp. 251-261.
a Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
b San Francisco VA Medical Center, Center for Imaging of Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, United States
c Alzheimer's Association, Chicago, IL, United States
d Department of Pathology, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia
e New York State Institute for Basic Research, Staten Island, NY, United States
f Worldwide Clinical Trials, Beverly Hills, CA, United States
g CHRU de Tours, Laboratoire de Médecine Nucléaire; Université François-Rabelais de Tours, PRES Centre-Val de Loire Université, Tours, France
h Washington University, St. Louis, MO, United States
i Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark
j University of British Columbia, Vancouver, Canada
k MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, United States
l Eli Lilly and Company, Windlesham, United Kingdom
m Hospital de Sant Pau, Barcelona, Spain
n Universitätsklinikum Erlangen, Erlangen, Germany
o Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari and Pasqual Maragall Foundation, Barcelona, Spain
p Institute of Neurological Sciences, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
q Basel University Hospital, Basel, Switzerland
r School of Medicine, University California, San Diego, CA, United States
s Hadassah Hebrew University Medical Center, Jerusalem, Israel
t General Hospital of University of Rome Tor Vergata, Rome, Italy
u Sektion Gerontopsychiatrie Universitätsklinikum, Heidelberg, Germany
v University of Pennsylvania, Philadelphia, PA, United States
w Department of Clinical Chemistry, VU University Medical Center, Amsterdam, Netherlands
x ADx NeuroSciences, Gent, Belgium
y Innogenetics Nv (Part of Fujirebio), Gent, Belgium
z Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
aa Institute of Neurology, University College London, Queen Square, London, United Kingdom
ab University of Tübingen, Tübingen, Germany
Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians. © 2013 The Alzheimer's Association. All rights reserved.
Alzheimer's disease; Biomarkers; Cerebrospinal fluid; External assurance; Proficiency testing; Quality control
Lockhart, E.M.a , Willingham, M.D.b , Abdallah, A.B.a , Helsten, D.L.a , Bedair, B.A.c , Thomas, J.d , Duntley, S.e , Avidan, M.S.a
Obstructive sleep apnea screening and postoperative mortality in a large surgical cohort
(2013) Sleep Medicine, 14 (5), pp. 407-415.
a Washington University, School of Medicine, 660 S. Euclid, Box 8054, St. Louis, MO 63110, United States
b Internal Medicine - Infectious Disease, Washington University, School of Medicine, 660 S. Euclid, Box 8051, St. Louis, MO 63110, United States
c Washington University School of Medicine, 660 S. Euclid, Box 8107, St. Louis, MO 63110, United States
d Periop Performance Improvement Administration and Information Systems, Barnes-Jewish Hospital, 1 Barnes-Jewish Hospital Drive, Mail Stop 90-72-408, St. Louis, MO 63110, United States
e Washington University, School of Medicine, 660 S. Euclid, Box 8111, St. Louis, MO 63110, United States
Objective: A recent investigation at Barnes-Jewish Hospital located in St. Louis, Missouri, found that an estimated 22% of adults presenting for inpatient surgery screened as high risk for obstructive sleep apnea (OSA). Surgical patients with OSA have multiple comorbidities and are at increased risk for perioperative complications. Our objective was to determine if a prior diagnosis of OSA or a positive screen for OSA was associated with increased risk for 30-day and one-year mortality. Methods: B-J APNEAS (Barnes-Jewish Apnea Prevalence in Every Admission Study) was a prospective cohort study. Unselected adult surgical patients at Barnes Jewish Hospital were prospectively enrolled between February 2006 and April 2010. All patients completed preoperative OSA screening and those who were at risk for OSA according to a combination of the Berlin and Flemons screening tools received targeted postoperative interventions. STOP (loud Snoring, daytime Tiredness, Observed apneas, and high blood Pressure) and STOP-BANG (STOP, plus body mass index [BMI], age, neck circumference, and gender) scores also were obtained. Results: Overall, the sample included 14,962 patients, of whom 1939 (12.9%) reported a history of OSA. All four screening tools identified a high prevalence of undiagnosed patients at risk for OSA (9.5%-41.6%), but agreement among screens was not strong with κ statistic ranging from 0.225 to 0.611. There was no significant difference in 30-day postoperative mortality between patients with possible OSA (based on their history or on a positive OSA screen with any of the four instruments) and the rest of the surgical population. Significant differences in one-year mortality were noted between the low-risk and high-risk groups as identified by the Flemons' (4.96% vs 6.91%; p<0.0001), STOP (5.28% vs 7.57%; p<0.0001) and STOP-BANG (4.13% vs 7.45%; p<0.0001) screens. After adjusting for risk factors, none of the OSA screening tools independently predicted mortality rate up to one year postoperatively. Conclusion: Neither a prior diagnosis of OSA nor a positive screen for OSA risk was associated with increased 30-day or one-year postoperative mortality. Differences in 1 year postoperative mortality were noted with three of the screening tools. The results of our study highlight uncertainties and research priorities for the medical community. © 2012 Elsevier B.V..
Berlin; Flemons; Obstructive sleep apnea; OSA screening tools; Perioperative mortality; Perioperative screening; STOP; STOP-BANG
Litvin, M.a , Clark, A.L.b , Fisher, S.J.a
Recurrent hypoglycemia: Boosting the brain's metabolic flexibility
(2013) Journal of Clinical Investigation, 123 (5), pp. 1922-1924.
a Department of Medicine, Cell Biology and Physiology, Division of Endocrinology, Metabolism, and Lipid Research, Washington University in St. Louis, 660 South Euclid Ave., St. Louis, MO 63110, United States
b Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University, St. Louis, MO, United States
Cruchaga, C.a g , Kauwe, J.S.K.h , Harari, O.a , Jin, S.C.a , Cai, Y.a , Karch, C.M.a , Benitez, B.A.a , Jeng, A.T.a , Skorupa, T.a , Carrell, D.a , Bertelsen, S.a , Bailey, M.h , McKean, D.h , Shulman, J.M.i , De Jager, P.L.j k l , Chibnik, L.j k l , Bennett, D.A.m , Arnold, S.E.n , Harold, D.o , Sims, R.o , Gerrish, A.o , Williams, J.o , Van Deerlin, V.M.p , Lee, V.M.-Y.p , Shaw, L.M.p , Trojanowski, J.Q.p , Haines, J.L.q , Mayeux, R.r , Pericak-Vance, M.A.s , Farrer, L.A.t , Schellenberg, G.D.u , Peskind, E.R.v w , Galasko, D.x , Fagan, A.M.b f g , Holtzman, D.M.b e f g , Morris, J.C.b c f , Goate, A.M.a b d f g
GWAS of cerebrospinal fluid tau levels identifies risk variants for alzheimer's disease
(2013) Neuron, 78 (2), pp. 256-268. Cited 1 time.
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
g Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
h Department of Biology, Brigham Young University, Provo UT 84602, United States
i Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, United States
j Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, United States
k Harvard Medical School, Boston, MA 02115, United States
l Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, MA 02142, United States
m Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago IL 60062, United States
n Department of Psychiatry and Neurology, University of Pennsylvania, Philadelphia, PA 19104, United States
o Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF10 3AT, United Kingdom
p Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
q Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, United States
r Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Columbia University, New York, NY 10027, United States
s The John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33124, United States
t Departments of Biostatistics, Medicine, Genetics Program, Ophthalmology, Epidemiology, and Neurology, Boston University, Boston, MA 02118, United States
u Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
v Departments of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 99204, United States
w Veterans Affairs Northwest Network Mental Illness Research Education and Clinical Center, Seattle, WA 99204, United States
x Department of Neurosciences, University of California, San Diego, La Jolla CA 92093, United States
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10-9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10-8 and p = 3.22 × 10-9 for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10-8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10-4, 0.039, 4.86 × 10-5, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci. © 2013 Elsevier Inc.
Ajith Karunarathne, W.K.a , Giri, L.a , Kalyanaraman, V.a , Gautam, N.a b
Optically triggering spatiotemporally confined GPCR activity in a cell and programming neurite initiation and extension
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (17), pp. E1565-E1574. Cited 1 time.
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
G-protein-coupled receptor (GPCR) activity gradients evoke important cell behavior but there is a dearth of methods to induce such asymmetric signaling in a cell. Here we achieved reversible, rapidly switchable patterns of spatiotemporally restricted GPCR activity in a single cell. We recruited properties of nonrhodopsin opsins-rapid deactivation, distinct spectral tuning, and resistance to bleaching-to activate native Gi, Gq, or Gs signaling in selected regions of a cell. Optical inputs were designed to spatiotemporally control levels of second messengers, IP3, phosphatidylinositol (3,4,5)-triphosphate, and cAMP in a cell. Spectrally selective imaging was accomplished to simultaneously monitor optically evoked molecular and cellular response dynamics. We show that localized optical activation of an opsin-based trigger can induce neurite initiation, phosphatidy-linositol (3,4,5)-triphosphate increase, and actin remodeling. Serial optical inputs to neurite tips can refashion early neuron differentiation. Methods here can be widely applied to program GPCR-mediated cell behaviors.
Cell polarity; Optogenetics
Zhang, C., Zhou, Y., Li, C., Wang, L.V.
Slow-sound photoacoustic microscopy
(2013) Applied Physics Letters, 102 (16), art. no. 163702, .
Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
We propose to enhance the axial resolution of photoacoustic microscopy (PAM) by reducing the speed of sound within the imaging region of interest. With silicone oil immersion, we have achieved a finest axial resolution of 5.8 μm for PAM, as validated by phantom experiments. The axial resolution was also enhanced in vivo when mouse ears injected with silicone oil were imaged. When tissue-compatible low-speed liquid becomes available, this approach may find broad applications in PAM as well as in other imaging modalities, such as photoacoustic computed tomography and ultrasound imaging. © 2013 AIP Publishing LLC.
Nattkemper, L.A.a b , Zhao, Z.-Q.c , Nichols, A.J.d , Papoiu, A.D.P.e , Shively, C.A.f , Chen, Z.-F.c , Yosipovitch, G.a b g
Overexpression of the Gastrin-Releasing Peptide in Cutaneous Nerve Fibers and Its Receptor in the Spinal Cord in Primates with Chronic Itch
(2013) Journal of Investigative Dermatology, . Article in Press.
a 1] Department of Dermatology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
b Department of Neurobiology and Anatomy, University Wake Forest School of Medicine, Winston Salem, North Carolina, USA
c Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA
d Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA
e Department of Dermatology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
f Department of Comparative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
g Department of Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
Partsalis, A.M.a , Blazquez, P.M.b , Triarhou, L.C.c
The renaissance of the neuron doctrine:Cajal rebuts the rector of granada
(2013) Translational Neuroscience, 4 (1), pp. 104-114.
a Intensive Care Unit, Hadjikosta General Hospital, 45500 loannina, Greece
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Division of Basic Neuroscience, Department of Educational and Social Policy, University of Macedonia, 54006 Thessaloniki, Greece
The Spanish histologist Santiago Ramón y Cajal and the Italian anatomist Camillo Golgi, who were jointly awarded the 1906 Nobel Prize in Physiology or Medicine for their discoveries on the structure of the nervous system, are two of the most notable figures in neuroscience. It was the 'Golgi method' that enabled Cajal to gather evidence and defend neuronism (the contiguity of neurons as independent cellular units) against his chief rival's reticularism (the intracellular continuity of the cytoplasm among neurons in a widespread reticulum). Seven months after his Nobel lecture in Stockholm, Cajal wrote a powerful article which he titled 'El renacimiento de la doctrina neuronal' (the rebirth, revival, or renaissance of the neuron doctrine) as a response to an insurrection of reticularist ideas. This new wave of reticularism was instigated in Spain by the pathologist Eduardo García Solá, Rector of the University of Granada at the time, and stemmed from the interpretation of nerve regeneration experiments conducted by the German physiologist Albrecht von Bethe in Strassburg (today Strasbourg, France) and the Hungarian histologist Stephan von Apáthy in Kolozsvár (today Cluj-Napoca, Romania). Cajal's article was hosted by four different journals (three in Spain and one in Argentina). It constitutes an important testimony for the history of the neuron theory that has gone unheeded thus far. Therefore, we provide an English translation of Cajal's Spanish paper, placing it in the context of evolving notions during that first decade of the twentieth century crucial for neurobiology. ©Versita Sp. z o.o.
Catenary theory; Eduardo garcía solá (1845-1922); History of neuroscience; Neuron theory; Reticularism; Santiago ramón y cajal (1852-1934)
What makes people healthy, happy, and fulfilled in the face of current world challenges
(2013) Mens Sana Monographs, 11 (1), pp. 16-24. Cited 1 time.
Department of Psychiatry, Campus Box 8134, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
Recent research on the relations of personality to well-being shows that the people who are most healthy, happy and fulfilled are those who are high in all three of the character traits of self-directedness, cooperativeness, and self-transcendence as measured by the Temperament and Character Inventory. In the past, the healthy personality has often been considered to require only high self-directedness and high cooperativeness. However, now the self-centred behaviour of people who are low in self-transcendence is degrading the conditions needed for sustainable life by all human beings. Consequently, human beings need to and can develop their capacity for self-transcendence in order to maintain their individual and collective well-being.© MSM 2013.
Character; Cooperativeness; Ecological shift; Health promotion; Human evolution; Self-directedness; Self-transcendence; Well-being
Malcolm, H.R., Heo, Y.Y., Caldwell, D.B., McConnell, J.K., Hawkins, J.F., Guayasamin, R.C., Elmore, D.E., Maurer, J.A.
Ss-bCNGa: a unique member of the bacterial cyclic nucleotide gated (bCNG) channel family that gates in response to mechanical tension.
(2012) European biophysics journal : EBJ, 41 (12), pp. 1003-1013.
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.
Bacterial cyclic nucleotide gated (bCNG) channels are generally a nonmechanosensitive subset of the mechanosensitive channel of small conductance (MscS) superfamily. bCNG channels are composed of an MscS channel domain, a linking domain, and a cyclic nucleotide binding domain. Among bCNG channels, the channel domain of Ss-bCNGa, a bCNG channel from Synechocystis sp. PCC 6803, is most identical to Escherichia coli (Ec) MscS. This channel also exhibits limited mechanosensation in response to osmotic downshock assays, making it the only known full-length bCNG channel to respond to hypoosmotic stress. Here, we compare and contrast the ability of Ss-bCNGa to gate in response to mechanical tension with Se-bCNG, a nonmechanosensitive bCNG channel, and Ec-MscS, a prototypical mechanosensitive channel. Compared with Ec-MscS, Ss-bCNGa only exhibits limited mechanosensation, which is most likely a result of the inability of Ss-bCNGa to form the strong lipid contacts needed for significant function. Unlike Ec-MscS, Ss-bCNGa displays a mechanical response that increases with protein expression level, which may result from channel clustering driven by interchannel cation-π interactions.
A window into domain amplification through Piccolo in teleost fish.
(2012) G3 (Bethesda, Md.), 2 (11), pp. 1325-1339.
Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
I describe and characterize the extensive amplification of the zinc finger domain of Piccolo selectively in teleost fish. Piccolo and Bassoon are partially functionally redundant and play roles in regulating the pool of neurotransmitter-filled synaptic vesicles present at synapses. In mice, each protein contains two N-terminal zinc finger domains that have been implicated in interacting with synaptic vesicles. In all teleosts examined, both the Bassoon and Piccolo genes are duplicated. Both teleost bassoon genes and one piccolo gene show very similar domain structure and intron-exon organization to their mouse homologs. In contrast, in piccolo b a single exon that encodes a zinc finger domain is amplified 8 to 16 times in different teleost species. Analysis of the amplified exons suggests they were added and/or deleted from the gene as individual exons in rare events that are likely the result of unequal crossovers between homologous sequences. Surprisingly, the structure of the repeats from cod and zebrafish suggest that amplification of this exon has occurred independently multiple times in the teleost lineage. Based on the structure of the exons, I propose a model in which selection for high sequence similarity at the 5' and 3' ends of the exon drives amplification of the repeats and diversity in repeat length likely promotes the stability of the repeated exons by minimizing the likelihood of mispairing of adjacent repeat sequences. Further analysis of piccolo b in teleosts should provide a window through which to examine the process of domain amplification.
Wolf, T.J., Brey, J.K., Baum, C., Connor, L.T.
Activity participation differences between younger and older individuals with stroke
(2012) Brain Impairment, 13 (1), pp. 16-23.
Cognitive Rehabilitation Research Group, Washington University School of Medicine, Program in Occupational Therapy, 4444 Forest Park, St. Louis, MO 63108, United States
The purpose of this study was to describe differences in activity participation between younger and older individuals with stroke to inform transition after stroke. This was a cross-sectional study with individuals six-months poststroke (n = 177). All individuals completed an outcomes assessment battery that included the Stroke Impact Scale, the Reintegration to Normal Living Index and the Activity Card Sort. The sample was divided into two groups: (1) Young-those under the age of 65 (n = 89); and (2) Old-those 65 or older (n = 88). Analysis was completed to examine differences between the groups on the primary outcome measures of the study and to look at differences between the groups on individual questions/items on the specific measures. The results of this study demonstrate: (1) significant differences in both the quantity and nature of activity participation prior to and after stroke between younger and older stroke survivors and (2) total scores and measures of central tendency do not necessarily provide therapists with the information they need to guide treatment. Rehabilitation professionals should focus on providing clients with the tools they will need to be successful in transitioning back to home and community environments once rehabilitation has ended. © 2012 The Authors.
occupational therapy; participation; rehabilitation; stroke
Document Type: Article
May 1, 2013
Karasinska, J.M.a , de Haan, W.a , Franciosi, S.a , Ruddle, P.a , Fan, J.b , Kruit, J.K.a , Stukas, S.b , Lütjohann, D.c , Gutmann, D.H.d , Wellington, C.L.b , Hayden, M.R.a
ABCA1 influences neuroinflammation and neuronal death
(2013) Neurobiology of Disease, 54, pp. 445-455.
a Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
b Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
c Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux in the brain and influences whole brain cholesterol homeostasis. Activation of liver X receptors (LXRs), transcription factors that increase the expression of cholesterol transport genes including ABCA1, reduces neuroinflammation and pathology in neurodegenerative animal models suggesting that in addition to its involvement in cholesterol transport, ABCA1 may play a role in modulating the inflammatory response in the brain. We investigated the cell-type specific role of ABCA1 in neuroinflammation in vivo using mice specifically lacking brain ABCA1 (ABCA1-B/-B) as well as mice lacking neuronal (ABCA1-N/-N) and astrocytic (ABCA1-Ast/-Ast) ABCA1. ABCA1-B/-B mice exhibit cortical astrogliosis, increased inflammatory gene expression as well as activation of mitogen-activated protein kinases (MAPKs) following acute lipopolysaccharide (LPS) administration. Microglia cultured from ABCA1-B/-B mice exhibit augmented LPS-induced secretion of tumor necrosis factor α (TNFα) and decreased phagocytic activity, indicating an increase in a pro-inflammatory response. ABCA1-N/-N mice develop astrogliosis but show no change in inflammatory gene expression. Intriguingly, ABCA1-Ast/-Ast mice show neither astrogliosis nor elevated expression of inflammatory markers. Cortical apolipoprotein E (apoE) levels are reduced in ABCA1-Ast/-Ast but not in ABCA1-N/-N mice, providing in vivo evidence for the specific role of astrocyte ABCA1 in regulating brain apoE levels. Interestingly, cortical neuronal death is increased in 17month-old ABCA1-B/-B mice but not in ABCA1-N/-N or ABCA1-Ast/-Ast mice. Our findings suggest that coordinated ABCA1 activity across neurons and glial cells influences neuroinflammation and neurodegeneration. © 2013 Elsevier Inc.
ABCA1; Apolipoproteins; Brain cholesterol metabolism; Neurodegeneration; Neuroinflammation
Bernstein, A.I., O'Malley, K.L.
MPP+-induces PUMA- and p53-dependent, but ATF3-independent cell death
(2013) Toxicology Letters, 219 (2), pp. 93-98.
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and depletion of striatal dopamine (DA), leading to a range of motor symptoms, including resting tremor, rigidity, bradykinesia and postural abnormalities. The neurotoxin (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinium (MPP+), cause dopaminergic cell loss in a variety of animal species and produce symptoms similar to those seen in PD. Our lab has shown that MPP+ activates cell stress pathways, including the unfolded protein response (UPR) in mouse primary mesencephalic cultures. The BH3-only protein, PUMA (p53 upregulated mediator of apoptosis), has been shown to be activated in response to many cellular stresses, including endoplasmic reticulum (ER) stress and UPR, and to induce cell death. Therefore, we hypothesized that PUMA may mediate MPP+ toxicity. To test this hypothesis, we compared the response of primary mesencephalic cultures from wild-type and PUMA deficient (-/-) mice to MPP+. We also utilized cultures from p53 -/- and activating transcription factor 3 (ATF3) -/- mice to further elucidate the pathways involved. These studies revealed that PUMA and p53, but not ATF3, are required for MPP+-induced cell death, suggesting that UPR activation is parallel to the induction of MPP+-induced cell death. © 2013 Elsevier Ireland Ltd.
ATF3; MPP+; P53; Parkinson's; PUMA; UPR
Miller, T.M.a , Pestronk, A.a , David, W.b , Rothstein, J.c , Simpson, E.d , Appel, S.H.d , Andres, P.L.b , Mahoney, K.b , Allred, P.b , Alexander, K.f , Ostrow, L.W.c , Schoenfeld, D.b , Macklin, E.A.b , Norris, D.A.f , Manousakis, G.a , Crisp, M.a , Smith, R.e , Bennett, C.F.f , Bishop, K.M.f , Cudkowicz, M.E.b
An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: A phase 1, randomised, first-in-man study
(2013) The Lancet Neurology, 12 (5), pp. 435-442.
a Washington University School of Medicine, St Louis, MO, United States
b Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
c Johns Hopkins University School of Medicine, Baltimore, MD, United States
d Methodist Neurological Institute, Houston, TX, United States
e Center for Neurologic Study, La Jolla, CA, United States
f Isis Pharmaceuticals, Carlsbad, CA, United States
Background: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis. Methods: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11•5 h at increasing doses (0•15 mg, 0•50 mg, 1•50 mg, 3•00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222. Findings: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. Interpretation: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. Funding: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals. © 2013 Elsevier Ltd.
Rosnick, C.B.a , Rawson, K.S.b , Butters, M.A.c , Lenze, E.J.d
Association of cortisol with neuropsychological assessment in older adults with generalized anxiety disorder
(2013) Aging and Mental Health, 17 (4), pp. 432-440.
a Department of Psychology, Southern Illinois University Edwardsville, Edwardsville, IL, United States
b School of Aging Studies, University of South Florida, Tampa, FL, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Objectives: Older adults with generalized anxiety disorder (GAD) have elevated diurnal cortisol patterns and show an increased cortisol stress response, which may increase risk for cognitive dysfunction. The current secondary data analysis examined how neuropsychological assessment as a possible laboratory stressor affects cortisol levels in late-life GAD and, in turn, how cortisol levels affect cognitive performance. Methods: The current sample consisted of 69 individuals with late-life GAD and 39 psychiatrically healthy group-matched comparison participants. Cognitive performance was measured with a neuropsychological battery and salivary cortisol was collected at several time points. Hierarchical regressions were performed to assess the moderating role of cortisol in the relationship between GAD status and cognitive performance. Results: The results revealed that older adults with GAD showed significantly lower cortisol levels during neuropsychological assessment, compared to their baseline levels. Further, there was a significant interaction between post-neuropsychological assessment cortisol levels and GAD status on several measures of cognitive performance. The interaction indicated that there is a significant negative relationship between cortisol level and cognitive performance in the GAD participants and no such relationship in the comparison participants. Conclusions: Our results revealed that participating in a neuropsychological assessment was associated with reduced cortisol in GAD participants, suggesting that refocusing attention such as engaging in cognitive tasks had a cortisol-lowering effect. Further, a higher cortisol level appears to have a detrimental effect on cognitive performance for individuals with GAD, but not psychiatrically healthy comparison participants. The methodological and treatment implications of these findings are discussed. © 2013 Taylor & Francis Group, LLC.
cortisol; generalized anxiety disorder; HPA axis; neuropsychological assessment; stress
Sartor, C.E.a , Waldron, M.b , Duncan, A.E.c , Grant, J.D.d , Mccutcheon, V.V.d , Nelson, E.C.d , Madden, P.A.F.d , Bucholz, K.K.d , Heath, A.C.d
Childhood sexual abuse and early substance use in adolescent girls: The role of familial influences
(2013) Addiction, 108 (5), pp. 993-1000. Cited 1 time.
a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b Indiana University School of Education, Bloomington, IN, United States
c George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Aim: To assess the extent to which the association between childhood sexual abuse (CSA) and early use of alcohol, cigarettes and cannabis in adolescent girls is mediated by risk factors that tend to cluster in families where CSA occurs. Design: An abridged version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered by telephone. Participants: A total of 3761 female twins aged 18-29 (14.6% African American, 85.4% European American). Measurements: CSA experiences and history of substance use were queried in the SSAGA-based interviews. Findings: After controlling for familial influences on early substance use by including co-twin early use status in models, separate Cox proportional hazards regression analyses predicting onset of alcohol, cigarette and cannabis use revealed a significant association with CSA. The effect was observed to age 19years for cigarettes and to age 21years for cannabis, but was limited to age 14years or younger for alcohol, with the most pronounced risk before age 10 [hazard ratio (HR)=4.59; confidence interval (CI): 1.96-10.74]. CSA-associated risk for initiation of cigarette and cannabis use was also highest in the youngest age range, but the decline with age was much more gradual and the hazard ratios significantly lower (HR: 1.70; CI: 1.13-2.56 for cigarettes and HR: 2.34, CI: 1.57-3.48 for cannabis). Conclusions: Childhood sexual abuse history is a distinct risk factor for use of cigarettes and cannabis, and a very strong predictor of early age at first drink. © 2013 The Authors, Addiction © 2013 Society for the Study of Addiction.
Alcohol; Cannabis; Cigarettes; Sexual abuse; Twins; Women
Lee, M.J.a , Hasche, L.K.b , Choi, S.c , Proctor, E.K.d , Morrow-Howell, N.d
Comparison of major depressive disorder and subthreshold depression among older adults in community long-term care
(2013) Aging and Mental Health, 17 (4), pp. 461-469.
a Department of Social Welfare, Konkuk University, Danwol-dong, Chungju-si, South Korea
b Graduate School of Social Work, University of Denver, Denver, CO, United States
c College of Social Work, University of Tennessee-Knoxville, Knoxville, TN, United States
d George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
Objectives: This study extends existing knowledge regarding the continuum between major depression (MD) and subthreshold depression (SD) by examining differences in symptomology and associative factors for a subpopulation of older adults with functional disability. Method: Our sample consisted of clients age 60 and above entering public community long term care derived from the baseline survey of a longitudinal study (315 non-depressed, 74 MD, and 221 SD). We used the Diagnostic Interview Schedule to establish diagnoses of MD, the Center for Epidemiological Studies Depression Scale (CES-D) to assess SD, and other self-report measures to explore potential associative factors of demographics, comorbidity, social support, and stressors. Results: No differences in CES-D identified symptoms occurred between the two groups. MD and SD were both associated with lower education, poorer social support, more severe medical conditions, and higher stress when compared to non-depressed older adults. Younger age and being female were associated solely with MD; whereas, worse perceived health and more trouble affording food were associated solely with SD. The only associative factor significantly different between MD and SD was age. Those with MD were more likely to be younger than those with SD. Conclusion: Our findings of symptom profiles and associative factors lend support to the continuum notion of depression. Identification of only older adults within the community long-term care service system who meet criteria for MD would leave many older adults, who also face multiple comorbidities, high levels of stress and social isolation, and substantial depressive symptoms undiagnosed and untreated. © 2013 Taylor & Francis Group, LLC.
depressive symptoms; diagnosis; functional impairment; homecare
Vemuri, C.a , Wittenberg, A.M.a , Caputo, F.J.a , Earley, J.A.d , Driskill, M.R.d , Rastogi, R.b , Emery, V.B.a , Thompson, R.W.a c
Early effectiveness of isolated pectoralis minor tenotomy in selected patients with neurogenic thoracic outlet syndrome
(2013) Journal of Vascular Surgery, 57 (5), pp. 1345-1352.
a Center for Thoracic Outlet Syndrome, Department of Surgery (Section of Vascular Surgery), Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Anesthesiology/Pain Management, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Rehabilitation Institute of St. Louis, St. Louis, MO, United States
Objective: This study evaluated the early effectiveness of isolated pectoralis minor tenotomy (PMT) in the surgical treatment of selected patients with neurogenic thoracic outlet syndrome (NTOS) compared with supraclavicular decompression (SCD; as scalenectomy, neurolysis, and first rib resection) plus PMT (SCD+PMT). Methods: Data were obtained for 200 patients undergoing operative treatment for disabling NTOS between 2008 and 2011. Isolated PMT was offered to 57 patients with physical examination findings limited to the subcoracoid space, and SCD+PMT was offered to 143 with scalene triangle and subcoracoid findings. Functional outcomes were assessed before and 3 months after surgery using the Disabilities of the Arm, Shoulder and Hand (DASH) survey and related instruments. Results: There were no significant differences (P >.05) between PMT and SCD+PMT patients with respect to age (overall, 37 ± 1 years), sex (73% women), side affected (52% right, 14% bilateral), or the frequency of various NTOS symptoms, but fewer PMT patients had a bony anomaly (0% vs 18%; P <.01) or a history of injury (35% vs 61%; P <.01). Mean preoperative DASH scores were similar between PMT and SCD+PMT groups (49.9 ± 3.6 vs 50.8 ± 1.6), but previous use of opiate pain medications was higher in PMT patients (47% vs 20%; P =.0004). PMT was conducted as an outpatient procedure, whereas the mean hospital stay after SCD+PMT was 4.8 ± 0.1 days, with two patients (1%) requiring early reoperations for persistent lymph leaks. Mean DASH scores 3 months after surgery were significantly improved after isolated PMT (29.6 ± 4.2; P <.01) and SCD+PMT (41.5 ± 2.2; P <.01), but the mean extent of improvement in DASH scores was not significantly different in PMT (32% ± 9%) vs SCD+PMT (19% ± 5%). There were also no significant differences in the proportion of PMT vs SCD+PMT patients demonstrating improvement in functional outcome measures (75% vs 72%) or in overall use of opiate medications (35% vs 27%). Conclusions: Isolated PMT is a low-risk outpatient procedure that is effective for the treatment of selected patients with disabling NTOS, with early outcomes similar to SCD+PMT. These findings emphasize the importance of recognizing subcoracoid brachial plexus compression as part of the spectrum of NTOS and support the role of PMT in surgical management. Copyright © 2013 by the Society for Vascular Surgery.
Randolph, G.J., Gautier, E.L.
Emerging roles of neural guidance molecules in atherosclerosis: Sorting out the complexity
(2013) Arteriosclerosis, Thrombosis, and Vascular Biology, 33 (5), pp. 882-883.
Department of Pathology and Immunology, Washington University School of Medicine, Washington University, St. Louis, MO 63110, United States
Editorials; macrophages; mice; netrin-1; semaphorin 3E
Vogel, A.C.a , Church, J.A.a , Power, J.D.a , Miezin, F.M.a b , Petersen, S.E.a b c d , Schlaggar, B.L.a b c e
Functional network architecture of reading-related regions across development
(2013) Brain and Language, 125 (2), pp. 231-243. Cited 1 time.
a Dept. of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Dept. of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Dept. of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis. MO, United States
d Dept. of Psychology, Washington University in St. Louis, St. Louis, MO, United States
e Dept. of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
Reading requires coordinated neural processing across a large number of brain regions. Studying relationships between reading-related regions informs the specificity of information processing performed in each region. Here, regions of interest were defined from a meta-analysis of reading studies, including a developmental study. Relationships between regions were defined as temporal correlations in spontaneous fMRI signal; i.e., resting state functional connectivity MRI (RSFC). Graph theory based network analysis defined the community structure of the "reading-related" regions. Regions sorted into previously defined communities, such as the fronto-parietal and cingulo-opercular control networks, and the default mode network. This structure was similar in children, and no apparent "reading" community was defined in any age group. These results argue against regions, or sets of regions, being specific or preferential for reading, instead indicating that regions used in reading are also used in a number of other tasks. © 2013 Elsevier Inc.
Child; Functional connectivity; Graph theory; Resting-state
Pineda, J.A.a b , Leonard, J.R.d e , Mazotas, I.G.c , Noetzel, M.b , Limbrick, D.D.d e , Keller, M.S.c , Gill, J.c f g , Doctor, A.a h
Mortality in severe traumatic brain injury - Authors' reply
(2013) The Lancet Neurology, 12 (5), pp. 427-428.
a Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
c Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, United States
d Department of Neurosurgery, Washington University School of Medicine, St Louis, MO 63110, United States
e Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, United States
f Department of Political Science, Washington University School of Medicine, St Louis, MO 63110, United States
g Department of Biostatistics, Washington University School of Medicine, St Louis, MO 63110, United States
h Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110, United States
Jaeger, A.a b , Konkel, A.a , Dobbins, I.G.a
Unexpected novelty and familiarity orienting responses in lateral parietal cortex during recognition judgment
(2013) Neuropsychologia, 51 (6), pp. 1061-1076.
a Department of Psychology, Washington University in Saint Louis, United States
b Department of Physiology, Biosciences Institute, University of São Paulo, São Paulo, Brazil
The role of lateral parietal cortex during recognition memory is heavily debated. We examined parietal activation during an Explicit Memory Cueing recognition paradigm that biases participants towards expecting novel or familiar stimuli on a trial-by-trial basis using anticipatory cues ("Likely Old", "Likely New"), compared to trials with neutral cues ("????"). Three qualitatively distinct patterns were observed in the left lateral parietal cortex. An unexpected novelty response occurred in left anterior intraparietal cortex (IPS)/post-central gyrus (PoCG) in which greater activation was observed for new vs. old materials following the "Likely Old" cue, but not following the "Likely New" cue. In contrast, anterior angular gyrus demonstrated an unexpected familiarity response with greater activation for old vs. new materials following the "Likely New" cue, but not the "Likely Old" cue. Thus these two regions demonstrated increased responses that were selective for either new or old materials respectively, but only when they were unexpected. In contrast, a mid IPS area demonstrated greater response for whichever class of memoranda was unanticipated given the cue condition (an unexpected memory response). Analogous response patterns in regions outside of parietal cortex, and the results of a resting state connectivity analysis, suggested these three response patterns were associated with visuo-spatial orienting following unexpected novelty, source monitoring operations following unexpected familiarity, and general executive control processes following violated expectations. These findings support a Memory Orienting Model of the left lateral parietal cortex in which the region is linked to the investigation of unexpected novelty or familiarity in the environment. © 2013 Elsevier Ltd.
Decision biasing; Episodic memory; External cues; Parietal cortex; Prefrontal cortex
Yamada, K.A.a , Patel, A.Y.a , Ewald, G.A.a , Whitehead, D.S.a , Pasque, M.K.b , Silvestry, S.C.b , Janks, D.L.c , Mann, D.L.a , Nerbonne, J.M.c
How to Build an Integrated Biobank: The Washington University Translational Cardiovascular Biobank & Repository Experience
(2013) Clinical and Translational Science, . Article in Press.
a Cardiovascular Division, Department of Medicine Washington University School of Medicine St. Louis Missouri USA
b Division of Cardiothoracic Surgery, Department of Surgery Washington University School of Medicine St. Louis Missouri USA
c Department of Developmental Biology Washington University School of Medicine St. Louis Missouri USA
Translational studies that assess and extend observations made in animal models of human pathology to elucidate relevant and important determinants of human diseases require the availability of viable human tissue samples. However, there are a number of technical and practical obstacles that must be overcome in order to perform cellular and electrophysiological studies of the human heart. In addition, changing paradigms of how diseases are diagnosed, studied and treated require increasingly complex integration of rigorous disease phenotyping, tissue characterization and detailed delineation of a multitude of "_omics". Realizing the need for quality-controlled human cardiovascular tissue acquisition, annotation, biobanking and distribution, we established the Translational Cardiovascular Biobank & Repository at Washington University School of Medicine. Several critical details are essential for the success of cardiovascular biobanking including coordinated, trained and dedicated staff members; adequate, nonrestrictive informed consent protocols; and fully integrated clinical data management applications for annotating, tracking and sharing of tissue and data resources. Labor and capital investments into growing biobanking resources will facilitate collaborative efforts aimed at limiting morbidity and mortality due to heart disease and improving overall cardiovascular health. © 2013 Wiley Periodicals, Inc.
Cardiovascular diseases; Heart failure; Tissue; Transplantation
Chen, X.a , Errangi, B.b , Li, L.b , Glasser, M.F.c , Westlye, L.T.d e , Fjell, A.M.d , Walhovd, K.B.d , Hu, X.b , Herndon, J.G.f , Preuss, T.M.f , Rilling, J.K.a g h i
Brain aging in humans, chimpanzees (Pan troglodytes), and rhesus macaques (Macaca mulatta): magnetic resonance imaging studies of macro- and microstructural changes
(2013) Neurobiology of Aging, . Article in Press.
a Department of Anthropology, Emory University, Atlanta, GA, USA
b Department of Biomedical Engineering, Georgia Institute of Technology/Emory, Atlanta, GA, USA
c Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA
d Center for the Study of Human Cognition, Department of Psychology, University of Oslo, Oslo, Norway
e K. G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
f Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
g Department of Psychiatry and Behavioral Science, Emory University, Atlanta, GA, USA
h Center for Translational Social Neuroscience, Emory University, Atlanta, GA, USA
i Division of Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
Among primates, humans are uniquely vulnerable to many age-related neurodegenerative disorders. We used structural and diffusion magnetic resonance imaging (MRI) to examine the brains of chimpanzees and rhesus monkeys across each species' adult lifespan, and compared these results with published findings in humans. As in humans, gray matter volume decreased with age in chimpanzees and rhesus monkeys. Also like humans, chimpanzees showed a trend for decreased white matter volume with age, but this decrease occurred proportionally later in the chimpanzee lifespan than in humans. Diffusion MRI revealed widespread age-related decreases in fractional anisotropy and increases in radial diffusivity in chimpanzees and macaques. However, both the fractional anisotropy decline and the radial diffusivity increase started at a proportionally earlier age in humans than in chimpanzees. Thus, even though overall patterns of gray and white matter aging are similar in humans and chimpanzees, the longer lifespan of humans provides more time for white matter to deteriorate before death, with the result that some neurological effects of aging may be exacerbated in our species. © 2013 Elsevier Inc. All rights reserved.
Brain aging; Chimpanzees; Comparative anatomy; Diffusion tensor imaging; Female; Humans; Magnetic resonance imaging; Non-human primates; Rhesus macaques
Orsmond, G.I.a , Shattuck, P.T.b , Cooper, B.P.b , Sterzing, P.R.c , Anderson, K.A.d
Social Participation Among Young Adults with an Autism Spectrum Disorder
(2013) Journal of Autism and Developmental Disorders, pp. 1-10. Article in Press.
a Department of Occupational Therapy, Boston University, Boston, 02215, United States
b Brown School of Social Work, Washington University, St. Louis, United States
c School of Social Welfare, University of California, Berkeley, United States
d Waisman Center, University of Wisconsin Madison, Madison, United States
Investigating social participation of young adults with an autism spectrum disorder (ASD) is important given the increasing number of youth aging into young adulthood. Social participation is an indicator of life quality and overall functioning. Using data from the National Longitudinal Transition Study 2, we examined rates of participation in social activities among young adults who received special education services for autism (ASD group), compared to young adults who received special education for intellectual disability, emotional/behavioral disability, or a learning disability. Young adults with an ASD were significantly more likely to never see friends, never get called by friends, never be invited to activities, and be socially isolated. Among those with an ASD, lower conversation ability, lower functional skills, and living with a parent were predictors of less social participation. © 2013 Springer Science+Business Media New York.
Autism spectrum disorder; Social participation; Young adulthood
Ma, C.X.a b , Suman, V.J.c , Goetz, M.d , Haluska, P.d , Moynihan, T.d , Nanda, R.e , Olopade, O.e , Pluard, T.a b , Guo, Z.a , Chen, H.X.f , Erlichman, C.d , Ellis, M.J.a b , Fleming, G.F.e
A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer
(2013) Breast Cancer Research and Treatment, pp. 1-9. Article in Press.
a Section of Breast Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, United States
b Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, United States
c Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, United States
d Department of Oncology, Mayo Clinic, Rochester, United States
e Division of Hematology and Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, United States
f Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, United States
The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies. A 3 + 3 Phase I design was chosen. Temsirolimus and Cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34-72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing. © 2013 Springer Science+Business Media New York.
Cixutumumab; IGF-1R; Metastatic breast cancer; mTOR; Temsirolimus
Pitman, K.M.a , Hofmeister, A.M.b , Speck, A.K.c
Revisiting astronomical crystalline forsterite in the UV to near-IR
(2013) Earth, Planets and Space, 65 (3), pp. 129-138.
a Planetary Science Institute, 1700 East Fort L9-138owell Road, Tucson, AZ 85719-2395, United States
b Department of Earth and Planetary Sciences, Washington University, Campus Box 1169, 1 Brookings Drive, St. Louis, MO 63130-4899, United States
c Department Ofof Physics and Astronomy, 223 Physics Bldg., University of Missouri, Columbia, MO 65211-7010, United States
Optical functions (n and k) of cosmic dust species like forsterite (Mg 2SiO4) are required at all wavelengths to quantify the temperature and amount of dust. Astronomers combine optical functions of forsterite and olivine in different ways, which will affect radiative transfer models. We investigated what recent updates to the ultraviolet-visible-near- infrared (UV-VIS-NIR) laboratory spectra of forsterite and the choice of forsterite n, k dataset will have on radiative transfer models. We measured the UV-VIS-NIR transmission spectra of synthetic forsterite, MgO, SiO2, olivine (Fo90), and meteoritic olivine (pallasite). We derived optical functions for these and compared the UV-IR behavior of our k, absorption cross-section (Cabs), and total flux to that of "astronomical silicate" and olivine. Laboratory-derived k is substantially lower than "astronomical silicate" k at λ ∼ 0.2-5 μm. In the IR, different laboratory n and k produce equivocal (Cabs), whereas total flux is different for "astronomical silicate" versus laboratory n, k. From 0.35-5 μm the choice of "forsterite" k values has the most effect on modeled quantities. For environments with significant UV flux, astronomers should use recent UV-VIS-NIR laboratory n,k. Copyright © The Society of Geomagnetism and Earth Planetary and Space Sciences (SGEPSS).
Dust; Extinction; Forsterite; Laboratory spectroscopy; Near-infrared; Optical constants; Ultraviolet
Johnston, A.a , Yoakum, J.b , Singh, K.c
Taking on webRTC in an enterprise
(2013) IEEE Communications Magazine, 51 (4), art. no. 6495760, pp. 48-54.
a Washington University, St Louis, MO, United States
b Motorola, Nortel, and Avaya, United States
c Columbia University, United States
WebRTC, Web Real-Time Communications, will have a major impact on enterprise communications, as well as consumer communications and their interactions with enterprises. This article illustrates and discusses a number of issues that are specific to WebRTC enterprise usage. Some of these relate to security: firewall traversal, access control, and peer-to-peer data flows. Others relate to compliance: recording, logging, and enforcing enterprise policies. Additional enterprise considerations relate to integration and interoperation with existing communication infrastructure and session-centric telephony systems. © 1979-2012 IEEE.
Berry, J.D.a , Shefner, J.M.b , Conwit, R.c , Schoenfeld, D.d , Keroack, M.e , Felsenstein, D.f , Krivickas, L.a , David, W.S.a , Vriesendorp, F.b , Pestronk, A.g , Caress, J.B.h , Katz, J.i , Simpson, E.j , Rosenfeld, J.k , Pascuzzi, R.l , Glass, J.m , Rezania, K.n , Rothstein, J.D.o , Greenblatt, D.J.p , Cudkowicz, M.E.a
Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis
(2013) PLoS ONE, 8 (4), art. no. e61177, .
a Neurology Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
b Department of NeurologyState University of New York Upstate Medical University, Syracuse, NY, United States
c National Institute of Neurologic Disorders and Stroke, Bethesda, MD, United States
d Department of Biostatistics, Massachusetts General Hospital, Boston, MA, United States
e Department of Gastroenterology, Marshfield Clinic, Eau Claire, WI, United States
f Infectious Disease Unit/Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Neurology, Wake Forest University, Winston-Salem, NC, United States
i Department of Neurology, California Pacific Medical Center, San Francisco, CA, United States
j Department of Neurology, Methodist Neurological Institute, Houston, TX, United States
k Department of Neurology, University of California San Francisco Fresno, Neuroscience Institute, Fresno, CA, United States
l Department of Neurology, Indiana University, Indianapolis, IN, United States
m Department of Neurology, Emory University, Atlanta, GA, United States
n Department of Neurology, University of Chicago, Chicago, IL, United States
o Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
p Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, United States
Objectives:Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing.Methods:In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug.Results:Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 μM (0.55 μg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy.Conclusions:The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed.Trial Registration:ClinicalTrials.gov NCT00349622.
Goyal, M.S., Raichle, M.E.
Gene expression-based modeling of human cortical synaptic density
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (16), pp. 6571-6576.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Postnatal cortical synaptic development is characterizedbystages of exuberant growth, pruning, and stabilization during adulthood. How gene expression orchestrates these stages of synaptic development is poorly understood. Here we report that synaptic growth-related gene expression alone does not determine cortical synaptic density changes across the human lifespan, but instead,the dynamics of cortical synaptic density can be accurately simulated by a first-order kinetic model of synaptic growth and elimination that incorporates two separate gene expression patterns. Surprisingly, modeling of cortical synaptic density is optimized when genes related to oligodendrocytes are used to determine synaptic elimination rates. Expression of synaptic growth and oligodendrocyte genes varies regionally, resulting in different predictions of synaptic density among cortical regions that concur with previous regional data in humans. Our analysis suggests that modest ratesof synaptic growth persist in adulthood, but that this is counterbalanced by increasing rates of synaptic elimination, resulting in stable synaptic number and ongoing synaptic turnover in the human adult cortex. Our approach provides a promising avenue for exploring how complex interactions among genes may contribute to neurobiological phenomena across the human lifespan.
Kim, T.-I.a b , McCall, J.G.c d e f , Jung, Y.H.a o , Huang, X.a , Siuda, E.R.c d e f , Li, Y.g , Song, J.h , Song, Y.M.a , Pao, H.A.a , Kim, R.-H.a , Lu, C.i , Lee, S.D.j , Song, I.-S.k , Shin, G.a , Al-Hasani, R.c d e , Kim, S.a , Tan, M.P.j , Huang, Y.g , Omenetto, F.G.l m , Rogers, J.A.a j k n , Bruchas, M.R.c d e f
Injectable, cellular-scale optoelectronics with applications for wireless optogenetics
(2013) Science, 340 (6129), pp. 211-216.
a Department of Materials Science and Engineering, Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
b School of Chemical Engineering, Sungkyunkwan University (SKKU), Suwon 440-746, South Korea
c Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO 63110, United States
d Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Civil and Environmental Engineering, Institute for Public Health and Medicine, Northwestern University, Evanston, IL 60208, United States
h Department of Mechanical and Aerospace Engineering, University of Miami, Coral Gables, FL 33146, United States
i Soft Matter Research Center, Department of Civil Engineering, Zhejiang University, 38 Zheda Road, Hangzhou 310027, China
j Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
k Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
l Department of Biomedical Engineering, Tufts University, Medford, MA 02115, United States
m Department of Physics, Tufts University, Medford, MA 02115, United States
n Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
o Department of Electrical and Computer Engineering, University of Wisconsin-Madison, Madison, WI 53706, United States
Successful integration of advanced semiconductor devices with biological systems will accelerate basic scientific discoveries and their translation into clinical technologies. In neuroscience generally, and in optogenetics in particular, the ability to insert light sources, detectors, sensors, and other components into precise locations of the deep brain yields versatile and important capabilities. Here, we introduce an injectable class of cellular-scale optoelectronics that offers such features, with examples of unmatched operational modes in optogenetics, including completely wireless and programmed complex behavioral control over freely moving animals. The ability of these ultrathin, mechanically compliant, biocompatible devices to afford minimally invasive operation in the soft tissues of the mammalian brain foreshadow applications in other organ systems, with potential for broad utility in biomedical science and engineering.
Bennett, T.M.a , Maraini, G.b , Jin, C.c , Sun, W.c , Fielding Hejtmancik, J.c , Shiels, A.a
Noncoding variation of the gene for ferritin light chain in hereditary and age-related cataract
(2013) Molecular Vision, 19, pp. 835-844.
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Ophthalmology, University of Parma, Parma, Italy
c Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, United States
Purpose: Cataract is a clinically and genetically heterogeneous disorder of the ocular lens and an important cause of visual impairment. The aim of this study was to map and identify the gene underlying autosomal dominant cataract segregating in a four-generation family, determine the lens expression profile of the identified gene, and test for its association with age-related cataract in a case-control cohort. Methods: Genomic DNA was prepared from blood leukocytes, and genotyping was performed by means of single-nucleotide polymorphism markers and microsatellite markers. Linkage analyses were performed using the GeneHunter and MLINK programs, and mutation detection was achieved by dideoxy cycle sequencing. Lens expression studies were performed using reverse-transcription polymerase chain reaction (RT-PCR) and in situ hybridization. Results: Genome-wide linkage analysis with single nucleotide polymorphism markers in the family identified a likely disease-haplotype interval on chromosome 19q (rs888861-[~17Mb]-rs8111640) that encompassed the microsatellite marker D19S879 (logarithm of the odds score [Z]=2.03, recombination distance [θ]=0). Mutation profiling of positional- candidate genes detected a heterozygous, noncoding G-to-T transversion (c.-168G>T) located in the iron response element (IRE) of the gene coding for ferritin light chain (FTL) that cosegregated with cataract in the family. Serum ferritin levels were found to be abnormally elevated (~fourfold), without evidence of iron overload, in an affected family member; this was consistent with a diagnosis of hereditary hyperferritinemia-cataract syndrome. No sequence variations located within the IRE were detected in a cohort of 197 cases with age-related cataract and 102 controls with clear lenses. Expression studies of human FTL, and its mouse counterpart FTL1, in the lens detected RT-PCR amplicons containing full-length protein-coding regions, and strong in situ localization of FTL1 transcripts to the lens equatorial epithelium and peripheral cortex. Conclusions: The data are consistent with robust transcription of FTL in the lens, and suggest that whereas variations clustered in the IRE of the FTL gene are directly associated with hereditary hyperferritinemia-cataract syndrome, such IRE variations are unlikely to play a significant role in the genetic etiology of age-related cataract. © 2013 Molecular Vision.
Berger, J.R.a , Aksamit, A.J.b , Clifford, D.B.c , Davis, L.d , Koralnik, I.J.e f , Sejvar, J.J.g , Bartt, R.h , Major, E.O.i , Nath, A.j
PML diagnostic criteria: Consensus statement from the AAN neuroinfectious disease section
(2013) Neurology, 80 (15), pp. 1430-1438.
a Department of Neurology, University of Kentucky, Lexington, United States
b Department of Neurology, Mayo Clinic, Rochester, MN, United States
c Washington University, St. Louis, MO, United States
d Department of Neurology, University of New Mexico, Albuquerque, United States
e Division of Neurovirology, Department of Neurology, Center for Virology and Vaccine Research, Boston, MA, United States
f Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
g Centers for Disease Control, Atlanta, GA, United States
h Blue Sky Neurosciences, Englewood, CO, United States
i Laboratory of Molecular Medicine and Neuroscience, NINDS, NIH, Bethesda, MD, United States
j Section of Infections of the Nervous System, NINDS, NIH, Bethesda, MD, United States
Objective: To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML). Methods: We reviewed available literature to identify various diagnostic criteria employed. Several search strategies employing the terms "progressive multifocal leukoencephalopathy" with or without "JC virus" were performed with PubMed, SCOPUS, and EMBASE search engines. The articles were reviewed by a committee of individuals with expertise in the disorder in order to determine the most useful applicable criteria. Results: A consensus statement was developed employing clinical, imaging, pathologic, and virologic evidence in support of the diagnosis of PML. Two separate pathways, histopathologic and clinical, for PML diagnosis are proposed. Diagnostic classification includes certain, probable, possible, and not PML. Conclusion: Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. The presence of clinical and imaging manifestations consistent with the diagnosis and not better explained by other disorders coupled with the demonstration of JC virus by PCR in CSF is also considered diagnostic. Algorithms for establishing the diagnosis have been recommended. © 2013 American Academy of Neurology.
Bloesch, E.K.a , Davoli, C.C.b , Abrams, R.A.a
Age-Related Changes in Attentional Reference Frames for Peripersonal Space
(2013) Psychological Science, 24 (4), pp. 557-561.
a Washington University in St. Louis, United States
b University of Notre Dame, United States
Neurological changes in older adults suggest that their mental representation of peripersonal space, the space around their bodies, might be degraded compared with that of young adults. These changes may lead to differences in how attention is allocated within peripersonal space, affecting how older adults plan and guide their actions. In the present study, we show that there are indeed profound differences between the spatial representations of older and young adults: In a task involving simple hand movements, young adults adopted an attentional reference frame centered on the hand, and older adults adopted a reference frame centered on the body. Such differences may help to explain age-related changes observed in the performance of many common movement tasks. © The Author(s) 2013.
aging; attention; perceptual motor coordination; spatial perception
Lang, C.E., Bland, M.D., Bailey, R.R., Schaefer, S.Y., Birkenmeier, R.L.
Assessment of upper extremity impairment, function, and activity after stroke: Foundations for clinical decision making
(2013) Journal of Hand Therapy, 26 (2), pp. 104-115.
Program in Physical Therapy, Department of Neurology, Washington University, 4444 Forest Park, Saint Louis, MO 63108, United States
The purpose of this review is to provide a comprehensive approach for assessing the upper extremity (UE) after stroke. First, common UE impairments and how to assess them are briefly discussed. Although multiple UE impairments are typically present after stroke, the severity of one's impairment, paresis, is the primary determinant of UE functional loss. Second, UE function is operationally defined and a number of clinical measures are discussed. It is important to consider how impairment and loss of function affect UE activity outside of the clinical environment. Thus, this review also identifies accelerometry as an objective method for assessing UE activity in daily life. Finally, the role that each of these levels of assessment should play in clinical decision making is discussed to optimize the provision of stroke rehabilitation services. © 2013 Hanley & Belfus, an imprint of Elsevier Inc. All rights reserved.
Assessment; Clinical decision making; Outcomes; Stroke
Araujo, G.C.a , Christ, S.E.b , Grange, D.K.c , Steiner, R.D.d , Coleman, C.a , Timmerman, E.a , White, D.A.a
Executive response monitoring and inhibitory control in children with phenylketonuria: Effects of expectancy
(2013) Developmental Neuropsychology, 38 (3), pp. 139-152.
a Department of Psychology, Washington University, Campus Box 1125, St. Louis, MO 63130, United States
b Department of Psychology, University of Missouri, Columbia, MO, United States
c Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Oregon Health and Science University, Portland, OR, United States
Response monitoring (post-error slowing) and inhibitory control (commission errors) were examined in children with phenylketonuria (PKU) and controls (6-18 years) using Go/No-Go tasks with higher (PKU n = 37; control n = 55) versus lower (PKU n = 24; control n = 25) non-target expectancy. On both tasks children with PKU exhibited impaired monitoring and inhibitory control, but the post-error slowing pattern was different. With higher expectancy children with PKU slowed more (less efficient monitoring) and with lower expectancy slowed less (less monitoring) than controls. No effects of age or phenylalanine level were noted. These results indicate that expectancy differentially effects monitoring and inhibitory control in PKU. © 2013 Copyright Taylor and Francis Group, LLC.
Dosenbach, N.U.F., Petersen, S.E., Schlaggar, B.L.
The Teenage Brain: Functional Connectivity
(2013) Current Directions in Psychological Science, 22 (2), pp. 101-107.
Department of Neurology, Washington University in St. Louis, 4525 Scott Ave., St. Louis, MO 63110, United States
Distant brain regions are organized into large-scale functional networks specialized for specific cognitive processes. The brain's functional-network architecture and its development can be investigated using functional connectivity MRI (fcMRI), which measures correlations in spontaneous fluctuations of brain activity. fcMRI studies have provided important insights into typical brain organization and development, as well as insights into the atypical organization of the brain in neuropsychiatric disorders. fcMRI data can be easily collected and carry much information. Therefore, they are now being analyzed using powerful multivariate-pattern-analysis (MVPA) methods, with the goal of one day being able to diagnose disease states in individuals. However, great care must be taken during these analyses to eliminate confounds such as head movement. © The Author(s) 2013.
functional connectivity; individual predictions; movement effects; multivariate pattern analysis; resting state; support vector machines
Snider, B.J., Buckles, V.D.
"Will I get alzheimer disease?" When cognitively normal patients ask to be tested for alzheimer disease
(2013) CONTINUUM Lifelong Learning in Neurology, 19 (2), pp. 470-474.
Washington University, Campus B. 8111, 660 S Euclid Ave, St Louis, MO 63110, United States
This article presents the case of a cognitively normal patient who is requesting a procedure (amyloid imaging) recently approved for the diagnosis of Alzheimer disease (AD) in patients with cognitive impairment. The predictive value of this test in unaffected people is not clearly established. Knowing the results of the test will have no effect on therapeutic options, although the patient may make lifestyle decisions based on the results. There is potential risk to the patient in terms of insurability, employability, and psychological consequences. Physicians will face this situation with increasing frequency as the AD biomarker field progresses. © 2013 American Academy of Neurology.
Nichols, C.G.a , Singh, G.K.b , Grange, D.K.c
KATP channels and cardiovascular disease: Suddenly a syndrome
(2013) Circulation Research, 112 (7), pp. 1059-1072.
a Center for the Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Pediatrics, St. Louis, MO, United States
c Washington University School of Medicine, St. Louis, MO, United States
ATP-sensitive potassium (KATP) channels were first discovered in the heart 30 years ago. Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1, KCNJ8, and Kir6.2 KCNJ11) with sulfonylurea receptors (SUR1, ABCC8, and SUR2, ABCC9) of the ABCC protein subfamily has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular KATP2 and the detrimental consequences of genetic deletions or mutations in mice have been recognized. However, despite this extensive body of knowledge, there has been a paucity of defined roles of KATP subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the ECG, and 2 isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. This realization of previously unconsidered consequences provides significant insight into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities. Copyright © 2013 American Heart Association, Inc.
arrhythmias, cardiac; Cantu syndrome; edema; Kir6.1 protein, human; Kir6.2 channel; SUR2 receptor, human; vasodilation
Thomas, J.B.a , Brier, M.R.a , Snyder, A.Z.a b , Vaida, F.F.c , Ances, B.M.a
Pathways to neurodegeneration: Effects of HIV and aging on resting-state functional connectivity
(2013) Neurology, 80 (13), pp. 1186-1193. Cited 1 time.
a Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Family and Preventive Medicine, University of California, San Diego, CA, United States
Objective: Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging. Methods: In this cross-sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV-uninfected (HIV-) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks. Results: Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV-controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4+ cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV-participants. No interaction was observed between HIV and aging. Conclusions: HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging. © 2013 American Academy of Neurology.
Viader, A., Sasaki, Y., Kim, S., Strickland, A., Workman, C.S., Yang, K., Gross, R.W., Milbrandt, J.
Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy.
(2013) Neuron, 77 (5), pp. 886-898.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells [SCs]) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response (ISR) through the actions of heme-regulated inhibitor (HRI) kinase, and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines (ACs), an intermediate of fatty acid β-oxidation. Importantly, we show that ACs are released from SCs and induce axonal degeneration. A maladaptive ISR as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies. Copyright © 2013 Elsevier Inc. All rights reserved.
Naismith, R.T.a , Banwell, B.L.b
Can dissemination include the PNS in adults with acute disseminated encephalomyelitis?
(2013) Neurology, 80 (10), pp. 876-877.
a Department of Neurology, Washington University, St. Louis, MO, United States
b Department of Pediatrics, Division of Neurology, University of Pennsylvania, Philadelphia, United States
Document Type: Editorial
Schor, N.F.a , Carlson, D.W.b
Pediatric neurohospitalists: An idea that has come of age?
(2013) Neurology, 80 (10), pp. 880-881.
a Department of Pediatrics, University of Rochester, School of Medicine and Dentistry, Rochester, NY, United States
b Department of Pediatrics, Washington University, St. Louis, MO, United States
Murata, T.a , Dietrich, H.H.a b , Xiang, C.a , Dacey Jr., R.G.a
G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats
(2013) Stroke, 44 (3), pp. 779-785.
a Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO, United States
Background and Purpose-Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury. Methods-Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls. Results-G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls. Conclusions-GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury. © 2013 American Heart Association, Inc.
Brain hypoxia; GPER protein; Recovery of function; Sex differences
Copyright © 2009 | Contact Us | SitemapOffice of Neuroscience Research660 South Euclid Ave., Campus Box 8111, St. Louis, Missouri 63110Email: ONR@neuro.wustl.edu