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WUSTL Neuroscience Publications Archive - July 2012

Scopus weekly report:

July 26, 2012

July 11, 2012

July 4, 2012

 

July 26, 2012

Miller, R.L.a , Knuepfer, M.M.b , Wang, M.H.a , Denny, G.O.a , Gray, P.A.a , Loewy, A.D.a
Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats
(2012) Neuroscience, 218, pp. 110-125. 
a Department of Anatomy and Neurobiology, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Pharmacological and Physiological Science, St. Louis University, School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, United States

Abstract
The parabrachial nucleus (PB) is a brainstem cell group that receives a strong input from the nucleus tractus solitarius regarding the physiological status of the internal organs and sends efferent projections throughout the forebrain. Since the neuroanatomical organization of the PB remains unclear, our first step was to use specific antibodies against two neural lineage transcription factors: Forkhead box protein2 (FoxP2) and LIM homeodomain transcription factor 1 beta (Lmx1b) to define the PB in adult rats. This allowed us to construct a cytoarchitectonic PB map based on the distribution of neurons that constitutively express these two transcription factors. Second, the in situ hybridization method combined with immunohistochemistry demonstrated that mRNA for glutamate vesicular transporter Vglut2 (Slc17a6) was present in most of the Lmx1b+ and FoxP2+ parabrachial neurons, indicating these neurons use glutamate as a transmitter. Third, conscious rats were maintained in a hypotensive or hypertensive state for 2. h, and then, their brainstems were prepared by the standard c-Fos method which is a measure of neuronal activity. Both hypotension and hypertension resulted in c-Fos activation of Lmx1b+ neurons in the external lateral-outer subdivision of the PB (PBel-outer). Hypotension, but not hypertension, caused c-Fos activity in the FoxP2+ neurons of the central lateral PB (PBcl) subnucleus. The Kölliker-Fuse nucleus as well as the lateral crescent PB and rostral-most part of the PBcl contain neurons that co-express FoxP2+ and Lmx1b+, but none of these were activated after blood pressure changes. Salt-sensitive FoxP2 neurons in the pre-locus coeruleus and PBel-inner were not c-Fos activated following blood pressure changes. In summary, the present study shows that the PBel-outer and PBcl subnuclei originate from two different neural progenitors, contain glutamatergic neurons, and are affected by blood pressure changes, with the PBel-outer reacting to both hypo- and hypertension, and the PBcl signaling only hypotensive changes. © 2012 IBRO.

Author Keywords
Blood pressure;  FoxP2;  Lmx1b;  Parabrachial nucleus;  Transcription factors

Document Type: Article
Source: Scopus

 

Mouannes-Srour, J.J.a , Shin, W.b , Ansari, S.A.c d , Hurley, M.C.c d , Vakil, P.a , Bendok, B.R.c d , Lee, J.L.e , Derdeyn, C.P.e f g , Carroll, T.J.a c
Correction for arterial-tissue delay and dispersion in absolute quantitative cerebral perfusion DSC MR imaging
(2012) Magnetic Resonance in Medicine, 68 (2), pp. 495-506. 

a Department of Biomedical Engineering, Northwestern University, Evanston, IL, United States
b Imaging Institute, Mellen Center, Cleveland Clinic, Cleveland, OH, United States
c Department of Radiology, Northwestern University, Feinberg School of Medicine, 737 N. Michigan Ave, Chicago, IL 60611, United States
d Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
e Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
g Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
The singular value decomposition deconvolution of cerebral tissue concentration-time curves with the arterial input function is commonly used in dynamic susceptibility contrast cerebral perfusion MR imaging. However, it is sensitive to the time discrepancy between the arrival of the bolus in the tissue concentration-time curve and the arterial input function signal. This normally causes inaccuracy in the quantitative perfusion maps due to delay and dispersion effects. A comprehensive correction algorithm has been achieved through slice-dependent time-shifting of the arterial input function, and a delay-dependent dispersion correction model. The correction algorithm was tested in 11 healthy subjects and three ischemic stroke patients scanned with a quantitative perfusion pulse sequence at 1.5 T. A validation study was performed on five patients with confirmed cerebrovascular occlusive disease scanned with MRI and positron emission tomography at 3.0 T. A significant effect (P < 0.05) was reported on the quantitative cerebral blood flow and mean transit time measurements (up to 50%). There was no statistically significant effect on the quantitative cerebral blood volume values. The in vivo results were in agreement with the simulation results, as well as previous literature. This minimizes the bias in patient diagnosis due to the existing errors and artifacts in dynamic susceptibility contrast imaging. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc. Copyright © 2011 Wiley Periodicals, Inc.

Author Keywords
arterial-tissue delay and dispersion;  ischemic stroke;  quantitative cerebral perfusion;  singular value decomposition

Document Type: Article
Source: Scopus

 

Kirk, K.A.a , Shoykhet, M.b , Jeong, J.H.c , Tyler-Kabara, E.C.d , Henderson, M.J.e , Bell, M.J.f , Fink, E.L.f
Dysautonomia after pediatric brain injury
(2012) Developmental Medicine and Child Neurology, 54 (8), pp. 759-764.


a University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
b The Division of Pediatric Critical Care Medicine, The Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biostatistics, The University of Pittsburgh School of Public Health, Pittsburgh, PA, United States
d Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
e The Children's Institute of Pittsburgh, Pittsburgh, PA, United States
f University of Pittsburgh Medical Center, Departments of Critical Care Medicine and Pediatrics, Safar Center for Resuscitation Research, Pittsburgh, PA, United States

Abstract
Aim Dysautonomia after brain injury is a diagnosis based on fever, tachypnea, hypertension, tachycardia, diaphoresis, and/or dystonia. It occurs in 8 to 33% of adults with brain injury and is associated with poor outcome. We hypothesized that children with brain injury with dysautonomia have worse outcomes and prolonged rehabilitation, and sought to determine the prevalence of dysautonomia in children and to characterize its clinical features. Method We developed a database of children (n=249, 154 males, 95 females; mean [SD] age 11years 10months [5y 7mo]) with traumatic brain injury, cardiac arrest, stroke, infection of the central nervous system, or brain neoplasm admitted for rehabilitation to The Children's Institute of Pittsburgh between 2002 and 2009. Dysautonomia diagnosis, injury type, clinical signs, length of stay, and Functional Independence Measure for Children (WeeFIM) testing were extracted from medical records, and analysed for differences between groups with and without dysautonomia. Results Dysautonomia occurred in 13% of children with brain injury (95% confidence interval 9.3-18.0%), occurring in 10% after traumatic brain injury and 31% after cardiac arrest. The combination of hypertension, diaphoresis, and dystonia best predicted a diagnosis of dysautonomia (area under the curve=0.92). Children with dysautonomia had longer stays, worse WeeFIM scores, and improved less on the score's motor component (all p≤0.001). Interpretation Dysautonomia is common in children with brain injury and is associated with prolonged rehabilitation. Prospective study and standardized diagnostic approaches are needed to maximize outcomes. This article is commented on by Baguley on page of this issue © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Document Type: Article
Source: Scopus

 

Porter, R.F., Kumar, N., Drapekin, J.E., Gyawali, C.P.
Fragmented esophageal smooth muscle contraction segments on high resolution manometry: A marker of esophageal hypomotility
(2012) Neurogastroenterology and Motility, 24 (8), pp. 763-e353. 

Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background Esophageal peristalsis consists of a chain of contracting striated and smooth muscle segments on high resolution manometry (HRM). We compared smooth muscle contraction segments in symptomatic subjects with reflux disease to healthy controls. Methods High resolution manometry Clouse plots were analyzed in 110 subjects with reflux disease (50±1.4years, 51.5% women) and 15 controls (27±2.1years, 60.0% women). Using the 30mmHg isobaric contour tool, sequences were designated fragmented if either smooth muscle contraction segment was absent or if the two smooth muscle segments were separated by a pressure trough, and failed if both smooth muscle contraction segments were absent. The discriminative value of contraction segment analysis was assessed. Key Results A total of 1115 swallows were analyzed (reflux group: 965, controls: 150). Reflux subjects had lower peak and averaged contraction amplitudes compared with controls (P<0.0001 for all comparisons). Fragmented sequences followed 18.4% wet swallows in the reflux group, compared with 7.5% in controls (P<0.0001), and were seen more frequently than failed sequences (7.9% and 2.5%, respectively). Using a threshold of 30% in individual subjects, a composite of failed and/or fragmented sequences was effective in segregating reflux subjects from control subjects (P=0.04). Conclusions & Inferences Evaluation of smooth muscle contraction segments adds value to HRM analysis. Specifically, fragmented smooth muscle contraction segments may be a marker of esophageal hypomotility. © 2012 Blackwell Publishing Ltd.

Author Keywords
Esophageal hypomotility;  Failed sequences;  High resolution manometry

Document Type: Article
Source: Scopus

 

Stevens, W.D.a b , Kahn, I.b c , Wig, G.S.a b d , Schacter, D.L.a b
Hemispheric asymmetry of visual scene processing in the human brain: Evidence from repetition priming and intrinsic activity
(2012) Cerebral Cortex, 22 (8), pp. 1935-1949. 

a Department of Psychology, Harvard University, Cambridge, MA 02138, United States
b Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, United States
c Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, United States
d Department of Neurology, Washington University Medical School, St. Louis, MO 63104, United States

Abstract
Asymmetrical specialization of cognitive processes across the cerebral hemispheres is a hallmark of healthy brain development and an important evolutionary trait underlying higher cognition in humans. While previous research, including studies of priming, divided visual field presentation, and split-brain patients, demonstrates a general pattern of right/left asymmetry of form-specific versus form-abstract visual processing, little is known about brain organization underlying this dissociation. Here, using repetition priming of complex visual scenes and high-resolution functional magnetic resonance imaging (MRI), we demonstrate asymmetrical form specificity of visual processing between the right and left hemispheres within a region known to be critical for processing of visual spatial scenes (parahippocampal place area [PPA]). Next, we use resting-state functional connectivity MRI analyses to demonstrate that this functional asymmetry is associated with differential intrinsic activity correlations of the right versus left PPA with regions critically involved in perceptual versus conceptual processing, respectively. Our results demonstrate that the PPA comprises lateralized subregions across the cerebral hemispheres that are engaged in functionally dissociable yet complementary components of visual scene analysis. Furthermore, this functional asymmetry is associated with differential intrinsic functional connectivity of the PPA with distinct brain areas known to mediate dissociable cognitive processes. © 2011 The Author.

Author Keywords
conceptual;  laterality;  parahippocampal place area;  repetition suppression;  resting-state functional connectivity

Document Type: Article
Source: Scopus

 

Landgrebe, M.a b , Azevedo, A.c , Baguley, D.d , Bauer, C.e , Cacace, A.f , Coelho, C.g , Dornhoffer, J.h , Figueiredo, R.c , Flor, H.i , Hajak, G.j , van de Heyning, P.k , Hiller, W.l , Khedr, E.m , Kleinjung, T.n , Koller, M.o , Lainez, J.M.p , Londero, A.q , Martin, W.H.r , Mennemeier, M.s , Piccirillo, J.t , De Ridder, D.u , Rupprecht, R.a , Searchfield, G.v , Vanneste, S.u , Zeman, F.o , Langguth, B.a b
Methodological aspects of clinical trials in tinnitus: A proposal for an international standard
(2012) Journal of Psychosomatic Research, 73 (2), pp. 112-121. 

a Department of Psychiatry and Psychotherapy, University of Regensburg, Germany
b Interdisciplinary Tinnitus Clinic, University of Regensburg, Germany
c Department of Otolaryngology, Otosul-Otorrinolaringologia Sul-Fluminense, Volta Redonda, Brazil
d Audiology Department, Cambridge University Hospitals, Cambridge, United Kingdom
e Division of Otolaryngology Head and Neck Surgery, Southern Illinois University, School of Medicine, Springfield, IL, United States
f Department of Communications Sciences and Disorders, Wayne State University, Detroit, MI, United States
g Instituto de Avaliaçao de Tecnologia em Saude, Grupo de Pesquisa em Neurotologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
h Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
i Institute of Neuropsychology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
j Department of Psychiatry Psychosomatics and Psychotherapy, Sozialstiftung Bamberg, Germany
k Department of Otorhinolaryngology and Head and Neck Surgery, Antwerp University Hospital, Belgium
l Clinical Psychology and Psychotherapy, Psychological Institute, University of Mainz, Germany
m Department of Neurology, Assiut University Hospital, Assiut, Egypt
n Department of Otorhinolaryngology, Head and Neck Surgery, University of Zurich, Switzerland
o Center for Clinical Studies, University Hospital Regensburg, Germany
p Department of Neurology, University of Valencia, Valencia, Spain
q Service ORL et CCF, Hôpital Européen G. Pompidou, Paris, France
r Department of Otolaryngology, Head and Neck Surgery, Oregon Health and Science University, Portland, OR, United States
s Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, United States
t Department of Otolaryngology-Head and Neck and Surgery, Washington University, School of Medicine, St. Louis, MO, United States
u TRI Tinnitus Clinic Antwerp, University Hospital Antwerp, Belgium
v Section of Audiology, School of Population Health, University of Auckland, New Zealand

Abstract
Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus. © 2012 Elsevier Inc.

Author Keywords
Clinical trials;  Guideline;  Tinnitus;  Trial methodology

Document Type: Article
Source: Scopus

 

Zlotnik, A., Li Jr., S.
Optimal entrainment of neural oscillator ensembles
(2012) Journal of Neural Engineering, 9 (4), art. no. 046015, . 

Department of Electrical and Systems Engineering, Washington University, Saint Louis, MO 63130, United States

Abstract
In this paper, we derive the minimum-energy periodic control that entrains an ensemble of structurally similar neural oscillators to a desired frequency. The state-space representation of a nominal oscillator is reduced to a phase model by computing its limit cycle and phase response curve, from which the optimal control is derived by using formal averaging and the calculus of variations. We focus on the case of a 1:1 entrainment ratio and suggest a simple numerical method for approximating the optimal controls. The method is applied to asymptotically control the spiking frequency of neural oscillators modeled using the Hodgkin-Huxley equations. Simulations are used to illustrate the optimality of entrainment controls derived using phase models when applied to the original state-space system, which is crucial for using phase models in control synthesis for practical applications. This work addresses a fundamental problem in the field of neural dynamics and provides a theoretical contribution to the optimal frequency control of uncertain oscillating systems. © 2012 IOP Publishing Ltd.

Document Type: Article
Source: Scopus

 

Schulte-Baukloh, H.a , Mürtz, G.b , Heine, G.a , Austin, P.c , Miller, K.d , Michael, T.e , Strugala, G.b , Knispel, H.H.a
Urodynamic effects of propiverine in children and adolescents with neurogenic bladder: Results of a prospective long-term study
(2012) Journal of Pediatric Urology, 8 (4), pp. 386-392. 

a Department of Urology, St. Hedwig Hospital, Medical School of Charité Universitätsmedizin, 10115 Berlin, Germany
b APOGEPHA Arzneimittel GmbH, Dresden, Germany
c Division of Pediatric Urology, St. Louis Children's Hospital, Washington University, United States
d Department of Urology, Charité Universitätsmedizin Berlin, Germany
e Clinic of Neuropaediatrics, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany

Abstract
Objective: To evaluate prospectively the efficacy and tolerability of propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children. Materials and methods: 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of propiverine. Results: Average follow-up was 3.6 years (range 2.0-5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH 2O and bladder compliance was 20.0 ± 5.4 ml/cmH 2O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period. Conclusion: Long-term efficacy and tolerability of propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score. © 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Author Keywords
Myelomeningocele;  Neurogenic bladder;  Neurogenic detrusor overactivity;  Propiverine hydrochloride;  Urinary incontinence

Document Type: Article
Source: Scopus

 

Bell, M.J.a , Pineda, J.A.b , Vavilala, M.S.c , Wainwright, M.S.d , Doctor, A.e , Stanley, R.f , Thompson, A.E.g
Neurocritical Care Research Networks-Pediatric Considerations
(2012) Neurocritical Care, pp. 1-2. Article in Press. 

a PNCRG, University of Pittsburgh, Pittsburgh, United States
b PNCRG, Washington University of St. Louis, St. Louis, United States
c PNCRG, University of Washington, Seattle, United States
d PNCRG, Northwestern University, Chicago, United States
e CPCCRN, Washington University of St. Louis, St. Louis, United States
f PECARN, University of Michigan, Ann Arbor, United States
g PALISI, University of Pittsburgh, Pittsburgh, United States

Document Type: Article in Press
Source: Scopus

 

Pet, M., Robertson, J.O., Bailey, M., Guthrie, T.J., Moon, M.R., Lawton, J.S., Rinne, A., Damiano Jr., R.J., Maniar, H.S.
The impact of CHADS 2 score on late stroke after the Cox maze procedure
(2012) Journal of Thoracic and Cardiovascular Surgery, . Article in Press. 

Division of Cardiothoracic Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, St Louis, Mo

Abstract
Objective: The Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society jointly recommend indefinite warfarin anticoagulation in patients with CHADS 2 (congestive heart failure, hypertension, age, diabetes, and stroke) score of at least 2 who have undergone ablation for atrial fibrillation. This study determined the impact of CHADS 2 score on risk of late stroke or transient ischemic attack after the performance of a surgical Cox maze procedure. Methods: A retrospective review of 433 patients who underwent a Cox maze procedure at our institution was conducted. Three months after surgery, warfarin was discontinued regardless of CHADS 2 score if the patient showed no evidence of atrial fibrillation, was off antiarrhythmic medications, and had no other indication for anticoagulation. A follow-up questionnaire was used to determine whether any neurologic event had occurred since surgery. Results: Follow-up was obtained for 90% of the study group (389/433) at a mean of 6.6 ± 5.0 years. Among these patients, 32% (125/389) had a CHADS 2 score of at least 2, of whom only 40% (51/125) remained on long-term warfarin after surgery. Six patients had late neurologic events (annualized risk of 0.2%). Neither CHADS 2 score nor warfarin anticoagulation was significantly associated with the occurrence of late neurologic events. Among the individual CHADS 2 criteria, both diabetes mellitus and previous stroke or transient ischemic attack were predictive of late neurologic events. Conclusions: The risk of stroke or transient ischemic attack in patients after a surgical Cox maze procedure was low and not associated with CHADS 2 score or warfarin use. Given the known risks of warfarin, we recommend discontinuation of anticoagulation 3 months after the procedure if the patient has no evidence of atrial fibrillation, has discontinued antiarrhythmic medications, and is without any other indication for systemic anticoagulation. © 2012 The American Association for Thoracic Surgery.

Document Type: Article in Press
Source: Scopus

 

Gaffrey, M.S.a , Luby, J.L.a , Barch, D.M.a b c
Towards the study of functional brain development in depression: An Interactive Specialization approach
(2012) Neurobiology of Disease, . Article in Press. 


a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
b Department of Psychology, Washington University in St. Louis, Saint Louis, MO, USA
c The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA

Abstract
Depression is a significant and impairing mood disorder with onset possible as early as age 3 and into adulthood. Given this varying pattern of age of onset, identifying the relationship between brain development and depression across the lifespan has proven elusive. This review identifies some of the factors that may have limited the advancement of our knowledge in this area and discusses how synthesizing established models of depression and normative brain development may help to overcome them. More specifically, it is suggested that current neurobiological models of depression fail to account for the developmental variance associated with early neural network development and the potential influence of experience on this process. The utility of applying an established framework of normative brain development to this topic is described and its potential utility for conceptualizing the influence of depression on brain function across the life span is addressed. Future directions including longitudinal neuroimaging studies of early onset depression and groups at risk for this disorder are proposed. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Brain;  Brain development;  Depression;  Interactive Specialization;  Pediatric depression;  Preschool depression

Document Type: Article in Press
Source: Scopus

 

Kushnir, V., Sayuk, G.S., Gyawali, C.P.
Multiple rapid swallow responses segregate achalasia subtypes on high-resolution manometry
(2012) Neurogastroenterology and Motility, . Article in Press. 


Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Background Multiple rapid swallows (MRS) inhibit esophageal peristalsis and lower esophageal sphincter (LES) tone; a rebound excitatory response then results in an exaggerated peristaltic sequence. Multiple rapid swallows responses are dependent on intact inhibitory and excitatory neural function and could vary by subtype in achalasia spectrum disorders. Methods Consecutive subjects with incomplete LES relaxation on high-resolution manometry (HRM) (Sierra Scientific, Los Angeles, CA, USA) in the absence of mechanical obstruction were prospectively identified. Achalasia spectrum disorders were classified and HRM plots reviewed according to Chicago criteria. Esophageal peristaltic performance and LES function were assessed after 10 wet swallows and MRS (five 2mL water swallows 2-3 s apart). Findings were compared with 18 healthy controls (28.5±0.6years, 44% women). Key Results A total of 46 subjects (57.1±2.1years, 52.2% women) met inclusion criteria. There was complete failure of peristalsis with MRS in all subjects with achalasia subtypes 1 and 2. In contrast, 80% of achalasia subtype 3 and incomplete LES relaxation (EGJ outflow obstruction) with preserved esophageal body peristalsis had a contractile response to MRS (P<0.001 compared with subtypes 1 and 2); controls demonstrated 94.4% peristalsis. Percent decrease in LES residual pressure during MRS (compared to wet swallows) segregated achalasia subtypes; those with aperistalsis (subtypes 1 and 2) had a lesser decline (22.6%) compared to those with retained esophageal body peristalsis (40.5%) and controls (51.3%, P<0.001 across groups). Conclusions & Inferences Multiple rapid swallow responses segregate achalasia spectrum disorders into two patterns differentiated by presence or absence of esophageal body contraction response to wet swallows. These findings support subtyping of achalasia, with pathophysiologic implications. © 2012 Blackwell Publishing Ltd.

Author Keywords
Achalasia;  High-resolution manometry;  Multiple rapid swallows

Document Type: Article in Press
Source: Scopus

 

Thompson, R.a , Dancy, B.L.b , Wiley, T.R.A.a , Najdowski, C.J.b , Perry, S.P.c , Wallis, J.d , Mekawi, Y.e , Knafl, K.A.f
African American Families' Expectations and Intentions for Mental Health Services
(2012) Administration and Policy in Mental Health and Mental Health Services Research, pp. 1-13. Article in Press. 

a Juvenile Protective Association, 1707 N Halsted, Chicago, 60614, United States
b University of Illinois at Chicago, Chicago, United States
c Yale University, New Haven, United States
d Washington University, St. Louis, United States
e University of Illinois at Urbana-Champaign, Champaign, United States
f University of North Carolina at Chapel Hill, Chapel Hill, United States

Abstract
A cross-sectional qualitative descriptive design was used to examine the links among expectations about, experiences with, and intentions toward mental health services. Individual face-to-face interviews were conducted with a purposive sample of 32 African American youth/mothers dyads. Content analysis revealed that positive expectations were linked to positive experiences and intentions, that negative expectations were not consistently linked to negative experiences or intentions, nor were ambivalent expectations linked to ambivalent experiences or intentions. Youth were concerned about privacy breeches and mothers about the harmfulness of psychotropic medication. Addressing these concerns may promote African Americans' engagement in mental health services. © 2012 Springer Science+Business Media, LLC.

Author Keywords
African American;  Expectations;  Intentions;  Mental health services

Document Type: Article in Press
Source: Scopus

 

Mercuri, E.a b , McDonald, C.c , Mayhew, A.d , Florence, J.e , Mazzone, E.a , Bianco, F.a , Decostre, V.f , Servais, L.f , Ricotti, V.b , Goemans, N.g , Vroom, E.h
International workshop on assessment of upper limb function in Duchenne Muscular Dystrophy. Rome, 15-16 February 2012
(2012) Neuromuscular Disorders, . Article in Press. 

a Department of Paediatric Neurology, Catholic University, Rome, Italy
b Dubowitz Neuromuscular Centre, Institute of Child Health, London, UK
c Department of Physical Medicine and Rehabilitation, University of California, Davis, USA
d Institute of Genetic Medicine, Newcastle Upon Tyne, UK
e Department of Neurology, Washington University School of Medicine, St. Louis, USA
f Institut de Myologie, GH Pitié Salpêtrière, Paris, France
g Child Neurology, University Hospitals Leuven, Leuven, Belgium
h Duchenne Parent Project, The Netherlands

Document Type: Article in Press
Source: Scopus

 

Feczko, E.a , Miezin, F.M.b c , Constantino, J.N.a d , Schlaggar, B.L.b c d e , Petersen, S.E.b c e f g , Pruett Jr., J.R.a
The hemodynamic response in children with Simplex Autism
(2012) Developmental Cognitive Neuroscience, . Article in Press. 

a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, USA
b Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, USA
c Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, USA
d Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, USA
e Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, USA
f Department of Psychology, Washington University, One Brookings Drive, St Louis, MO 63130, USA
g Department of Biomedical Engineering, Washington University, One Brookings Drive, St Louis, MO 63130, USA

Abstract
Background: Numerous functional magnetic resonance imaging (fMRI) studies of the brain-bases of autism have demonstrated altered cortical responses in subjects with autism, relative to typical subjects, during a variety of tasks. These differences may reflect altered neuronal responses or altered hemodynamic response. This study searches for evidence of hemodynamic response differences by using a simple visual stimulus and elementary motor actions, which should elicit similar neuronal responses in patients and controls. Methods: We acquired fMRI data from two groups of 16 children, a typical group and a group with Simplex Autism, during a simple visuomotor paradigm previously used to assess this question in other cross-group comparisons. A general linear model estimated the blood-oxygen-level-dependent (BOLD) signal time course, and repeated-measures analysis of variance tested for potential cross-group differences in the BOLD signal. Results: The hemodynamic response in Simplex Autism is similar to that found in typical children. Although the sample size was small for a secondary analysis, medication appeared to have no effect on the hemodynamic response within the Simplex Autism group. Conclusions: When fMRI studies show BOLD response differences between autistic and typical subjects, these results likely reflect between-group differences in neural activity and not an altered hemodynamic response. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
Autism spectrum disorders;  Event-related;  Functional magnetic resonance imaging;  Medication effects;  Neurovascular coupling;  Visuomotor

Document Type: Article in Press
Source: Scopus

 

Lentine, K.L.a b , Schnitzler, M.A.a , Xiao, H.a , Axelrod, D.c , Davis, C.L.d , McCabe, M.e , Brennan, D.C.e , Leander, S.a f , Garg, A.X.g , Waterman, A.D.e
Depression diagnoses after living kidney donation: Linking U.S. Registry data and administrative claims
(2012) Transplantation, 94 (1), pp. 77-83. 


a Saint Louis University Center for Outcomes Research, Salus Center, 3545 Lafayette Ave., St. Louis, MO 63104, United States
b Saint Louis University School of Medicine, St. Louis, MO, United States
c Department of Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH, United States
d Kidney and Pancreas Transplant Program, University of Washington, Seattle, WA, United States
e Washington University School of Medicine, St. Louis, MO, United States
f Saint Louis University School of Nursing, St. Louis, MO, United States
g Department of Medicine, Division of Nephrology, University of Western Ontario, London, ON, Canada

Abstract
Background: Limited data exist on correlates of psychological outcomes after kidney donation. Methods: We used a database integrating Organ Procurement and Transplantation Network registrations for 4650 living kidney donors from 1987 to 2007 with administrative data of a U.S. private health insurer (2000-2007 claims) to identify depression diagnoses among prior living donors. The burden and demographic correlates of depression after enrollment in the insurance plan were estimated by Cox regression. Graft failure and death of the donor's recipient were examined as time-varying exposures. Results: After start of insurance benefits, the cumulative frequency of depression diagnosis was 4.2% at 1 year and 11.5% at 5 years, and depression among donors was less common than among age-and gender-matched general insurance beneficiaries (rate ratio, 0.70; 95% confidence intervals [CI], 0.60-0.81). Demographic and clinical correlates of increased likelihood of depression diagnoses among the prior donors included female gender, white race, and some perioperative complications. After adjustment for donor demographic factors, recipient death (adjusted hazard ratio (aHR), 2.23; 95% CI, 1.11-4.48) and death-censored graft failure (aHR, 3.30; 95% CI, 1.49-7.34) were associated with two to three times the relative risk of subsequent depression diagnosis among nonspousal unrelated donors. There were trends toward increased depression diagnoses after recipient death and graft failure among spousal donors but no evidence of associations of these recipient events with the likelihood of depression diagnosis among related donors. Conclusions: Recipient death and graft loss predict increased depression risk among unrelated living donors in this privately insured sample. Informed consent and postdonation care should consider the potential impact of recipient outcomes on the psychological health of the donor. © 2012 Lippincott Williams & Wilkins.

Author Keywords
Administrative claims;  Depression;  Diagnoses;  Kidney transplantation;  Living donors;  Registries

Document Type: Article
Source: Scopus

 

Chen, H.-J.a , Balan, S.b , Price, R.K.b
Association of Contextual Factors with Drug Use and Binge Drinking among White, Native American, and Mixed-Race Adolescents in the General Population
(2012) Journal of Youth and Adolescence, pp. 1-16. Article in Press. 

a Department of Social Work, Fu-Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City, 24205, Taiwan
b Department of Psychiatry, Washington University in St. Louis, 660 S. Euclid Ave., Campus Box 8134, St. Louis, 63110, United States

Abstract
Large-scale surveys have shown elevated risk for many indicators of substance abuse among Native American and Mixed-Race adolescents compared to other minority groups in the United States. This study examined underlying contextual factors associated with substance abuse among a nationally representative sample of White, Native American, and Mixed-Race adolescents 12-17 years of age, using combined datasets from the National Survey on Drug Use and Health (NSDUH 2006-2009, N = 46,675, 48.77 % female). Native American adolescents displayed the highest rate of past-month binge drinking and past-year illicit drug use (14.06 and 30.91 %, respectively). Results of a logistic regression that included seven predictors of social bonding, individual views of substance use, and delinquent peer affiliations showed that friendships with delinquent peers and negative views of substance use were associated significantly with both substance abuse outcomes among White and Mixed-Race adolescents and, to a lesser extent, Native American adolescents. The association of parental disapproval with binge drinking was stronger for White than for Native American adolescents. Greater attention to specific measures reflecting racial groups' contextual and historical differences may be needed to delineate mechanisms that discourage substance abuse among at-risk minority adolescent populations. © 2012 Springer Science+Business Media, LLC.

Author Keywords
Adolescents;  Binge drinking;  Contextual factors;  Illicit drug use;  Mixed race;  Native American

Document Type: Article in Press
Source: Scopus

 

Lind, P.A.a , Zhu, G.b , Montgomery, G.W.c , Madden, P.A.F.d , Heath, A.C.d , Martin, N.G.b , Slutske, W.S.e
Genome-wide association study of a quantitative disordered gambling trait
(2012) Addiction Biology, . Article in Press. 

a Quantitative Genetics
b Genetic Epidemiology
c Molecular Epidemiology
d Queensland Institute of Medical Research, Brisbane, QLD, Australia, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
e Department of Psychological Sciences, University of Missouri, Columbia, MO, USA

Abstract
Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1312 twins from 894 Australian families. Association was conducted for 2381914 single-nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values&lt;1×10 -5 with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime Diagnostic and Statistical Manual of Mental Disorders, fourth edition pathological gambling and South Oaks Gambling Screen classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist-induced gambling in individuals with Parkinson's disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling. © 2012 The Authors. Addiction Biology © 2012 Society for the Study of Addiction.

Author Keywords
Association;  Canonical pathways;  Disordered gambling;  Enrichment analysis;  Genomewide;  MERLIN;  Quantitative

Document Type: Article in Press
Source: Scopus

 

Zheng, J.a , Watanabe, H.a , Wines-Samuelson, M.a , Zhao, H.a , Gridley, T.b , Kopan, R.c , Shen, J.a
Reply to Gaiano et al.: Expression of notch proteins in pyramidal neurons in vivo
(2012) Journal of Biological Chemistry, 287 (29), p. 24596. 

a Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
b Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States
c Departments of Developmental Biology and Medicine, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

 

Cross, A.H.a , Waubant, E.b
Antibodies to potassium channels in multiple sclerosis
(2012) New England Journal of Medicine, 367 (2), pp. 172-174. 

a Department of Neurology, Washington University School of Medicine, St. Louis, WA, United States
b Department of Neurology, University of California, San Francisco, San Francisco, CA, United States

Document Type: Editorial
Source: Scopus

 

Rao, R.C.a , Dlouhy, B.J.b
Diabetic retinopathy [6]
(2012) New England Journal of Medicine, 367 (2), p. 184. 

a Washington University School of Medicine, St. Louis, MO, United States
b University of Iowa Hospitals and Clinics, Iowa City, IA, United States

Document Type: Letter
Source: Scopus

 

Cicero, T.J.a , Ellis, M.S.a , Surratt, H.L.b
Effect of abuse-deterrent formulation of oxycontin
(2012) New England Journal of Medicine, 367 (2), pp. 187-189. 

a Washington University in St. Louis, St. Louis, MO, United States
b Nova Southeastern University Coral, Gables, FL, United States

Document Type: Letter
Source: Scopus

 

Dougherty, J.D.a b , Zhang, J.a , Feng, H.c , Gong, S.c , Heintz, N.a c d
Mouse transgenesis in a single locus with independent regulation for multiple fluorophores
(2012) PLoS ONE, 7 (7), art. no. e40511, . 

a Laboratory of Molecular Biology, The Rockefeller University, New York, NY, United States
b Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c The GENSAT project, The Rockefeller University, New York, NY, United States
d Howard Hughes Medical Institute, The Rockefeller University, New York, NY, United States

Abstract
A major barrier to complex experimental design in mouse genetics is the allele problem: combining three or more alleles is time-consuming and inefficient. Here, we solve this problem for transgenic animals with a simple modification of existing BAC transgenesis protocols, and generate triple-colored 'prism' mice in which the major cell types of the brain: neurons, astrocytes, and oligodendrocytes, are each labeled with a distinct fluorophore. All three fluorophores are expressed from the same locus, yet each fluorophore is expressed in an independent temporal and spatial pattern. All three transgenes are generally co-inherited across multiple generations with stable genomic copy number and expression patterns. This generic solution should permit more sophisticated experimental manipulations to assess functional interactions amongst populations of cell types in vivo in a more rapid and efficient manner. © 2012 Dougherty et al.

Document Type: Article
Source: Scopus

 

Hershey, T.a b c , Lugar, H.M.a , Shimony, J.S.c , Rutlin, J.a , Koller, J.M.a , Perantie, D.C.a , Paciorkowski, A.R.e , Eisenstein, S.A.a , Permutt, M.A.d
Early brain vulnerability in Wolfram syndrome
(2012) PLoS ONE, 7 (7), art. no. e40604, . 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, University of Washington, St. Louis, MO, United States

Abstract
Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development. © 2012 Hershey et al.

Document Type: Article
Source: Scopus

 

Lee, D.Y., Gianino, S.M., Gutmann, D.H.
Innate Neural Stem Cell Heterogeneity Determines the Patterning of Glioma Formation in Children
(2012) Cancer Cell, 22 (1), pp. 131-138. 

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

Abstract
The concept that gliomas comprise a heterogeneous group of diseases distinguished by their developmental origin raises the intriguing possibility that neural stem cells (NSCs) from different germinal zones have differential capacities to respond to glioma-causing genetic changes. We demonstrate that lateral ventricle subventricular zone NSCs are molecularly and functionally distinct from those of the third ventricle. Consistent with a unique origin for pediatric low-grade glioma, third ventricle, but not lateral ventricle, NSCs hyperproliferate in response to mutations characteristic of childhood glioma. Finally, we demonstrate that pediatric optic gliomas in Nf1 genetically engineered mice arise from the third ventricle. Collectively, these observations establish the importance of innate brain region NSC heterogeneity in the patterning of gliomagenesis in children and adults. © 2012 Elsevier Inc.

Document Type: Article
Source: Scopus

 

Lee, M.H., Hacker, C.D., Snyder, A.Z., Corbetta, M., Zhang, D., Leuthardt, E.C., Shimony, J.S.
Clustering of resting state networks
(2012) PLoS ONE, 7 (7), art. no. e40370, . 

Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: The goal of the study was to demonstrate a hierarchical structure of resting state activity in the healthy brain using a data-driven clustering algorithm. Methodology/Principal Findings: The fuzzy-c-means clustering algorithm was applied to resting state fMRI data in cortical and subcortical gray matter from two groups acquired separately, one of 17 healthy individuals and the second of 21 healthy individuals. Different numbers of clusters and different starting conditions were used. A cluster dispersion measure determined the optimal numbers of clusters. An inner product metric provided a measure of similarity between different clusters. The two cluster result found the task-negative and task-positive systems. The cluster dispersion measure was minimized with seven and eleven clusters. Each of the clusters in the seven and eleven cluster result was associated with either the task-negative or task-positive system. Applying the algorithm to find seven clusters recovered previously described resting state networks, including the default mode network, frontoparietal control network, ventral and dorsal attention networks, somatomotor, visual, and language networks. The language and ventral attention networks had significant subcortical involvement. This parcellation was consistently found in a large majority of algorithm runs under different conditions and was robust to different methods of initialization. Conclusions/Significance: The clustering of resting state activity using different optimal numbers of clusters identified resting state networks comparable to previously obtained results. This work reinforces the observation that resting state networks are hierarchically organized. © 2012 Lee et al.

Document Type: Article
Source: Scopus

 

Beaumont, T.L., Limbrick, D.D., Smyth, M.D.
Advances in the management of subependymal giant cell astrocytoma
(2012) Child's Nervous System, 28 (7), pp. 963-968. 

Department of Neurological Surgery, Washington University School of Medicine, Campus Box 8057, 660 S. Euclid Ave., St. Louis, MO 63110, United States

Abstract
Background: Subependymal giant cell astrocytoma (SEGA) is the most common central nervous system tumor in patients with tuberous sclerosis complex (TSC). Although these lesions are generally benign and non-infiltrative, they commonly arise in the region of the foramen of Monro, where they can cause obstructive hydrocephalus and sudden death. Methods: Surgical resection has been, and presently remains, the standard treatment for SEGAs demonstrating serial growth on neuroimaging in the setting of symptomatic hydrocephalus or progressive ventriculomegaly. Discussion Surgery can be curative; however, not all SEGAs are amenable to safe and complete resection. Gamma Knife stereotactic radiosurgery provides another treatment option but has highly variable response rates with limited data demonstrating its efficacy. Newer medical therapy targeting mammalian target of rapamycin (mTOR), the key protein kinase that is constitutively activated in TSC, has demonstrated promising results in recent clinical trials. In both case reports and clinical trials, treatment with mTOR inhibitors results in a significant reduction in SEGA volume and improvement or resolution of ventriculomegaly. This has led to the approval of everolimus for the treatment of SEGA in tuberous sclerosis patients who are not candidates for surgery. This review summarizes the surgical and medical management of SEGA in patients with TSC. © Springer-Verlag 2012.

Author Keywords
Everolimus;  Sirolimus;  Subependymal giant cell astrocytoma;  Tuberous sclerosis complex

Document Type: Article
Source: Scopus

 

Yan, Y., Sun, H.H., Hunter, D.A., MacKinnon, S.E., Johnson, P.J.
Efficacy of short-term FK506 administration on accelerating nerve regeneration
(2012) Neurorehabilitation and Neural Repair, 26 (6), pp. 570-580. 

Washington University in St Louis, School of Medicine, Division of Plastic and Reconstructive Surgery, 660 South Euclid, St Louis, MO 63110, United States

Abstract
Background. The slow rate of nerve regeneration following injury can cause extended muscle denervation, leading to irreversible muscle atrophy, fibrosis, and destruction of motor endplates. The immunosuppressant FK506 (tacrolimus) has been shown to accelerate the rate of nerve regeneration and functional recovery. However, the toxic and immunosuppressive properties of FK506 make it undesirable for long-term use. Objective. To take advantage of the regeneration-enhancing effects of FK506 but avoid the potential adverse effects of long-term administration, the current study evaluates and quantifies the efficacy of short-term FK506 treatment in rat models. Methods. Clinically relevant transection and graft models were evaluated, and walking track analysis (WTA) was used to evaluate functional recovery. FK506 was administered for 5 and 10 days post transection injury and 10 and 20 days post graft injury. Both groups involving a short course were compared with the continuous administration group. Results. In the transection model, FK506 was administered for 5 and 10 days postoperatively. WTA demonstrated that 10 days of FK506 administration was sufficient to reduce functional recovery time by 29% compared with negative controls. In the graft model, FK506 was administered for 10 and 20 days postoperatively. Short treatment courses of 10 and 20 days reduced recovery time by 15% and 21%, respectively, compared with negative controls. Analysis of blood-nerve barrier (BNB) integrity demonstrated that FK506 facilitated early reconstitution of the BNB. Conclusions. The results of this study indicate that short-term FK506 delivery following nerve injury imparts a significant therapeutic effect. © 2012 The Author(s).

Author Keywords
accelerated nerve regeneration;  FK506;  nerve injury;  tacrolimus;  walking track

Document Type: Article
Source: Scopus

 

Lin, K.F.a , Sun, H.H.a , MacEwan, M.R.b , MacKinnon, S.E.a , Johnson, P.J.a
GDNF overexpression fails to provoke muscle recovery from botulinum toxin poisoning: A preliminary study
(2012) Microsurgery, 32 (5), pp. 370-376. 

a Division of Plastic and Reconstructive Surgery, Washington University, School of Medicine, 660 South Euclid, St. Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Glial cell line-derived neurotrophic factor (GDNF) has potent axonal growth and survival effects on motoneurons. This study used transgenic Myo-GDNF mice to assess the effects of targeted GDNF overexpression on functional recovery after botulinum toxin type A (BTxA) chemodenervation. BTxA (0.1 U) was injected into the tibialis anterior (TA) muscle of wild-type CF1 and transgenic Myo-GDNF mice. On days 1, 7, 14, and 21 after injection, evoked muscle force production and muscle mass were measured (n = 6, for each group at each time point). Greater maximal tetanic force and calculated specific force were evoked in Myo-GDNF animals when compared with control CF1 animals at days 1, 7, and 21. However, the differences were not statistically significant. Similarly, modest reductions in muscle atrophy in the Myo-GDNF group at all time points were not statistically significant. Targeted overexpression of GDNF in the muscles of Myo-GDNF mice did not improve motor recovery in the first 21 days after BTxA chemodenervation. © 2012 Wiley Periodicals, Inc.

Document Type: Article
Source: Scopus

 

Heaps, J.M.a , Joska, J.b , Hoare, J.b , Ortega, M.c , Agrawa, A.c , Seedat, S.d , Ances, B.M.c , Stein, D.J.b , Paul, R.a
Neuroimaging markers of human immunodeficiency virus infection in South Africa
(2012) Journal of NeuroVirology, 18 (3), pp. 151-156. 

a Department of Psychology, University of Missouri-Saint Louis, One University Boulevard, 442-A Stadler Hall, Saint Louis, MO 63121, United States
b Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Stellenbosch University, Tygerberg, South Africa

Abstract
Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV? controls from South Africa. Volumetric measures were obtained from six regions of interest - caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<0.01), thalamus (p<0.01) and total gray matter (inclusive of cortical and subcortical regions, p<0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa. © Journal of NeuroVirology, Inc. 2012.

Author Keywords
Clade C virus;  HIVinfection;  Neuroimaging;  South Africa

Document Type: Article
Source: Scopus

 

Chang, J.J.a , Salas, J.a , Habicht, K.b , Pien, G.W.c , Stamatakis, K.A.d , Brownson, R.C.e
The Association of Sleep Duration and Depressive Symptoms in Rural Communities of Missouri, Tennessee, and Arkansas
(2012) Journal of Rural Health, 28 (3), pp. 268-276. 

a Department of Epidemiology, Saint Louis University School of Public Health, St. Louis, MO, United States
b Center for Disease Control CSTE Applied Epidemiology Fellowship Program, Division of Acute Disease Epidemiology, South Carolina Department of Health and Environmental Control, Columbia, SC, United States
c Sleep Medicine Division and Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, Pennsylvania, PA, United States
d The Division of Public Health Sciences, Department of Surgery and Alvin J. Siteman Cancer Center, School of Medicine, Washington University, St. Louis, MO, United States
e The Prevention Research Center in St. Louis, George Warren Brown School of Social Work, Department of Surgery and Alvin J. Siteman Cancer Center, School of Medicine, Washington University, St. Louis, MO, United States

Abstract
Purpose: To determine the association between sleep duration and depressive symptoms in a rural setting. Methods: We conducted a cross-sectional study using data from Wave 3 of the Walk the Ozarks to Wellness Project including 12 rural communities in Missouri, Arkansas, and Tennessee (N = 1,204). Sleep duration was defined based on average weeknight and weekend hours per day: short (<7), optimal (7-8), and long (>8). The primary outcome was self-reported elevated depressive symptoms. Multivariable logistic regression was used to estimate adjusted prevalence odds ratios (aPOR) and 95% confidence intervals (95% CI). Findings: Elevated depressive symptoms were common in this rural population (17%). Depressive symptoms were more prevalent among subjects with short (26.1%) and long (24%) sleep duration compared to those with optimal (11.8%) sleep duration. After adjusting for age, gender, race, education, employment status, income, and BMI, short sleep duration was associated with increased odds of elevated depressive symptoms (aPOR = 2.12, 95% CI: 1.49, 3.01), compared to optimal sleep duration. Conversely, the association between long sleep duration and depressive symptoms was not statistically significant after covariate adjustment. Similar findings were observed when we excluded individuals with insomnia symptoms for analysis. Conclusions: This study suggests that short sleep duration (<7 hours per night) and depressive symptoms are common among rural populations. Short sleep duration is positively associated with elevated depressive symptoms. The economic and health care burden of depression may be more overwhelming among rural populations, necessitating the need to target modifiable behaviors such as sleep habits to improve mental health. © 2011 National Rural Health Association.

Author Keywords
Depression;  Rural communities;  Sleep duration

Document Type: Article
Source: Scopus

 

Duvall, L.B., Taghert, P.H.
The circadian neuropeptide pdf signals preferentially through a specific adenylate cyclase isoform ac3 in m pacemakers of drosophila
(2012) PLoS Biology, 10 (6), art. no. e1001337, . 

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

Abstract
The neuropeptide Pigment Dispersing Factor (PDF) is essential for normal circadian function in Drosophila. It synchronizes the phases of M pacemakers, while in E pacemakers it decelerates their cycling and supports their amplitude. The PDF receptor (PDF-R) is present in both M and subsets of E cells. Activation of PDF-R stimulates cAMP increases in vitro and in M cells in vivo. The present study asks: What is the identity of downstream signaling components that are associated with PDF receptor in specific circadian pacemaker neurons? Using live imaging of intact fly brains and transgenic RNAi, we show that adenylate cyclase AC3 underlies PDF signaling in M cells. Genetic disruptions of AC3 specifically disrupt PDF responses: they do not affect other Gs-coupled GPCR signaling in M cells, they can be rescued, and they do not represent developmental alterations. Knockdown of the Drosophila AKAP-like scaffolding protein Nervy also reduces PDF responses. Flies with AC3 alterations show behavioral syndromes consistent with known roles of M pacemakers as mediated by PDF. Surprisingly, disruption of AC3 does not alter PDF responses in E cells-the PDF-R(+) LNd. Within M pacemakers, PDF-R couples preferentially to a single AC, but PDF-R association with a different AC(s) is needed to explain PDF signaling in the E pacemakers. Thus critical pathways of circadian synchronization are mediated by highly specific second messenger components. These findings support a hypothesis that PDF signaling components within target cells are sequestered into "circadian signalosomes," whose compositions differ between E and M pacemaker cell types. © 2012 Duvall, Taghert.

Document Type: Article
Source: Scopus

 

Li, M., Husic, N., Lin, Y., Snider, B.J.
Production of Lentiviral vectors for Transducing cells from the central nervous system
(2012) Journal of Visualized Experiments, (63), art. no. e4031, . 

Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, United States

Abstract
Efficient gene delivery in the central nervous system (CNS) is important in studying gene functions, modeling neurological diseases and developing therapeutic approaches. Lentiviral vectors are attractive tools in transduction of neurons and other cell types in CNS as they transduce both dividing and non-dividing cells, support sustained expression of transgenes, and have relatively large packaging capacity and low toxicity 1-3. Lentiviral vectors have been successfully used in transducing many neural cell types in vitro 4-6 and in animals 7-10. Great efforts have been made to develop lentiviral vectors with improved biosafety and efficiency for gene delivery. The current third generation replication-defective and self-inactivating (SIN) lentiviral vectors are depicted in Figure 1. The required elements for vector packaging are split into four plasmids. In the lentiviral transfer plasmid, the U3 region in the 5' long terminal repeat (LTR) is replaced with a strong promoter from another virus. This modification allows the transcription of the vector sequence independent of HIV-1 Tat protein that is normally required for HIV gene expression 11. The packaging signal (Ψ) is essential for encapsidation and the Rev-responsive element (RRE) is required for producing high titer vectors. The central polypurine tract (cPPT) is important for nuclear import of the vector DNA, a feature required for transducing non-dividing cells 12. In the 3× LTR, the cis-regulatory sequences are completely removed from the U3 region. This deletion is copied to 5' LTR after reverse transcription, resulting in transcriptional inactivation of both LTRs. Plasmid pMDLg/pRRE contains HIV-1 gag/pol genes, which provide structural proteins and reverse transcriptase. pRSV-Rev encodes Rev which binds to the RRE for efficient RNA export from the nucleus. pCMV-G encodes the vesicular stomatitis virus glycoprotein (VSV-G) that replaces HIV-1 Env. VSV-G expands the tropism of the vectors and allows concentration via ultracentrifugation 13. All the genes encoding the accessory proteins, including Vif, Vpr, Vpu, and Nef are excluded in the packaging system. The production and manipulation of lentiviral vectors should be carried out according to NIH guidelines for research involving recombinant DNA (http://oba.od.nih.gov/oba/rac/Guidelines/NIH_Guidelines.pdf). An approval from individual Institutional Biological and Chemical Safety Committee may be required before using lentiviral vectors. Lentiviral vectors are commonly produced by cotransfection of 293T cells with lentiviral transfer plasmid and the helper plasmids encoding the proteins required for vector packaging. Many lentiviral transfer plasmids and helper plasmids can be obtained from Addgene, a non-profit plasmid repository (http://www.addgene.org/). Some stable packaging cell lines have been developed, but these systems provide less flexibility and their packaging efficiency generally declines over time 14, 15. Commercially available transfection kits may support high efficiency of transfection 16, but they can be very expensive for large scale vector preparations. Calcium phosphate precipitation methods provide highly efficient transfection of 293T cells and thus provide a reliable and cost effective approach for lentiviral vector production. In this protocol, we produce lentiviral vectors by cotransfection of 293T cells with four plasmids based on the calcium phosphate precipitation principle, followed by purification and concentration with ultracentrifugation through a 20% sucrose cushion. The vector titers are determined by fluorescence- activated cell sorting (FACS) analysis or by real time qPCR. The production and titration of lentiviral vectors in this protocol can be finished with 9 days. We provide an example of transducing these vectors into murine neocortical cultures containing both neurons and astrocytes. We demonstrate that lentiviral vectors support high efficiency of transduction and cell type-specific gene expression in primary cultured cells from CNS. © 2012 Journal of Visualized Experiments.

Author Keywords
Astrocyte;  Cell culture;  CNS;  Genetics;  Issue 63;  Lentiviral vector;  Neuron;  Neuroscience;  Promoter;  Transduction

Document Type: Article
Source: Scopus

 

Barral, S.a b , Bird, T.c , Goate, A.d , Farlow, M.R.e , Diaz-Arrastia, R.g , Bennett, D.A.h , Graff-Radford, N.i , Boeve, B.F.j , Sweet, R.A.k , Stern, Y.a b , Wilson, R.S.h , Foroud, T.f , Ott, J.l , Mayeux, R.a b
Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory
(2012) Neurology, 78 (19), pp. 1464-1471. 

a Department of Neurology, Columbia University, College of Physicians, New York, NY, United States
b Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, United States
c Department of Neurology, University of Washington, Seattle, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Departments of Neurology, Indianapolis, United States
f Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, United States
g Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Health Sciences, Bethesda, United States
h Rush Alzheimer's Disease Center, Rush University, Medical Center, Chicago, IL, United States
i Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, United States
j Department of Neurology, Mayo Clinic, Rochester, MN, United States
k Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
l Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Abstract
Objective: Several genome-wide association studies (GWAS) have associated variants in lateonset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. Methods: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. Results: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (β = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (==-0.44, SE = 0.09, p = 0.009 and β = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (β = 0.26, SE = 0.10, p = 0.010). Conclusions: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease. Copyright © 2012 by AAN Enterprises, Inc.

Document Type: Article
Source: Scopus

 

Fensterl, V.a , Wetzel, J.L.a , Ramachandran, S.a , Ogino, T.a , Stohlman, S.A.b , Bergmann, C.C.b , Diamond, M.S.c , Virgin, H.W.c , Sen, G.C.a
Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis
(2012) PLoS Pathogens, 8 (5), art. no. e1002712, . 

a Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
b Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
c Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2 -/-) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1 -/- mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2 -/- mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2 -/- mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2 -/- mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2 -/- mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2 -/- mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2 -/- mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon. © 2012 Fensterl et al.

Document Type: Article
Source: Scopus

 

Tang, W.a , Bressler, S.L.a b , Sylvester, C.M.c , Shulman, G.L.d , Corbetta, M.c d e
Measuring granger causality between cortical regions from voxelwise fmRI BOLD signals with LASSO
(2012) PLoS Computational Biology, 8 (5), art. no. e1002513, . 

a Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, United States
b Department of Psychology, Florida Atlantic University, Boca Raton, FL, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Functional brain network studies using the Blood Oxygen-Level Dependent (BOLD) signal from functional Magnetic Resonance Imaging (fMRI) are becoming increasingly prevalent in research on the neural basis of human cognition. An important problem in functional brain network analysis is to understand directed functional interactions between brain regions during cognitive performance. This problem has important implications for understanding top-down influences from frontal and parietal control regions to visual occipital cortex in visuospatial attention, the goal motivating the present study. A common approach to measuring directed functional interactions between two brain regions is to first create nodal signals by averaging the BOLD signals of all the voxels in each region, and to then measure directed functional interactions between the nodal signals. Another approach, that avoids averaging, is to measure directed functional interactions between all pairwise combinations of voxels in the two regions. Here we employ an alternative approach that avoids the drawbacks of both averaging and pairwise voxel measures. In this approach, we first use the Least Absolute Shrinkage Selection Operator (LASSO) to pre-select voxels for analysis, then compute a Multivariate Vector AutoRegressive (MVAR) model from the time series of the selected voxels, and finally compute summary Granger Causality (GC) statistics from the model to represent directed interregional interactions. We demonstrate the effectiveness of this approach on both simulated and empirical fMRI data. We also show that averaging regional BOLD activity to create a nodal signal may lead to biased GC estimation of directed interregional interactions. The approach presented here makes it feasible to compute GC between brain regions without the need for averaging. Our results suggest that in the analysis of functional brain networks, careful consideration must be given to the way that network nodes and edges are defined because those definitions may have important implications for the validity of the analysis. © 2012 Tang et al.

Document Type: Article
Source: Scopus

 

Choi, J.Y.a , Hightower, G.K.b , Wong, J.K.c , Heaton, R.b , Woods, S.b , Grant, I.b , Marcotte, T.D.b , Ellis, R.J.b , Letendre, S.L.b , Collier, A.C.d , Marra, C.M.d , Clifford, D.B.e , Gelman, B.B.f , McArthur, J.C.g , Morgello, S.h , Simpson, D.M.h , McCutchan, J.A.b , Richman, D.D.b i , Smith, D.M.b i
Genetic features of cerebrospinal fluid-derived subtype B HIV-1 tat
(2012) Journal of NeuroVirology, 18 (2), pp. 81-90. 

a Department of Internal Medicine, AIDS Research Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea
b University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093-0679, United States
c University of California San Francisco, 4150 Clement St, 111W3, San Francisco, CA 94121, United States
d University of Washington, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104, United States
e Washington University in St Louis, 660 South Euclid Avenue, Saint Louis, MO 63110, United States
f University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
g Johns Hopkins University, 600 N Wolfe St, Baltimore, MD 21231, United States
h Mountain Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, United States
i Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States

Abstract
Since HIV-1 Tat has been associated with neurocognitive dysfunction, we investigated 60 HIV-1 subtype B-infected individuals who were characterized for neurocognitive functioning and had paired CSF and blood plasma samples available. To avoid issues with repeated sampling, we generated population-based HIV-1 tat sequences from each compartment and evaluated these data using a battery of phylogenetic, statistical, and machine learning tools. These analyses identified position HXB2 5905 within the cysteine-rich domain of tat as a signature of CSFderived HIV-1, and a higher number of mixed bases in CSF, as measure of diversity, was associated with HIV-associated neurocognitive disorder. Since identified mutations were synonymous, we evaluated the predicted secondary RNA structures, which showed that this mutation altered secondary structure. As a measure of divergence, the genetic distance between the blood and CSF-derived tat was inversely correlated with current and nadir CD4 + T cell counts. These data suggest that specific HIV-1 features of tat influence neurotropism and neurocognitive impairment. © Journal of NeuroVirology, Inc. 2012.

Author Keywords
Central nervous system;  Compartmentalization;  HIV;  Tat

Document Type: Article
Source: Scopus

 

Jackson, J.D., Balota, D.A.
Mind-wandering in younger and older adults: converging evidence from the Sustained Attention to Response Task and reading for comprehension.
(2012) Psychology and aging, 27 (1), pp. 106-119. 

Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA.

Abstract
One mechanism that has been hypothesized to contribute to older adults' changes in cognitive performance is goal neglect or impairment in maintaining task set across time. Mind-wandering and task-unrelated thought may underlie these potential age-related changes. The present study investigated age-related changes in mind-wandering in three different versions of the Sustained Attention to Response Task (SART), along with self-reported mind-wandering during a reading for comprehension task. In the SART, both younger and older adults produced similar levels of faster reaction times before No-Go errors of commission, whereas, older adults produced disproportionate post-error slowing. Subjective self-reports of mind-wandering recorded during the SART and the reading task indicated that older adults were less likely to report mind-wandering than younger adults. Discussion focuses on cognitive and motivational mechanisms that may account for older adults' relatively low levels of reported mind-wandering.

Document Type: Article
Source: Scopus

 

Scullin, M.K., Bugg, J.M., McDaniel, M.A.
Whoops, I did it again: commission errors in prospective memory.
(2012) Psychology and aging, 27 (1), pp. 46-53. 

Department of Psychology, Washington University, St. Louis, MO 63130, USA.

Abstract
Prospective memory research almost exclusively examines remembering to execute an intention, but the ability to forget completed intentions may be similarly important. We had younger and older adults perform a prospective memory task (press Q when you see corn or dancer) and then told them that the intention was completed. Participants later performed a lexical-decision task (Phase 2) in which the prospective memory cues reappeared. Initial prospective memory performance was similar between age groups, but older adults were more likely than younger adults to press Q during Phase 2 (i.e., commission errors). This study provides the first experimental demonstration of event-based prospective memory commission errors after all prospective memory tasks are finished and identifies multiple factors that increase risk for commission errors.

Document Type: Article
Source: Scopus

 

Özcan, A., Quirk, J.D., Wang, Y., Wang, Q., Sun, P., Spees, W.M., Song, S.K.
The validation of complete Fourier direct MR method for diffusion MRI via biological and numerical phantoms.
(2011) Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference, 2011, pp. 3756-3759. 

Mallinckrodt Institute of Radiology, Washington University in Saint Louis, School of Medicine, St Louis, MO 63110, USA.

Abstract
The equations of the Complete Fourier Direct (CFD) MR model are explicitly derived for diffusion weighted NMR experiments. The CFD-MR theory is validated by comparing a biological phantom constructed from nerve bundles and agar gel with its numerical implementation. The displacement integral distribution function estimated from the experimental data is in high agreement with the numerical phantom. CFD-MR's ability to estimate accurately and fully spin diffusion properties demonstrated here, provides the experimental validation of the theoretical CFD-MR model.

Document Type: Article
Source: Scopus

 

Shi, Y.a , De Maria, A.B.a , Wang, H.b , Mathias, R.T.b , FitzGerald, P.G.c , Bassnett, S.a
Further analysis of the lens phenotype in Lim2-deficient mice
(2011) Investigative Ophthalmology and Visual Science, 52 (10), pp. 7332-7339. 

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8096, St. Louis, MO 63110, United States
b Department of Physiology and Biophysics, SUNY, Stony Brook, NY, United States
c Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA, United States

Abstract
PURPOSE. Lim2 (MP20) is the second most abundant integral protein of lens fiber cell membranes. A comparative analysis was performed of wild-type and Lim2-deficient (Lim2 Gt/Gt) mouse lenses, to better define the anatomic and physiologic roles of Lim2. METHODS. Scanning electron microscopy (SEM) and confocal microscopy were used to assess the contribution of Lim2 to lens tissue architecture. Differentiation-dependent changes in cytoskeletal composition were identified by mass spectrometry and immunoblot analysis. The effects on cell- cell communication were quantified using impedance analysis. RESULTS. Lim2-null lenses were grossly normal. At the cellular level, however, subtle structural alterations were evident. Confocal microscopy and SEM analysis revealed that cortical Lim2 Gt/Gt fiber cells lacked the undulating morphology that characterized wild-type fiber cells. On SDS-PAGE analysis the composition of cortical fiber cells from wild-type and Lim2-null lenses appeared similar. However, marked disparities were evident in samples prepared from the lens core of the two genotypes. Several cytoskeletal proteins that were abundant in wild-type core fiber cells were diminished in the cores of Lim2 Gt/Gt lenses. Electrophysiological measurements indicated a small decrease in the membrane potential of Lim2 Gt/Gt lenses and a two-fold increase in the effective intracellular resistivity. In the lens core, this may have reflected decreased expression levels of the gap junction protein connexin 46 (Cx46). In contrast, increased resistivity in the outer cell layers of Lim2 Gt/Gt lenses could not be attributed to decreased connexin expression and may reflect the absence of cell fusions in Lim2 Gt/Gt lenses. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Document Type: Article
Source: Scopus

 

Perry, A.
Growing pains and the brain pathology stimulus package
(2009) Brain Pathology, 19 (3), . 

Division of Neuropathology, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110-1093, United States

Document Type: Editorial
Source: Scopus

July 11, 2012

Snyder, A.Z., Raichle, M.E.
A brief history of the resting state: The Washington University perspective
(2012) NeuroImage, 62 (2), pp. 902-910.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott Avenue, St Louis, MO 63110, United States

Abstract
We present a history of the concepts and developments that have led us to focus on the resting state as an object of study. We then discuss resting state research performed in our laboratory since 2005 with an emphasis on papers of particular interest. © 2012 Elsevier Inc.

Document Type: Review
Source: Scopus

 

Van Essen, D.C.
Cortical cartography and Caret software
(2012) NeuroImage, 62 (2), pp. 757-764.

Washington University, School of Medicine, Anatomy and Neurobiology, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Caret software is widely used for analyzing and visualizing many types of fMRI data, often in conjunction with experimental data from other modalities. This article places Caret's development in a historical context that spans three decades of brain mapping - from the early days of manually generated flat maps to the nascent field of human connectomics. It also highlights some of Caret's distinctive capabilities. This includes the ease of visualizing data on surfaces and/or volumes and on atlases as well as individual subjects. Caret can display many types of experimental data using various combinations of overlays (e.g., fMRI activation maps, cortical parcellations, areal boundaries), and it has other features that facilitate the analysis and visualization of complex neuroimaging datasets. © 2011 Elsevier Inc.

Author Keywords
Atlases;  Cerebral cortex;  Connectivity;  Human;  Surfaces;  Visualization

Document Type: Review
Source: Scopus

 

Van Essen, D.C.a , Ugurbil, K.b
The future of the human connectome
(2012) NeuroImage, 62 (2), pp. 1299-1310.

a Washington University, School of Medicine, Anatomy and Neurobiology, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
b University of Minnesota, Center for Magnetic Resonance Research, 2021 6th Street, SE, Minneapolis, MN 55455, United States

Abstract
The opportunity to explore the human connectome using cutting-edge neuroimaging methods has elicited widespread interest. How far will the field be able to progress in deciphering long-distance connectivity patterns and in relating differences in connectivity to phenotypic characteristics in health and disease? We discuss the daunting nature of this challenge in relation to specific complexities of brain circuitry and known limitations of in vivo imaging methods. We also discuss the excellent prospects for continuing improvements in data acquisition and analysis. Accordingly, we are optimistic that major insights will emerge from human connectomics in the coming decade. © 2012 Elsevier Inc.

Author Keywords
7 Tesla;  Brain;  Connectivity;  Diffusion imaging;  FMRI;  Functional imaging;  Magnetic Resonance Imaging;  MRI;  Multiband;  Resting state;  Tractography;  Ultrahigh field imaging

Document Type: Review
Source: Scopus

 

Petersen, S.E.a b c d , Dubis, J.W.a
The mixed block/event-related design
(2012) NeuroImage, 62 (2), pp. 1177-1184.

a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychology, Washington University, St. Louis, MO 63110, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Neuroimaging studies began using block design and event-related design experiments. While providing many insights into brain functions, these fMRI design types ignore components of the BOLD signal that can teach us additional elements. The development of the mixed block/event-related fMRI design allowed for a fuller characterization of nonlinear and time-sensitive neuronal responses: for example, the interaction between block and event related factors and the simultaneous extraction of transient activity related to trials and block transitions and sustained activity related to task-level processing. This review traces the origins of the mixed block/event-related design from conceptual precursors to a seminal paper and on to subsequent studies using the method. The review also comments on aspects of the experimental design that must be considered when attempting to use the mixed block/event-related design. When taking into account these considerations, the mixed block/event-related design allows fuller utilization of the BOLD signal allowing deeper interpretation of how regions of the brain function on multiple timescales. © 2011 Elsevier Inc.

Author Keywords
Mixed block/event-related;  Sustained;  Task control;  Transient

Document Type: Review
Source: Scopus

 

Kimberley, T.J.a b c
Differential activation in the primary motor cortex during individual digit movement in focal hand dystonia vs. healthy
(2012) Restorative Neurology and Neuroscience, 30 (3), pp. 247-254. 

a Program in Physical Therapy, University of Minnesota, MMC 388, 426 Church St SE, Minneapolis, MN 55455, United States
b Rehabilitative Science, University of Minnesota, MN, United States
c Program in Physical Therapy, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: The pathophysiology of focal hand dystonia (FHD) is not clearly understood. Previous studies have reported increased and decreased cortical activity associated with motor tasks. The aim of this study was to investigate blood oxygen level dependent (BOLD) signal changes in functional magnetic resonance imaging within the hand area of primary motor cortex during cued movement of individual digits. Methods: Eight healthy individuals and five individuals with right hand FHD participated. Beta weight contrasts were examined within the hand area of the motor cortex. Results: In both groups, BOLD signal changes in the hemisphere contralateral to the moving hand were greater in the left hemisphere than the right. Between groups, no difference was found during control of the left hand, but a significant difference was seen during right hand movement; specifically, individuals with dystonia showed increased contralateral and decreased ipsilateral cortical response associated with the affected hand as compared to healthy individuals. This suggests a similar, albeit exaggerated pattern of activation in individuals with FHD on the affected side. Conclusions: These results suggest different levels of ipsilateral and contralateral activation between healthy and dystonic individuals but also show a relative difference between symptomatic and asymptomatic control within the patient population. © 2012 - IOS Press and the authors. All rights reserved.

Author Keywords
fMRI;  Focal hand dystonia;  motor cortex

Document Type: Article
Source: Scopus

 

Duffis, E.J.a , Gandhi, C.D.a b , Prestigiacomo, C.J.a b c , Abruzzo, T.d , Albuquerque, F.e , Bulsara, K.R.f , Derdeyn, C.P.g , Fraser, J.F.h , Hirsch, J.A.i , Hussain, M.S.j , Do, H.M.k , Jayaraman, M.V.l , Meyers, P.M.m , Narayanan, S.n
Head, neck, and brain tumor embolization guidelines
(2012) Journal of NeuroInterventional Surgery, 4 (4), pp. 251-255. 

a Neurological Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 90 Bergen St, Newark, NJ 07103, United States
b Department of Radiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ, United States
c Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ, United States
d Neurosurgery, Radiology, Pediatrics and Biomedical Engineering, University of Cincinnati, Mayfield Clinic, Cincinnati, OH, United States
e Barrow Neurosurgical Associates, Ltd., Phoenix, AZ, United States
f Neuroendovascular and Skull Base Surgery, Yale Department of Neurosurgery, New Haven, CT, United States
g Mallinckrodt Institute of Radiology, Washington University School of Medicine/Barnes Jewish Hospital, St. Louis, MO, United States
h Department of Neurological Surgery, University of Kentucky, Lexington, KY, United States
i Massachusetts General Hospital, Boston, MA, United States
j Cerebrovascular Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
k Department of Radiology, Stanford University Medical Center, Stanford, CA, United States
l Warren Alpert School of Medicine at Brown University, Rhode Island Hospital, Providence, RI, United States
m Radiology and Neurological Surgery, Columbia University, Neurological Institute of New York, New York, NY, United States
n Deptartments of Neurosurgery and Neurology, Wayne State University School of Medicine, Detroit, MI, United States

Abstract
Background: Management of vascular tumors of the head, neck, and brain is often complex and requires a multidisciplinary approach. Peri-operative embolization of vascular tumors may help to reduce intra-operative bleeding and operative times and have thus become an integral part of the management of these tumors. Advances in catheter and non-catheter based techniques in conjunction with the growing field of neurointerventional surgery is likely to expand the number of peri-operative embolizations performed. The goal of this article is to provide consensus reporting standards and guidelines for embolization treatment of vascular head, neck, and brain tumors. Summary: This article was produced by a writing group comprised of members of the Society of Neurointerventional Surgery. A computerized literature search using the National Library of Medicine database (Pubmed) was conducted for relevant articles published between 1 January 1990 and 31 December 2010. The article summarizes the effectiveness and safety of perioperative vascular tumor embolization. In addition, this document provides consensus definitions and reporting standards as well as guidelines not intended to represent the standard of care, but rather to provide uniformity in subsequent trials and studies involving embolization of vascular head and neck as well as brain tumors. Conclusions: Peri-operative embolization of vascular head, neck, and brain tumors is an effective and safe adjuvant to surgical resection. Major complications reported in the literature are rare when these procedures are performed by operators with appropriate training and knowledge of the relevant vascular and surgical anatomy. These standards may help to standardize reporting and publication in future studies.

Document Type: Review
Source: Scopus

 

Li, Z.a b , Ptak, D.a , Zhang, L.a , Walls, E.K.a c , Zhong, W.d , Leung, Y.F.a e
Phenylthiourea specifically reduces zebrafish eye size
(2012) PLoS ONE, 7 (6), art. no. e40132, . 

a Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
b Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Cellular and Integrative Physiology, Indiana University School of Medicine Lafayette, West Lafayette, IN, United States
d Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, IL, United States
e Department of Biochemistry and Molecular Biology, Indiana University School of Medicine Lafayette, West Lafayette, IN, United States

Abstract
Phenylthiourea (PTU) is commonly used for inhibiting melanization of zebrafish embryos. In this study, the standard treatment with 0.2 mM PTU was demonstrated to specifically reduce eye size in larval fish starting at three days post-fertilization. This effect is likely the result of a reduction in retinal and lens size of PTU-treated eyes and is not related to melanization inhibition. This is because the eye size of tyr, a genetic mutant of tyrosinase whose activity is inhibited in PTU treatment, was not reduced. As PTU contains a thiocarbamide group which is presented in many goitrogens, suppressing thyroid hormone production is a possible mechanism by which PTU treatment may reduce eye size. Despite the fact that thyroxine level was found to be reduced in PTU-treated larvae, thyroid hormone supplements did not rescue the eye size reduction. Instead, treating embryos with six goitrogens, including inhibitors of thyroid peroxidase (TPO) and sodium-iodide symporter (NIS), suggested an alternative possibility. Specifically, three TPO inhibitors, including those that do not possess thiocarbamide, specifically reduced eye size; whereas none of the NIS inhibitors could elicit this effect. These observations indicate that TPO inhibition rather than a general suppression of thyroid hormone synthesis is likely the underlying cause of PTU-induced eye size reduction. Furthermore, the tissue-specific effect of PTU treatment might be mediated by an eye-specific TPO expression. Compared with treatment with other tyrosinase inhibitors or bleaching to remove melanization, PTU treatment remains the most effective approach. Thus, one should use caution when interpreting results that are obtained from PTU-treated embryos. © 2012 Li et al.

Document Type: Article
Source: Scopus

 

Henrich, J.a , Boyd, R.b , McElreath, R.c , Gurven, M.d , Richerson, P.J.e , Ensminger, J.f , Alvard, M.g , Barr, A.h , Barrett, H.C.b , Bolyanatz, A.i , Camerer, C.F.f , Cardenas, J.-C.j , Fehr, E.k , Gintis, H.M.l , Gil-White, F.m , Gwako, E.L.n , Henrich, N.o , Hill, K.p , Lesorogol, C.q , Patton, J.Q.r , Marlowe, F.W.s , Tracer, D.P.t , Ziker, J.u
Reply to van Hoorn: Converging lines of evidence
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (26), pp. E1678. 

a Departments of Psychology and Economics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
b Department of Anthropology, University of California, Los Angeles, CA 90095, United States
c Department of Anthropology, University of California, Davis, CA 95616-8522, United States
d Department of Anthropology, University of California, Santa Barbara, CA 93106, United States
e Department of Environmental Science and Policy, University of California, Davis, CA 95616-8522, United States
f Division of the Humanities and Social Sciences, California Institute of Technology, Pasadena, CA 91125, United States
g Department of Anthropology, Texas A and M University, College Station, TX 77843-4352, United States
h School of Economics, University of Nottingham, Nottingham NG7 2DR, United Kingdom
i Department of Anthropology, College of DuPage, Glen Ellyn, IL 60137, United States
j Facultad de Economia, Universidad de Los Andes, K1 No. 18A-70, Bogotá, Colombia
k Department of Economics, University of Zurich, CH-8006 Zurich, Switzerland
l Santa Fe Institute and Central European University, Northampton, MA 01060, United States
m Univeridad del Medio Ambiente, Valle de Bravo, Instituto Tecnologico Autonomo de Mexico, Mexico 01080, Mexico
n Department of Sociology and Anthropology, Guilford College, Greensboro, NC 27410, United States
o Centre for Health Evaluation and Outcome Sciences, Providence Health Care, Vancouver, BC V6Z 1Y6, Canada
p School of Human Evolution and Social Change, Arizona State University, AR 873403, United States
q George Warren Brown School of Social Work, Washington University, St. Louis, MO 63130, United States
r Department of Anthropology, California State University, Fullerton, CA 92831, United States
s Department of Anthropology, Cambridge University, Cambridge CB2 3DZ, United Kingdom
t Department of Anthropology, University of Colorado, Denver, CO 80217-3364, United States
u Department of Anthropology, Boise State University, Boise, ID 83725-1950, United States

Document Type: Letter
Source: Scopus

 

Gerrish, A.a , Russo, G.a , Richards, A.a , Moskvina, V.a , Ivanov, D.a , Harold, D.a , Sims, R.a , Abraham, R.a , Hollingworth, P.a , Chapman, J.a , Hamshere, M.a , Pahwa, J.S.a , Dowzell, K.a , Williams, A.a , Jones, N.a , Thomas, C.a , Stretton, A.a , Morgan, A.R.a , Lovestone, S.b , Powell, J.c , Proitsi, P.c , Lupton, M.K.c , Brayne, C.d , Rubinsztein, D.C.e , Gill, M.f , Lawlor, B.f , Lynch, A.f , Morgan, K.g , Brown, K.S.g , Passmore, P.A.h , Craig, D.h , McGuinness, B.h , Todd, S.h , Johnston, J.A.i , Holmes, C.i , Mann, D.j , Smith, A.D.k , Love, S.l , Kehoe, P.G.l , Hardy, J.m , Mead, S.n , Fox, N.o , Rossor, M.o , Collinge, J.n , Maier, W.p , Jessen, F.p , Kölsch, H.p , Heun, R.p q , Schürmann, B.p , Bussche, H.V.D.r , Heuser, I.s , Kornhuber, J.t , Wiltfang, J.u , Dichgans, M.v w , Frölich, L.x , Hampel, H.y , Hüll, M.z , Rujescu, D.z , Goate, A.M.aa , Kauwe, J.S.K.ab , Cruchaga, C.aa , Nowotny, P.aa , Morris, J.C.aa , Mayo, K.aa , Livingston, G.ac , Bass, N.J.ac , Gurling, H.ac , McQuillin, A.ac , Gwilliam, R.ad , Deloukas, P.ad , Davies, G.ae af , Harris, S.E.ae ag , Starr, J.M.ae ah , Deary, I.J.ae af , Al-Chalabi, A.ai , Shaw, C.E.ai , Tsolaki, M.aj , Singleton, A.B.ak , Guerreiro, R.ak , Mühleisen, T.W.al am , Nöthen, M.M.al am , Moebus, S.an , Jöckel, K.-H.an , Klopp, N.ao , Wichmann, H.-E.ao ap aq , Carrasquillo, M.M.ar , Pankratz, V.S.as , Younkin, S.G.ar , Jones, L.a , Holmans, P.A.a , O'Donovan, M.C.a , Owen, M.J.a , Williams, J.a
The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease
(2012) Journal of Alzheimer's Disease, 28 (2), pp. 377-387. 

a Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom
b King's College London, Institute of Psychiatry, Kings College, London, United Kingdom
c Department of Neuroscience, Institute of Psychiatry, Kings College, London, United Kingdom
d Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
e Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
f Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
g Human Genetics Group, School of Molecular Medical Sciences, University of Nottingham, United Kingdom
h Ageing Group, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, United Kingdom
i Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom
j Neurodegeneration and Mental Health Research Group, School of Community Based Medicine, University of Manchester, Salford, United Kingdom
k Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
l Dementia Research Group, University of Bristol, Frenchay Hospital, Bristol, United Kingdom
m Department of Molecular Neuroscience, Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom
n Department of Neurodegenerative Disease, Institute of Neurology, University College London, United Kingdom
o Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom
p Department of Psychiatry, University of Bonn, Bonn, Germany
q Radbourne Unit, Royal Derby Hospital, Derby, United Kingdom
r Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Germany
s Department of Psychiatry, Charité Berlin, Berlin, Germany
t Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Germany
u LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Germany
v Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany
w Department of Neurology, Klinikum der Universität München, Munich, Germany
x Department of Geriatric Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
y Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany
z Ludwig-Maximilians-University, Department of Psychiatry, Munich, Germany
aa Department of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, MO, United States
ab Department of Biology, Brigham Young University, Provo, UT, United States
ac Mental Health Unit, UCL, London, United Kingdom
ad Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
ae Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
af Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
ag Medical Genetics, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom
ah Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom
ai Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, United Kingdom
aj Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece
ak Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
al Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
am Institute of Human Genetics, University of Bonn, Bonn, Germany
an Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany
ao Institute of Epidemiology, Helmholtz Zentrum M¨nchen, German Research Center for Environmental Health, Neuherberg, Germany
ap Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
aq Klinikum Grosshadern, Munich, Germany
ar Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, United States
as Division of Biomedical Statistics and Informatics, Mayo Clinic, Mayo Foundation, Rochester, MN, United States

Abstract
Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. © 2012 - IOS Press and the authors. All rights reserved.

Author Keywords
Alzheimer's disease;  amyloid-β protein precursor;  genetics;  human;  MAPT protein;  PSEN1 protein;  PSEN2 protein

Document Type: Article
Source: Scopus

 

Wang, S.a b , Lee, S.-J.a , Heyman, S.a , Enkvetchakul, D.b , Nichols, C.G.a
Structural rearrangements underlying ligand-gating in Kir channels
(2012) Nature Communications, 3, art. no. 617, . 

a Department of Cell Biology and Physiology, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 425 S. Euclid Ave., St. Louis, MO 63110, United States
b Department of Pharmacological and Physiological Sciences, Saint Louis University, 1402 South Grand Blvd., St. Louis, MO 63104, United States

Abstract
Inward rectifier potassium (Kir) channels are physiologically regulated by a wide range of ligands that all act on a common gate, although structural details of gating are unclear. Here we show, using small molecule fluorescent probes attached to introduced cysteines, the molecular motions associated with gating of KirBac1.1 channels. The accessibility of the probes indicates a major barrier to fluorophore entry to the inner cavity. Changes in fluorescence resonance energy transfer between fluorophores, attached to KirBac1.1 tetramers, show that phosphatidylinositol-4,5-bisphosphate-induced closure involves tilting and rotational motions of secondary structural elements of the cytoplasmic domain that couple ligand binding to a narrowing of the cytoplasmic vestibule. The observed ligand-dependent conformational changes in KirBac1.1 provide a general model for ligand-induced Kir channel gating at the molecular level. © 2012 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus

 

Filonov, G.S.a , Krumholz, A.b , Xia, J.b , Yao, J.b , Wang, L.V.b , Verkhusha, V.V.a
Deep-tissue photoacoustic tomography of a genetically encoded near-infrared fluorescent probe
(2012) Angewandte Chemie - International Edition, 51 (6), pp. 1448-1451. 

a Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States
b Department of Biomedical Engineering, Optical Imaging Laboratory, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
Skin-deep: The combination of a near-infrared fluorescent protein (iRFP) and deep-tissue photoacoustic tomography clearly demonstrates the superiority of iRFP over other genetically encoded probes. Impressive resolution (280 μm lateral and 75 μm axial) was obtained at a depth of 4mm in a live animal, and volumetric images of a tumor were produced (see image), thus allowing the spatially resolved monitoring of its development. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Author Keywords
absorption;  cancer;  fluorescent proteins;  imaging agents;  photoacoustic imaging

Document Type: Article
Source: Scopus

Chen, D.Y.a , Lee, Y.a , Van Tine, B.A.a , Searleman, A.C.a , Westergard, T.D.a , Liu, H.c , Tu, H.-C.c , Takeda, S.c , Dong, Y.c , Piwnica-Worms, D.R.b , Oh, K.J.f , Korsmeyer, S.J.g , Hermone, A.h , Gussio, R.h , Shoemaker, R.H.i , Cheng, E.H.-Y.c d , Hsieh, J.J.-D.c e
A pharmacologic inhibitor of the protease taspase1 effectively inhibits breast and brain tumor growth
(2012) Cancer Research, 72 (3), pp. 736-746.

a Department of Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b BRIGHT Institute, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, Z801, 415 E. 68th Street, New York, NY 10065, United States
d Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
e Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
f Department of Biochemistry and Molecular Biology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL, United States
g Dana Farber Cancer Institute, Boston, MA, United States
h Information Technology Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD, United States
i Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD, United States

Abstract
The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities. Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers. We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the National Cancer Institute diversity library to identify Taspase1 inhibitors (TASPIN). On the basis of secondary and tertiary screens the 4-[(4-arsonophenyl)methyl]phenyl] arsonic acid NSC48300 was determined to be the most specific active compound. Structure-activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition. Additional fluorescence resonance energy transfer-based kinetic analysis characterized NSC48300 as a reversible, noncompetitive inhibitor of Taspase1 (K i = 4.22 μmol/L). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer, NSC48300 produced effective tumor growth inhibition. Our results offer an initial preclinical proof-of-concept to develop TASPINs for cancer therapy. ©2011 AACR.


Document Type: Article
Source: Scopus

 

Ramaglia, V.a , Hughes, T.R.a , Donev, R.M.a , Ruseva, M.M.a , Wu, X.b , Huitinga, I.c , Baas, F.d , Neal, J.W.e , Morgan, B.P.a
C3-dependent mechanism of microglial priming relevant to multiple sclerosis
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (3), pp. 965-970.

a Department of Infection, Immunity, and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom
b Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neuroimmunology, Netherlands Institute for Neuroscience, 1105 AZ Amsterdam, Netherlands
d Department of Genome Analysis, Academic Medical Center, 1105 AZ Amsterdam, Netherlands
e Department of Pathology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom

Abstract
Microglial priming predisposes the brain to neurodegeneration and affects disease progression. The signal to switch from the quiescent to the primed state is unknown. We show that deleting the C3 convertase regulator complement receptor 1-related protein y (Crry) induces microglial priming.Mice that were double-knockout for Crry and either C3 or factor B did not show priming, demonstrating dependence on alternative pathway activation. Colocalization of C3b/iC3b and CR3 implicated the CR3/iC3b interaction in priming. Systemic lipopolysaccharide challenge overactivated primed microglia with florid expression of proinflammatory molecules, whichwere blocked by complement inhibition. Relevance for neurodegenerative disease is exemplified by human multiple sclerosis (MS) and by experimental autoimmune encephalomyelitis (EAE), a model of MS. In human MS, microglial priming was evident in perilesional white matter, in close proximity to C3b/iC3b deposits. EAE was accelerated and exacerbated in Crry-deficient mice, and was dependent on C activation. In summary, C3-dependent microglial priming confers susceptibility to other challenges. Our observations are relevant to progression in MS and other neurological diseases exacerbated by acute insults.

Document Type: Article
Source: Scopus

July 4, 2012

Pepose, J.S.a b , Wang, D.c d , Altmann, G.E.c
Comparison of through-focus image sharpness across five presbyopia-correcting intraocular lenses
(2012) American Journal of Ophthalmology, 154 (1), pp. 20-28. 

a Pepose Vision Institute, 1815 Clarkson Rd, Chesterfield, MO 63017, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Bausch and Lomb, Rochester, NY, United States
d CooperVision, Inc., Pleasanton, CA, United States

Abstract
• PURPOSE: To assess through-focus polychromatic image sharpness of 5 FDA-approved presbyopia-correcting intraocular lenses (IOLs) through a range of object vergences and pupil diameters using an image sharpness algorithm. • DESIGN: Laboratory investigation. • METHODS: A 1951 USAF resolution target was imaged through Crystalens AO (AO), Crystalens HD (HD), aspheric ReSTOR +4 (R4), aspheric ReSTOR +3 (R3), and Tecnis Multifocal Acrylic (TMF) IOL in a model eye and captured digitally for each combination of pupil diameter and object vergence. The sharpness of each digital image was objectively scored using a 2-dimensional gradient function. • RESULTS: AO had the best distance image sharpness for all pupil diameters and was superior to the HD. With a 5-mm pupil, the R4 distance image sharpness was similar to the HD and at 6 mm the TMF was superior to the HD, R3, and R4. The R3 moved the near focal point farther from the patient compared to the R4, but did not improve image sharpness at intermediate distances and showed worse distance and near image sharpness. Consistent with apodization, the ReSTOR IOLs displayed better distance and poorer near image sharpness as pupil diameter increased. TMF showed consistent distance and near image sharpness across pupil diameters and the best near image sharpness for all pupil diameters. • CONCLUSIONS: Differing IOL design strategies to increase depth of field are associated with quantifiable differences in image sharpness at varying vergences and pupil sizes. Objective comparison of the imaging properties of specific presbyopia-correcting IOLs in relation to patient's pupil sizes can be useful in selecting the most appropriate IOL for each patient. © 2012 Elsevier Inc. All rights reserved.

Document Type: Article
Source: Scopus

 

Fehr, J.J., Murray, D.J.
In reply
(2012) Anesthesiology, 117 (1), p. 220. 


Washington University School of Medicine, St. Louis, MO, United States
Document Type: Letter
Source: Scopus

 

Nagele, P.
Notorious oxide
(2012) Anesthesiology, 117 (1), pp. 3-5. 


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

Document Type: Editorial
Source: Scopus

 

Fields, R.C.a , Busam, K.J.b , Chou, J.F.c , Panageas, K.S.c , Pulitzer, M.P.b , Allen, P.J.a , Kraus, D.H.a , Brady, M.S.a , Coit, D.G.a d
Recurrence after complete resection and selective use of adjuvant therapy for stage i through III Merkel cell carcinoma
(2012) Cancer, 118 (13), pp. 3311-3320. 

a Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
b Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
c Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
d Barnes-Jewish Hospital, Washington University, School of Medicine, St. Louis, MI, United States

Abstract
BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm whose natural history is poorly understood. Here, the authors describe their experience with a large cohort of patients who were treated at a single institution to describe patterns of recurrence after curative therapy. METHODS: Review of a prospective database was performed. Patient-related, tumor-related, and treatment-related variables were recorded, and the site and timing of initial recurrence were recorded. Factors associated with receipt of adjuvant therapy and recurrence were determined. RESULTS: In total, 364 patients with stage I through III MCC who underwent complete resection were identified. Adjuvant local radiation therapy (RT), lymph node RT, and chemotherapy were received selectively by 23%, 23%, and 15% of patients, respectively. Factors associated with the receipt of adjuvant therapy included younger age, primary tumor features (larger size, lymphovascular invasion [LVI], positive margin excision), and increasing pathologic stage. With median follow-up of 3.6 years, 108 patients (30%) developed a recurrence, including 11 local recurrences (3%), 12 in-transit recurrences (3%), 43 lymph node recurrences (12%), and 42 distant recurrences (12%). Clinically involved lymph nodes, primary tumor LVI, and a history of leukemia/lymphoma were predictive of recurrence. The majority of recurrences (80%) occurred in patients who had clinically involved lymph nodes or patients who did not undergo pathologic lymph node evaluation. CONCLUSIONS: A low recurrence rate in patients with clinically lymph node-negative MCC was achieved with adequate surgery (including sentinel lymph node biopsy) and the selective use of adjuvant RT for high-risk tumors. In contrast, patients with clinically lymph node-positive MCC had significantly higher rates of recurrence, especially distant recurrence. The authors concluded that contemporary natural history studies are critical in designing treatment pathways and clinical trials for MCC. © 2011 American Cancer Society.

Author Keywords
Chemotherapy;  Merkel cell carcinoma;  Outcomes;  Radiation therapy;  Recurrence;  Surgery;  Treatment

Document Type: Review
Source: Scopus

 

Kim, H.M.a , Galatz, L.M.a , Lim, C.a , Havlioglu, N.b , Thomopoulos, S.a
The effect of tear size and nerve injury on rotator cuff muscle fatty degeneration in a rodent animal model
(2012) Journal of Shoulder and Elbow Surgery, 21 (7), pp. 847-858.

a Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
b Department of Pathology, St. Claire Hospital, Fenton, MO, United States

Abstract
Background: Irreversible muscle changes after rotator cuff tears is a well-known negative prognostic factor after shoulder surgery. Currently, little is known about the pathomechanism of fatty degeneration of the rotator cuff muscles after chronic cuff tears. The purposes of this study were to (1) develop a rodent animal model of chronic rotator cuff tears that can reproduce fatty degeneration of the cuff muscles seen clinically, (2) describe the effects of tear size and concomitant nerve injury on muscle degeneration, and (3) evaluate the changes in gene expression of relevant myogenic and adipogenic factors after rotator cuff tears using the animal model. Materials and methods: Rotator cuff tears were created in rodents with and without transection of the suprascapular nerve. The supraspinatus and infraspinatus muscles were examined at 2, 8, and 16 weeks after injury for histologic evidence of fatty degeneration and expression of myogenic and adipogenic genes. Results: Histologic analysis revealed adipocytes, intramuscular fat globules, and intramyocellular fat droplets in the tenotomized and neurotomized supraspinatus and infraspinatus muscles. Changes increased with time and were most severe in the muscles with combined tenotomy and neurotomy. Adipogenic and myogenic transcription factors and markers were upregulated in muscles treated with tenotomy or tenotomy combined with neurotomy compared with normal muscles. Conclusions: The rodent animal model described in this study produces fatty degeneration of the rotator cuff muscles similar to human muscles after chronic cuff tears. The severity of changes was associated with tear size and concomitant nerve injury. © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees.

Author Keywords
Adipogenesis;  Basic science study;  Laboratory study;  Myogenesis;  Neurotomy;  Tendon;  Tenotomy

Document Type: Article
Source: Scopus

 

Namani, R.a , Feng, Y.a , Okamoto, R.J.a , Jesuraj, N.b , Sakiyama-Elbert, S.E.b , Genin, G.M.a , Bayly, P.V.a
Elastic characterization of transversely isotropic soft materials by dynamic shear and asymmetric indentation
(2012) Journal of Biomechanical Engineering, 134 (6), art. no. 4006848, . 

a Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis MO 63130 63130, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis MO 63130 63130, United States

Abstract
The mechanical characterization of soft anisotropic materials is a fundamental challenge because of difficulties in applying mechanical loads to soft matter and the need to combine information from multiple tests. A method to characterize the linear elastic properties of transversely isotropic soft materials is proposed, based on the combination of dynamic shear testing (DST) and asymmetric indentation. The procedure was demonstrated by characterizing a nearly incompressible transversely isotropic soft material. A soft gel with controlled anisotropy was obtained by polymerizing a mixture of fibrinogen and thrombin solutions in a high field magnet (B 11.7 T); fibrils in the resulting gel were predominantly aligned parallel to the magnetic field. Aligned fibrin gels were subject to dynamic (20-40 Hz) shear deformation in two orthogonal directions. The shear storage modulus was 1.08 ± 0. 42 kPa (mean ± std. dev.) for shear in a plane parallel to the dominant fiber direction, and 0.58 ± 0.21 kPa for shear in the plane of isotropy. Gels were indented by a rectangular tip of a large aspect ratio, aligned either parallel or perpendicular to the normal to the plane of transverse isotropy. Aligned fibrin gels appeared stiffer when indented with the long axis of a rectangular tip perpendicular to the dominant fiber direction. Three-dimensional numerical simulations of asymmetric indentation were used to determine the relationship between direction-dependent differences in indentation stiffness and material parameters. This approach enables the estimation of a complete set of parameters for an incompressible, transversely isotropic, linear elastic material. © 2012 American Society of Mechanical Engineers.

Document Type: Article
Source: Scopus

 

Gillespie, N.A.a b , Gehrman, P.c , Byrne, E.M.b , Kendler, K.S.b d , Heath, A.C.e , Martin, N.G.b
Modeling the direction of causation between cross-sectional measures of disrupted sleep, anxiety and depression in a sample of male and female Australian twins
(2012) Journal of Sleep Research, . Article in Press. 

a Queensland Institute of Medical Research, Brisbane, Qld, Australia
b Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA
c Behavioral Sleep Medicine Program, Department of Psychiatry and Penn Sleep Center, University of Pennsylvania, PA, USA
d Department of Human Genetics, Virginia Commonwealth University, VA, USA
e Department of Psychology, Washington University in St Louis, St Louis, MI, USA

Abstract
The direction of causation between measures of disrupted sleep, anxiety and depression is not well understood. Under certain conditions, cross-sectional analysis based on genetically informative data can provide important information about the direction of causation between variables. Two community-based samples of 7235 Australian twins aged 18-87years were mailed an extensive questionnaire that covered a wide range of personality and behavioral measures. Included were self-report measures of disrupted sleep, as well as symptoms of anxiety and depression. Among all females, modeling the direction of causation did not support the hypothesis of sleep having a direct causal impact on risk of anxiety or depression. Among older females, we found evidence that both anxiety and depression interact reciprocally with disrupted sleep, whereas among younger women both anxiety and depression appear to have a causal impact on sleep. Results for males were equivocal. The nosological implications of our findings are discussed. © 2012 European Sleep Research Society.

Author Keywords
Anxiety;  Depression;  Direction of causation;  Disrupted sleep;  Environment;  Genes;  Twins

Document Type: Article in Press
Source: Scopus

 

Bailey, H.
Computer-paced versus experimenter-paced working memory span tasks: Are they equally reliable and valid?
(2012) Learning and Individual Differences, . Article in Press. 

439 Psychology Building, One Brookings Drive, Campus Box 1125, Washington University, Saint Louis, MO 63130, United States

Abstract
Working memory span tasks are popular measures, in part, because performance on these tasks predicts performance on other measures of cognitive ability. The traditional method of span-task administration is the experimenter-paced version, whose reliability and validity have been repeatedly demonstrated. However, computer-paced span tasks are becoming increasingly more popular. Despite their popularity, no study had systematically compared experimenter-paced and computer-paced versions of the reading span and operation span tasks. Such a comparison is important because research labs in many universities across many countries administer these span tasks with a variety of methods. The purpose of the present study was to evaluate the reliability and validity of computer-paced span tasks and to compare these estimates to those of experimenter-paced span tasks. Results indicated that experimenter-paced and computer-paced span tasks share some overlap, but also measure additional and distinct processes. Computer-paced span tasks were highly reliable measures as well as valid indicators of fluid intelligence (Gf). Thus, computer-paced span tasks may be the optimal type of administration given their methodological advantages over experimenter-paced span tasks. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Administration;  Computer-paced;  Fluid intelligence;  Span tasks;  Working memory

Document Type: Article in Press
Source: Scopus

 

Bailey, R.a , McNamara, A.b , Costello, A.a , Sridharan, S.a , Grimm, C.c
Impact of subtle gaze direction on short-term spatial information recall
(2012) Eye Tracking Research and Applications Symposium (ETRA), pp. 67-74. 

a Rochester Institute of Technology, United States
b Texas A and M, United States
c Washington University, St. Louis, United States

Abstract
Contents of Visual Short-Term Memory depend highly on viewer attention. It is possible to influence where attention is allocated using a technique called Subtle Gaze Direction (SGD). SGD combines eye tracking with subtle image-space modulations to guide viewer gaze about a scene. Modulations are terminated before the viewer can scrutinize them with high acuity foveal vision. This approach is preferred to overt techniques that require permanent alterations to images to highlight areas of interest. In our study, participants were asked to recall the location of objects or regions in images. We investigated if using SGD to guide attention to these regions would improve recall. Results showed that the influence of SGD significantly improved accuracy of target count and spatial location recall. This has implications for a wide range of applications including spatial learning in virtual environments as well as image search applications, virtual training and perceptually based rendering. © 2012 ACM.

Author Keywords
eye-tracking;  gaze direction;  short-term memory

Document Type: Conference Paper
Source: Scopus

 

Sridharan, S.a , Bailey, R.a , McNamara, A.b , Grimm, C.c
Subtle gaze manipulation for improved mammography training
(2012) Eye Tracking Research and Applications Symposium (ETRA), pp. 75-82. 

a Rochester Institute of Technology, United States
b Texas A and M University, United States
c Washington University, St. Louis, United States

Abstract
We use the Subtle Gaze Direction technique (SGD) to guide novices as they try to find abnormalities in mammograms. SGD works by performing image-space modulations on specific regions of the peripheral vision to attract attention. Gaze is monitored and modulations are terminated before they are scrutinized with high-acuity foveal vision. This approach is preferred to overt techniques which permanently alter images to highlight areas of interest. SGD is used to guide novices along the scanpath of an expert radiologist. We hypothesized that this would increase the likelihood of novices correctly identifying irregularities. Results reveal that novices who were guided in this manner performed significantly better than the control group (no gaze manipulation). Furthermore, a short-term post-training lingering effect was observed among subjects guided using SGD. They continued to perform better than the control group once the training was complete and gaze manipulation was disabled. © 2012 ACM.

Author Keywords
gaze manipulation;  image-space modulations;  mammography;  radiological training

Document Type: Conference Paper
Source: Scopus

 

Lavernia, C.J.a , Contreras, J.S.b , Parvizi, J.c , Sharkey, P.F.c , Barrack, R.d , Rossi, M.D.e
Do Patient Expectations About Arthroplasty at Initial Presentation for Hip or Knee Pain Differ by Sex and Ethnicity?
(2012) Clinical Orthopaedics and Related Research, pp. 1-11. Article in Press. 

a Orthopaedic Institute at Mercy Hospital, 3659 S Miami Avenue, Suite 4008, Miami, 33133, United States
b Arthritis Surgery Research Foundation, Miami, United States
c The Rothman Institute, Philadelphia, United States
d Department of Orthopaedic Surgery, Washington University School of Medicine Barnes-Jewish Hospital, St Louis, United States
e Department of Physical Therapy, Florida International University, Miami, United States

Abstract
Background: Many studies show gender and ethnic differences in healthcare utilization and outcomes. Patients' presurgical cognitions regarding surgical outcomes also may vary by gender and ethnicity and play a role in explaining utilization and outcome differences. However, it is unclear whether and to what extent gender and ethnicity play a role in patients' presurgical cognitions. Questions/Purposes: Do gender and ethnicity influence outcome expectations? Is arthroplasty-related knowledge affected by gender and ethnicity? Do gender and ethnicity influence willingness to pay for surgery? Methods: In a prospective, multicenter study we gave 765 patients an anonymous questionnaire on expectations, arthroplasty knowledge, and preferences before their consultation for hip and/or knee pain, from March 2005 to July 2007. Results: Six hundred seventy-two of the 765 patients (88%) completed questionnaires. Non-Hispanics and men were more likely to indicate they would be able to engage in more activities. Non-Hispanics and men had greater arthroplasty knowledge. Hispanics and women were more likely to report they would not pay for a total joint arthroplasty (TJA) relative to non-Hispanics and men. Conclusions: Sex and ethnic differences in patients presenting for their initial visit to the orthopaedists for hip or knee pain influence expectations, knowledge, and preferences concerning TJAs. Longitudinal study of relationships between patients' perceptions and utilization or outcomes regarding TJA is warranted. © 2012 The Association of Bone and Joint Surgeons®.

Document Type: Article in Press
Source: Scopus

 

Miller, R.L.a , Knuepfer, M.M.b , Wang, M.H.a , Denny, G.O.a , Gray, P.A.a , Loewy, A.D.a
Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats
(2012) Neuroscience, . Article in Press. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
b Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA

Abstract
The parabrachial nucleus (PB) is a brainstem cell group that receives a strong input from the nucleus tractus solitarius regarding the physiological status of the internal organs and sends efferent projections throughout the forebrain. Since the neuroanatomical organization of the PB remains unclear, our first step was to use specific antibodies against two neural lineage transcription factors: Forkhead box protein2 (FoxP2) and LIM homeodomain transcription factor 1 beta (Lmx1b) to define the PB in adult rats. This allowed us to construct a cytoarchitectonic PB map based on the distribution of neurons that constitutively express these two transcription factors. Second, the in situ hybridization method combined with immunohistochemistry demonstrated that mRNA for glutamate vesicular transporter Vglut2 (Slc17a6) was present in most of the Lmx1b+ and FoxP2+ parabrachial neurons, indicating these neurons use glutamate as a transmitter. Third, conscious rats were maintained in a hypotensive or hypertensive state for 2 h, and then, their brainstems were prepared by the standard c-Fos method which is a measure of neuronal activity. Both hypotension and hypertension resulted in c-Fos activation of Lmx1b+ neurons in the external lateral-outer subdivision of the PB (PBel-outer). Hypotension, but not hypertension, caused c-Fos activity in the FoxP2+ neurons of the central lateral PB (PBcl) subnucleus. The Kölliker-Fuse nucleus as well as the lateral crescent PB and rostral-most part of the PBcl contain neurons that co-express FoxP2+ and Lmx1b+, but none of these were activated after blood pressure changes. Salt-sensitive FoxP2 neurons in the pre-locus coeruleus and PBel-inner were not c-Fos activated following blood pressure changes. In summary, the present study shows that the PBel-outer and PBcl subnuclei originate from two different neural progenitors, contain glutamatergic neurons, and are affected by blood pressure changes, with the PBel-outer reacting to both hypo- and hypertension, and the PBcl signaling only hypotensive changes. © 2012 IBRO.

Author Keywords
blood pressure;  FoxP2;  Lmx1b;  parabrachial nucleus;  transcription factors

Document Type: Article in Press
Source: Scopus

 

Tu, Z.a , Wang, W.a , Cui, J.a , Zhang, X.a , Lu, X.a , Xu, J.a , Parsons, S.M.b
Synthesis and evaluation of in vitro bioactivity for vesicular acetylcholine transporter inhibitors containing two carbonyl groups
(2012) Bioorganic and Medicinal Chemistry, . Article in Press. 

a Department of Radiology, Washington University, St. Louis, MO 63110, United States
b Department of Chemistry and Biochemistry and The Graduate Program in Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106, United States

Abstract
To identify selective high-affinity ligands for the vesicular acetylcholine transporter (VAChT), we have incorporated a carbonyl group into the structures of trozamicol and prezamicol scaffolds, and also converted the secondary amines of the piperidines of trozamicols and prezamicols into amides. Of 18 new racemic compounds, 4 compounds displayed high affinity for VAChT (K i = 10-20 nM) and greater than 300-fold selectivity for VAChT over σ 1 and σ 2 receptors, namely (4-(4-fluorobenzoyl)-4′-hydroxy-[1,3′-bipiperidin]-1′-yl)(3-methylthiophen-2-yl)methanone oxalate (9g) (K i-VAChT = 11.4 nM, VAChT/σ 1 = 1063, VAChT/σ 2 = 370), (1′-benzoyl-4′-hydroxy-[1,3′-bipiperidin]-4-yl)(4-methoxyphenyl)methanone oxalate (10c) (K i-VAChT = 15.4 nM, VAChT/σ 1 = 374, VAChT/σ 2 = 315), (4′-hydroxy-1′-(thiophene-2-carbonyl)-[1,3′-bipiperidin]-4-yl)(4-methoxyphenyl)methanone oxalate (10e) (K i-VAChT = 19.0 nM, VAChT/σ 1 = 1787, VAChT/σ 2 = 335), and (4′-hydroxy-1′-(3-methylthiophene-2-carbonyl)-[1,3′-bipiperidin]-4-yl)(4-methoxyphenyl)methanone oxalate (10g) (K i-VAChT = 10.2 nM, VAChT/σ 1 = 1500, VAChT/σ 2 = 2030). These four compounds can be radiosynthesized with C-11 or F-18 to validate their possibilities of serving as PET probes for quantifying the levels of VAChT in vivo. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
σ Receptor;  CNS disorders;  Parkinson's disease;  VAChT;  Vesamciol

Document Type: Article in Press
Source: Scopus

 

Kolesnikov, A.V., Kefalov, V.J.
Transretinal ERG recordings from mouse retina: rod and cone photoresponses.
(2012) Journal of visualized experiments : JoVE, (61), . 

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Washington, USA.

Abstract
There are two distinct classes of image-forming photoreceptors in the vertebrate retina: rods and cones. Rods are able to detect single photons of light whereas cones operate continuously under rapidly changing bright light conditions. Absorption of light by rod- and cone-specific visual pigments in the outer segments of photoreceptors triggers a phototransduction cascade that eventually leads to closure of cyclic nucleotide-gated channels on the plasma membrane and cell hyperpolarization. This light-induced change in membrane current and potential can be registered as a photoresponse, by either classical suction electrode recording technique or by transretinal electroretinogram recordings (ERG) from isolated retinas with pharmacologically blocked postsynaptic response components. The latter method allows drug-accessible long-lasting recordings from mouse photoreceptors and is particularly useful for obtaining stable photoresponses from the scarce and fragile mouse cones. In the case of cones, such experiments can be performed both in dark-adapted conditions and following intense illumination that bleaches essentially all visual pigment, to monitor the process of cone photosensitivity recovery during dark adaptation. In this video, we will show how to perform rod- and M/L-cone-driven transretinal recordings from dark-adapted mouse retina. Rod recordings will be carried out using retina of wild type (C57Bl/6) mice. For simplicity, cone recordings will be obtained from genetically modified rod transducin α-subunit knockout (Tα(-/-)) mice which lack rod signaling(8).

Document Type: Article
Source: Scopus

 

Brenner, D.S.a b c , Golden, J.P.a , Gereau IV, R.W.a b
A novel behavioral assay for measuring cold sensation in mice
(2012) PLoS ONE, 7 (6), art. no. e39765, . 

a Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Neuroscience Program, Washington University School of Medicine, St. Louis, MO, United States
c Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Behavioral models of cold responses are important tools for exploring the molecular mechanisms of cold sensation. To complement the currently cold behavioral assays and allow further studies of these mechanisms, we have developed a new technique to measure the cold response threshold, the cold plantar assay. In this assay, animals are acclimated on a glass plate and a cold stimulus is applied to the hindpaw through the glass using a pellet of compressed dry ice. The latency to withdrawal from the cooled glass is used as a measure of the cold response threshold of the rodents, and the dry ice pellet provides a ramping cold stimulus on the glass that allows the correlation of withdrawal latency values to rough estimates of the cold response threshold temperature. The assay is highly sensitive to manipulations including morphine-induced analgesia, Complete Freund's Adjuvant-induced inflammatory allodynia, and Spinal Nerve Ligation-induced neuropathic allodynia. © 2012 Brenner et al.

Document Type: Article
Source: Scopus

 

Dlouhy, B.J.a , Rao, R.C.b
Amantadine for severe traumatic brain injury [4]
(2012) New England Journal of Medicine, 366 (25), p. 2427. 

a University of Iowa Hospitals and Clinics, Iowa City, IA, United States
b Washington University School of Medicine, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

 

Shin, J.E.a , Cho, Y.b , Beirowski, B.c , Milbrandt, J.c d , Cavalli, V.b d , DiAntonio, A.a d d
Dual Leucine Zipper Kinase Is Required for Retrograde Injury Signaling and Axonal Regeneration
(2012) Neuron, 74 (6), pp. 1015-1022. Cited 1 time.


a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Here we demonstrate that the dual leucine zipper kinase (DLK) promotes robust regeneration of peripheral axons after nerve injury in mice. Peripheral axon regeneration is accelerated by prior injury; however, DLK KO neurons do not respond to a preconditioning lesion with enhanced regeneration in vivo or in vitro. Assays for activation of transcription factors in injury-induced proregenerative pathways reveal that loss of DLK abolishes upregulation of p-STAT3 and p-cJun in the cell body after axonal injury. DLK is not required for the phosphorylation of STAT3 at the site of nerve injury but is necessary for retrograde transport of p-STAT3 to the cell body. These data demonstrate that DLK enhances regeneration by promoting a retrograde injury signal that is required for the activation of the neuronal proregenerative program. Peripheral nerve injury activates a neuronal transcriptional program that enhances axonal regeneration. Shin et al. report that dual leucine zipper kinase promotes axon regeneration by regulating retrograde transport of injury signals in mammals. © 2012 Elsevier Inc.

Document Type: Article
Source: Scopus

 

Müller, V.a , Anokhin, A.P.b
Neural synchrony during response production and inhibition
(2012) PLoS ONE, 7 (6), art. no. e38931, . 


a Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
b Washington University School of Medicine, St. Louis, MO, United States

Abstract
Inhibition of irrelevant information (conflict monitoring) and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs) elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG) recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations. © 2012 Müller, Anokhin.

Document Type: Article
Source: Scopus

 

Robinson, G.a b c , Parker, M.a d , Kranenburg, T.A.a b , Lu, C.a e , Chen, X.a d , Ding, L.a e f , Phoenix, T.N.a b , Hedlund, E.a d , Wei, L.a d g , Zhu, X.a b , Chalhoub, N.a b , Baker, S.J.a b , Huether, R.a d h , Kriwacki, R.a h , Curley, N.a b , Thiruvenkatam, R.a b , Wang, J.a i , Wu, G.a d , Rusch, M.a d , Hong, X.a e , Becksfort, J.a i , Gupta, P.a i , Ma, J.a g , Easton, J.a d , Vadodaria, B.a d , Onar-Thomas, A.a j , Lin, T.a j , Li, S.a j , Pounds, S.a j , Paugh, S.a k , Zhao, D.a i , Kawauchi, D.a l , Roussel, M.F.a l , Finkelstein, D.a d , Ellison, D.W.a g , Lau, C.C.a m , Bouffet, E.a n , Hassall, T.a o , Gururangan, S.a p , Cohn, R.a q , Fulton, R.S.a e f , Fulton, L.L.a e f , Dooling, D.J.a e f , Ochoa, K.a e f , Gajjar, A.a c , Mardis, E.R.a e f r , Wilson, R.K.a e f s , Downing, J.R.a g , Zhang, J.a d , Gilbertson, R.J.a b c
Novel mutations target distinct subgroups of medulloblastoma
(2012) Nature, . Article in Press. 


a 1] St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA
b Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
c Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
d Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
e The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA
f Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA
g Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
h Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
i Department of Information Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
j Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
k Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
l Department of Tumour Biology and Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
m Texas Children's Cancer and Hematology Centers, 6701 Fannin Street, Ste. 1420, Houston, Texas 77030, USA
n The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
o The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia
p Duke University Medical Center, 102382, Durham, North Carolina 27710, USA
q The School of Women's and Children's Health, University of New South Wales, Kensington, New South Wales NSW 2052, Australia
r Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA
s Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA

Abstract
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

Document Type: Article in Press
Source: Scopus

 

Shaw, P.J.a , Duntley, S.P.b
Neurological disorders: Towards a mechanistic understanding of restless legs syndrome
(2012) Current Biology, 22 (12), pp. R485-R486. 


a Anatomy and Neurobiology, Washington University School of Medicine, Campus Box 8108, 660 S. Euclid Ave, St. Louis, MO 63110, United States
b Department of Neurology, Washington University Sleep Medicine Center, 212 North Kingshighway, St. Louis, MO 63108, United States

Abstract
Restless legs syndrome is a curious neurological disorder of unknown aetiology. A new study has found that Drosophila mutants in the fly homologue of a human gene, BTBD9, that has been implicated as a risk factor for restless legs display important features of the syndrome. © 2012 Elsevier Ltd All rights reserved.

Document Type: Article
Source: Scopus

 

Churchland, M.M.a b c , Cunningham, J.P.d e , Kaufman, M.T.c f , Foster, J.D.b , Nuyujukian, P.g h , Ryu, S.I.f i , Shenoy, K.V.c f j k
Neural population dynamics during reaching
(2012) Nature, . Article in Press. 


a 1] Department of Neuroscience, Kavli Institute for Brain Science, David Mahoney Center, Columbia University Medical Center, New York, New York 10032, USA
b Department of Electrical Engineering, Stanford University, Stanford, California 94305, USA
c Neurosciences Program, Stanford University, Stanford, California 94305, USA
d 1] Department of Biomedical Engineering, Washington University in St Louis, St Louis, Missouri 63130, USA
e Department of Engineering, University of Cambridge, Cambridge CB2 1PZ, UK
f 1] Department of Electrical Engineering, Stanford University, Stanford, California 94305, USA
g 1] Department of Bioengineering, Stanford University, Stanford, California 94705, USA
h Stanford University School of Medicine, Stanford, California 94305, USA
i Department of Neurosurgery, Palo Alto Medical Foundation, Palo Alto, California 94301, USA
j Department of Bioengineering, Stanford University, Stanford, California 94705, USA
k Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA

Abstract
Most theories of motor cortex have assumed that neural activity represents movement parameters. This view derives from what is known about primary visual cortex, where neural activity represents patterns of light. Yet it is unclear how well the analogy between motor and visual cortex holds. Single-neuron responses in motor cortex are complex, and there is marked disagreement regarding which movement parameters are represented. A better analogy might be with other motor systems, where a common principle is rhythmic neural activity. Here we find that motor cortex responses during reaching contain a brief but strong oscillatory component, something quite unexpected for a non-periodic behaviour. Oscillation amplitude and phase followed naturally from the preparatory state, suggesting a mechanistic role for preparatory neural activity. These results demonstrate an unexpected yet surprisingly simple structure in the population response. This underlying structure explains many of the confusing features of individual neural responses.

Document Type: Article in Press
Source: Scopus

 

Postuma, R.B.a b , Arnulf, I.c , Hogl, B.d , Iranzo, A.e , Miyamoto, T.f , Dauvilliers, Y.g , Oertel, W.h , Ju, Y.-E.i , Puligheddu, M.j , Jennum, P.k , Pelletier, A.a m , Wolfson, C.l m , Leu-Semenescu, S.c , Frauscher, B.d , Miyamoto, M.n , Cochen De Cock, V.g , Unger, M.M.h , Stiasny-Kolster, K.h , Livia Fantini, M.j o , Montplaisir, J.Y.b p
A single-question screen for rapid eye movement sleep behavior disorder: A multicenter validation study
(2012) Movement Disorders, 27 (7), pp. 913-916. 


a Department of Neurology, McGill University, Montreal General Hospital, Montreal, QC, Canada
b Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada
c Unité des pathologies du sommeil, Hôpital Pitié-Salpêtrière, APHP and Inserm U975-CRICM-Pierre and Marie Curie University, Paris, France
d Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
e Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain
f Department of Neurology, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan
g Department of Neurology, Hôpital Gui de Chauliac, Montpellier, INSERM U1061, Montpellier, France
h Department of Neurology, Philipps-Universität, Marburg, Germany
i Washington University Multidisciplinary Sleep Center, St. Louis, MO, United States
j Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy
k Danish Center for Sleep Medicine, University of Copenhagen, Denmark
l Department of Epidemiology and Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada
m Research Institute of the McGill University Health Center, Montreal, QC, Canada
n Department of Neurology, Dokkyo Medical University School of Medicine, Tochigi, Japan
o Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy
p Department of Psychiatry, Université de Montréal, Montreal, QC, Canada

Abstract
Background: Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinson's disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response. Methods:: Four hundred and eighty-four sleep-clinic-based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria. Results:: We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients with other sleep diagnoses. Conclusions:: A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires. © 2012 Movement Disorder Society.

Author Keywords
Diagnosis;  REM sleep behavior disorder;  Screening

Document Type: Article
Source: Scopus

 

Rawashdeh, Y.F.a , Austin, P.b , Siggaard, C.c , Bauer, S.B.d , Franco, I.e , De Jong, T.P.f , Jorgensen, T.M.g
International children's continence society's recommendations for therapeutic intervention in congenital neuropathic bladder and bowel dysfunction in children
(2012) Neurourology and Urodynamics, 31 (5), pp. 615-620. 


a Pediatric Urology, Aarhus University Hospital, Denmark
b Pediatric Urology, St. Louis Children's Hospital, Washington University, St. Louis, MO, United States
c Pediatrics, Aarhus University Hospital, Denmark
d Pediatric Urology, Children's Hospital, Boston, MA, United States
e Pediatric Urology, New York Medical College, Valhalla, NY, United States
f Pediatric Urology, UMC Utrecht, AMC Amsterdam, Netherlands
g Pediatric Urology, Institute of Clinical Medicine, Aarhus University, Denmark

Abstract
Purpose: We present a consensus view of members of the International Children's Continence Society on the therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. Material and Methods: Discussions were held by a group of pediatric urologists and gastroenterologists appointed by the board. The following draft review document was open to all the ICCS members via the ICCS web site. Feedback was considered by the core authors and by agreement, amendments were made as necessary. The final document is not a systematic literature review. It includes relevant research when available as well as expert opinion on the current understanding of therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. Results: Guidelines on pharmalogical and surgical intervention are presented. First the multiple modalities for intervention that do not involve surgical reconstruction are summarized concerning pharmacological agents, medical devices, and neuromodulation. The non-surgical intervention is promoted before undertaking major surgery. Indicators for non-surgical treatments depend on issues related to intravesical pressure, upper urinary tract status, prevalence of urinary tract infections, and the degree of incontinence. The optimal age for treatment of incontinence is also addressed. This is followed by a survey of specific treatments such as anticholinergics, botulinum-A toxin, antibiotics, and catheters. Neuromodulation of the bladder via intravesical electrical stimulation, sacral nerve stimulation, transcutaneous stimulation, and biofeedback is scrutinized. Then follows surgical intervention, which should be tailored to each individual, based on careful consideration of urodynamic findings, medical history, age, and presence of other disability. Treatments mentioned are: urethral dilation, vesicostomy, bladder, augmentation, fascial sling, artificial urinary sphincters, and bladder neck reconstruction and are summarized with regards to success rates and complications. Finally, the treatment on neuropathic bowel dysfunction with rectal suppositories irrigation and transrectal stimulation are scrutinized. © 2012 Wiley Periodicals, Inc.

Author Keywords
Bladder;  Bowel;  Neuropathic;  Recommendations;  Theraputic intervention

Document Type: Review
Source: Scopus

 

Bauer, S.B.a , Austin, P.F.b , Rawashdeh, Y.F.c , De Jong, T.P.d , Franco, I.e , Siggard, C.f , Jorgensen, T.M.g
International Children's Continence Society's recommendations for initial diagnostic evaluation and follow-up in congenital neuropathic bladder and bowel dysfunction in children
(2012) Neurourology and Urodynamics, 31 (5), pp. 610-614. 

a Children's Hospital, Boston, MA, United States
b Pediatric Urology, St. Louis Childrens Hospital, Washington University, St. Louis, MO, United States
c Pediatric Urology, Aarhus University Hospital, Aarhus, Denmark
d Pediatric Urology, UMC Utrecht and AMC Amsterdam, Netherlands
e Pediatric Urology, New York Medical College, Valhalla, NY, United States
f Pediatrics, Aarhus University Hospital, Aarhus, Denmark
g Pediatric Urology, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark

Abstract
Purpose: The objective of this ICCS standardization document is to report the initial diagnostic evaluation and subsequent work-up of children with neuropathic bladder dysfunction. Materials and Methods: Due to a paucity of level I or level II, "levels of evidence" publications, these recommendations are actually a compilation of best practices because they seem to be effective and reliable, although not with any control. Results: Throughout the document, the emphasis is on promoting early, comprehensive evaluation of lower urinary tract function that is thorough but with a minimum of unnecessary testing. This includes what tests to order, when to order them and what to do with the results. Some of the recommendations may not be practical in various worldwide locations but the suggested testing should be considered the ideal approach to completely diagnosing and then promulgating treatments based on the full knowledge of the condition and its effect on urinary tract function. Once the findings are delineated, those lower urinary tract patterns of dysfunction that put the kidneys at risk for deterioration, that are barriers to attaining eventual continence, and that have long-term consequence to the lower urinary track can be obviated by specific management recommendations. The indications and timing of investigations to achieve these objectives are clearly defined in each diagnostic category and during follow-up. Recommendations: This document should be used as a basis for appropriate evaluation and timely surveillance of the various neuro-urologic conditions that affect children. © 2012 Wiley Periodicals, Inc.

Author Keywords
Bladder;  Bowel;  Children;  Evaluation;  Neuropathic

Document Type: Review
Source: Scopus

 

Macauley, S.L.a , Roberts, M.S.a , Wong, A.M.b , McSloy, F.b , Reddy, A.S.a , Cooper, J.D.b , Sands, M.S.a c
Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis
(2012) Annals of Neurology, 71 (6), pp. 797-804. 


a Washington University School of Medicine, Department of Internal Medicine, Campus Box 8007, 660 S. Euclid Ave., St Louis, MO 63110, United States
b Department of Neuroscience, Institute of Psychiatry, King's College London, London, United Kingdom
c Department of Genetics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Objective: Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited childhood neurodegenerative disorder caused by the loss of palmitoyl protein thioesterase-1 (PPT1) activity. Affected children suffer from blindness, epilepsy, motor dysfunction, cognitive decline, and premature death. The Ppt1 -/- mouse shares the histological and clinical features of INCL. Previous single-therapy approaches using small molecule drugs, gene therapy, or neuronal stem cells resulted in partial histological correction, with minimal improvements in motor function or lifespan. Here, we combined central nervous system (CNS)-directed adeno-associated virus (AAV)2/5-mediated gene therapy with bone marrow transplantation (BMT) in the INCL mouse. Methods: At birth, Ppt1 -/- and wild-type mice were given either intracranial injections of AAV2/5-PPT1 or bone marrow transplantation, separately as well as in combination. To assess function, we measured rotorod performance monthly as well as lifespan. At terminal time points, we evaluated the therapeutic effects on several INCL-specific parameters, such as cortical thickness, autofluorescent accumulation, and glial activation. Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment in treated mice. Results: AAV2/5-mediated gene therapy alone resulted in significant histological correction, improved motor function, and increased lifespan. Interestingly, the addition of BMT further increased the lifespan of treated mice and led to dramatic, sustained improvements in motor function. These data are truly striking, given that BMT alone is ineffective, yet it synergizes with CNS-directed gene therapy to dramatically increase efficacy and lifespan. Interpretation: AAV2/5-mediated gene therapy in combination with BMT provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters. © 2012 American Neurological Association.

Document Type: Article
Source: Scopus

 

Hassenstab, J.J.a b f , Sweet, L.H.a c , Del Parigi, A.d , McCaffery, J.M.a f , Haley, A.P.e , Demos, K.E.a f , Cohen, R.A.a f , Wing, R.R.a f
Cortical thickness of the cognitive control network in obesity and successful weight loss maintenance: A preliminary MRI study
(2012) Psychiatry Research - Neuroimaging, 202 (1), pp. 77-79. 


a The Miriam Hospital, Providence, RI, United States
b Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States
c Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
d Butler Hospital, Providence, RI, United States
e Medical Affairs, Pfizer, Inc., New York, NY, United States
f Department of Psychology, The University of Texas at Austin, Austin, TX, United States

Abstract
Cortical thickness of the cognitive control network was contrasted between obese (OB), successful weight loss maintainers (SWLM), and lean individuals. OB individuals had significant thinning, most notably in the anterior cingulate and posterior parietal cortices. SWLM individuals exhibited trends towards thicker cortex than OB individuals, which may be important in future studies. © 2011 Elsevier Ireland Ltd.

Author Keywords
Freesurfer;  Magnetic resonance imaging;  Obese

Document Type: Article
Source: Scopus

 

Bryda, E.C.a , Johnson, N.T.a , Ohlemiller, K.K.b , Besch-Williford, C.L.a , Moore, E.a , Bram, R.J.c
Conditional deletion of calcium-modulating cyclophilin ligand causes deafness in mice
(2012) Mammalian Genome, 23 (3-4), pp. 270-276. 


a Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, 4011 Discovery Drive, Columbia, MO 65201, United States
b Department of Otolaryngology, Washington University, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States

Abstract
Calcium-modulating cyclophilin ligand (Caml) is a ubiquitously expressed cytoplasmic protein that is involved in multiple signaling and developmental pathways. An observation in our laboratory of a protein-protein interaction between Caml and the cytoplasmic region of Cadherin23 led us to speculate that Caml might be important in the inner ear and play a role in the development and/or function of hair cells. To address this question, we generated a mouse line in which Caml expression was eliminated in Atoh1-expressing cells of the inner ear upon administration of tamoxifen. Tamoxifen was administered immediately after birth to neonates to assess the effect of loss of Caml in the inner ear during postnatal development. Hearing in treated animals was tested by auditory brain stem response (ABR) analysis and cochlear pathology was evaluated by light microscopy. Lack of Caml expression in the inner ear leads to severe loss of cochlear hair cells and complete deafness. Elucidating the role of Caml in the inner ear will aid our understanding of the molecular pathways important for auditory development and function. © Springer Science+Business Media, LLC 2011.

Document Type: Article
Source: Scopus

 

Cramer, P.E.a , Cirrito, J.R.b , Wesson, D.W.a c , Lee, C.Y.D.a , Karlo, J.C.a , Zinn, A.E.a , Casali, B.T.a , Restivo, J.L.b , Goebel, W.D.b , James, M.J.d , Brunden, K.R.d , Wilson, D.A.c , Landreth, G.E.a
ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models
(2012) Science, 335 (6075), pp. 1503-1506. 


a Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States
b Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
c Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, New York University School of Medicine, Orangeburg, NY 10962, United States
d Center of Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

Document Type: Article
Source: Scopus

 

Zhang, B., Wong, M.
Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat
(2012) Epilepsia, 53 (3), pp. 506-511. 


Department of Neurology, School of Medicine, Washington University, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Purpose: The mammalian target of rapamycin (mTOR) pathway has been implicated in contributing to progressive epileptogenesis in models of chronic epilepsy. Conversely, seizures themselves may directly cause acute activation of the mTOR pathway. To isolate the direct effects of seizures on the mTOR pathway, the time course and mechanisms of mTOR activation were investigated with acute seizures induced by pentylenetetrazole (PTZ), which does not lead to chronic epilepsy. Methods: Western blot analysis was used to assay the phosphorylation of Akt and S6, as measures of activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR pathways, respectively, at various time points after PTZ-induced seizures in rats. The ability of wortmannin, a PI3K inhibitor, to inhibit PTZ seizure-induced activation of the mTOR pathway was tested. Key Findings: PTZ-induced seizures produced an immediate, transient mTOR activation lasting several hours, but no later, more chronic activation over days to weeks. This acute stimulation of the mTOR pathway by PTZ-induced seizures was mediated by upstream PI3K/Akt pathway activation and was blocked by a PI3K inhibitor. Significance: Compared with models of chronic epilepsy that exhibit biphasic (acute and chronic) mTOR pathway activation, PTZ-induced seizures produce only acute, but not chronic, mTOR activation. These results in the PTZ seizure model highlight potential differences in the involvement of the mTOR pathway between self-limited seizures and progressive epileptogenesis. These findings also suggest a potential therapeutic role of PI3K inhibitors in epilepsy. © 2012 International League Against Epilepsy.

Author Keywords
Epilepsy;  Kainate;  Pentylenetetrazole;  Rapamycin;  Rat;  Seizure

Document Type: Article
Source: Scopus

 

Wu, G.a , Broniscer, A.b , McEachron, T.A.c , Lu, C.d , Paugh, B.S.c , Becksfort, J.e , Qu, C.e , Ding, L.d , Huether, R.a , Parker, M.a , Zhang, J.c , Gajjar, A.b , Dyer, M.A.c , Mullighan, C.G.f , Gilbertson, R.J.c , Mardis, E.R.d , Wilson, R.K.d , Downing, J.R.f , Ellison, D.W.f , Zhang, J.a , Baker, S.J.c
Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas
(2012) Nature Genetics, 44 (3), pp. 251-253. 


a Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, United States
b Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States
c Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, United States
d Genome Institute, Washington University, School of Medicine, Saint Louis, MI, United States
e Hartwell Center of Biotechnology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, United States
f Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States

Abstract
To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration. © 2012 Nature America, Inc. All rights reserved.

Document Type: Article
Source: Scopus

 

Zhang, J.a , Benavente, C.A.b , McEvoy, J.b , Flores-Otero, J.b , Ding, L.c d , Chen, X.a , Ulyanov, A.a , Wu, G.a , Wilson, M.e f , Wang, J.g , Brennan, R.b , Rusch, M.a , Manning, A.L.h , Ma, J.i , Easton, J.a , Shurtleff, S.i , Mullighan, C.i , Pounds, S.j , Mukatira, S.g , Gupta, P.g , Neale, G.g , Zhao, D.k , Lu, C.c , Fulton, R.S.c d , Fulton, L.L.c d , Hong, X.c d , Dooling, D.J.c d , Ochoa, K.c d , Naeve, C.k , Dyson, N.J.h , Mardis, E.R.c d l , Bahrami, A.i , Ellison, D.i , Wilson, R.K.c d m , Downing, J.R.i , Dyer, M.A.b e n
A novel retinoblastoma therapy from genomic and epigenetic analyses
(2012) Nature, 481 (7381), pp. 329-334. 

a Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, TN 38105, United States
b Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, United States
c Genome Institute, Washington University School of Medicine in St Louis, St Louis, MO 63108, United States
d Department of Genetics, Washington University, School of Medicine in St Louis, St Louis, MO 63108, United States
e Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, United States
f Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, United States
g Hartwell Center for Biotechnology and Bioinformatics, St Jude Children's Research Hospital, Memphis, TN 38105, United States
h Massachusetts General Hospital, Charlestown, MA 02129, United States
i Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, United States
j Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, United States
k Department of Information Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, United States
l Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, MO 63108, United States
m Department of Medicine, Washington University School of Medicine in St Louis, St Louis, MO 63108, United States
n Howard Hughes Medical Institute, Chevy Chase, MD 20815, United States

Abstract
Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss. © 2012 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus