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WUSTL Neuroscience Publications Archive - September 2012

Scopus Weekly Report:

September 26, 2012

September 19, 2012

September 12, 2012

September 5, 2012

 

September 26, 2012

Babajani-Feremi, A.a , Gumenyuk, V.b , Roth, T.b , Drake, C.L.b , Soltanian-Zadeh, H.c d
Connectivity analysis of novelty process in habitual short sleepers
(2012) NeuroImage, 63 (3), pp. 1001-1010. Article in Press. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA
b Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, MI, USA
c CIPCE, School of Elec. and Comp. Eng., University of Tehran, Tehran, Iran
d Image Analysis Lab., Radiology Department, Henry Ford Hospital, Detroit, MI, USA

Abstract
Neurophysiological processes underlying auditory memory and attention are impaired in habitually short sleepers. The aim of this study was to use dynamic causal modeling (DCM) to study the mechanisms of these impairments in short sleepers. Eight normal sleepers (total sleep time (TST). =. 7-8. h) and nine habitual short sleepers (TST. ≤. 6. h) participated. The time in bed was increased from habitual (≤. 6. h) to extended (~. 8.5. h) for one week in the short sleep group. Event related potentials (ERPs) were collected using an auditory novelty task in "IGNORE" and "ATTEND" conditions. Fourteen DCM models were considered using different configurations of connections among the following six areas: left and right primary auditory cortices, superior temporal gyri (STG), and inferior temporal gyri (IFG). After fitting the ERPs to the 14 models (separately for the IGNORE and ATTEND conditions), the best model (across subjects) was chosen using the Bayesian model comparison. For both conditions, the connection from right-STG to right-IFG for normal sleepers was significantly greater than habitual short sleepers. This connection did not differ in habitual short sleepers before and after one week of extended sleep time. This connection for normal sleepers was not significantly greater than the habitual short sleepers after one week of extended sleep. These results show that the deficiency of novelty processing, seen in short sleepers, can be explained by the differences in connectivity of the pathway between frontal and temporal brain areas as compared to the normal sleepers. In addition, one week of extended time in bed was not enough to fully normalize this neuronal pathway between STG and IFG in short sleepers. © 2012 Elsevier Inc.

Author Keywords
Auditory oddball;  Dynamic causal modelling (DCM);  Electroencephalography (EEG);  Short sleepers

Document Type: Article in Press
Source: Scopus

 

Mantini, D.a b c , Corbetta, M.b c d e , Romani, G.L.b c , Orban, G.A.a f , Vanduffel, W.a g h
Data-driven analysis of analogous brain networks in monkeys and humans during natural vision
(2012) NeuroImage, 63 (3), pp. 1107-1118. Article in Press. 

a Laboratory of Neuro- and Psychophysiology, KU Leuven Medical School, Leuven, Belgium
b Department of Neuroscience and Imaging, G. D'Annunzio University, Chieti, Italy
c Institute for Advanced Biomedical Technology, D'Annunzio University Foundation, Chieti, Italy
d Department of Neurology, Washington University, St. Louis, MO, USA
e Department of Radiology, Washington University, St. Louis, MO, USA
f Department of Neuroscience, University of Parma Medical School, Parma, Italy
g Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA
h Department of Radiology, Harvard Medical School, Boston, MA, USA

Abstract
Inferences about functional correspondences between functional networks of human and non-human primates largely rely on proximity and anatomical expansion models. However, it has been demonstrated that topologically correspondent areas in two species can have different functional properties, suggesting that anatomy-based approaches should be complemented with alternative methods to perform functional comparisons. We have recently shown that comparative analyses based on temporal correlations of sensory-driven fMRI responses can reveal functional correspondent areas in monkeys and humans without relying on spatial assumptions. Inter-species activity correlation (ISAC) analyses require the definition of seed areas in one species to reveal functional correspondences across the cortex of the same and other species. Here we propose an extension of the ISAC method that does not rely on any seed definition, hence a method void of any spatial assumption. Specifically, we apply independent component analysis (ICA) separately to monkey and human data to define species-specific networks of areas with coherent stimulus-related activity. Then, we use a hierarchical cluster analysis to identify ICA-based ISAC clusters of monkey and human networks with similar timecourses. We implemented this approach on fMRI data collected in monkeys and humans during movie watching, a condition that evokes widespread sensory-driven activity throughout large portions of the cortex. Using ICA-based ISAC, we detected seven monkey-human clusters. The timecourses of several clusters showed significant correspondences either with the motion energy in the movie or with eye-movement parameters. Five of the clusters spanned putative homologous functional networks in either primary or extrastriate visual regions, whereas two clusters included higher-level visual areas at topological locations that are not predicted by cortical surface expansion models. Overall, our ICA-based ISAC analysis complemented the findings of our previous seed-based investigations, and suggested that functional processes can be executed by brain networks in different species that are functionally but not necessarily anatomically correspondent. Overall, our method provides a novel approach to reveal evolution-driven functional changes in the primate brain with no spatial assumptions. © 2012 Elsevier Inc.

Author Keywords
Cluster analysis;  Evolution;  Functional correspondence;  Functional magnetic resonance imaging;  Independent component analysis;  Primate brain

Document Type: Article in Press
Source: Scopus

 

Power, J.D.a , Barnes, K.A.a , Snyder, A.Z.a b , Schlaggar, B.L.a b c d , Petersen, S.E.a b d e
Corrigendum to "Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion" [NeuroImage 59 (3) (2012) 2142-2154]
(2012) NeuroImage, 63 (2), p. 999. 

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

Document Type: Erratum
Source: Scopus

 

Anticevic, A.a b c , Repovs, G.d , Krystal, J.H.a b c , Barch, D.M.e
A broken filter: Prefrontal functional connectivity abnormalities in schizophrenia during working memory interference
(2012) Schizophrenia Research, 141 (1), pp. 8-14. 

a Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, United States
b NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT 06519, United States
c Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, United States
d Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
e Departments of Psychology, Psychiatry and Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Characterizing working memory (WM) abnormalities represents a fundamental challenge in schizophrenia research given the impact of cognitive deficits on life outcome in patients. In prior work we demonstrated that dorsolateral prefrontal cortex (DLPFC) activation was related to successful distracter resistance during WM in healthy controls, but not in schizophrenia. Although understanding the impact of regional functional deficits is critical, functional connectivity abnormalities among nodes within WM networks may constitute a final common pathway for WM impairment. Therefore, this study tested the hypothesis that schizophrenia is associated with functional connectivity abnormalities within DLPFC networks during distraction conditions in WM. 28 patients and 24 controls completed a delayed non-verbal WM task that included transient visual distraction during the WM maintenance phase. We computed DLPFC whole-brain task-based functional connectivity (tb-fcMRI) specifically during the maintenance phase in the presence or absence of distraction. Results revealed that patients failed to modulate tb-fcMRI during distracter presentation in both cortical and sub-cortical regions. Specifically, controls demonstrated reductions in tb-fcMRI between DLPFC and the extended amygdala when distraction was present. Conversely, patients failed to demonstrate a change in coupling with the amygdala, but showed greater connectivity with medio-dorsal thalamus. While controls showed more positive coupling between DLPFC and other prefrontal cortical regions during distracter presentation, patients failed to exhibit such a modulation. Taken together, these findings support the notion that observed distracter resistance deficit involves a breakdown in coupling between DLPFC and distributed regions, encompassing both subcortical (thalamic/limbic) and control region connectivity. © 2012.

Author Keywords
Distraction;  DLPFC, amygdala, thalamus;  FMRI;  Functional connectivity;  Schizophrenia;  Working memory

Document Type: Article
Source: Scopus

 

Van Essen, D.C., Glasser, M.F., Dierker, D.L., Harwell, J.
Cortical parcellations of the macaque monkey analyzed on surface-based atlases
(2012) Cerebral Cortex, 22 (10), pp. 2227-2240. 

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Surface-based atlases provide a valuable way to analyze and visualize the functional organization of cerebral cortex. Surface-based registration (SBR) is a primary method for aligning individual hemispheres to a surface-based atlas. We used landmark-constrained SBR to register many published parcellation schemes to the macaque F99 surface-based atlas. This enables objective comparison of both similarities and differences across parcellations. Cortical areas in the macaque vary in surface area by more than 2 orders of magnitude. Based on a composite parcellation derived from 3 major sources, the total number of macaque neocortical and transitional cortical areas is estimated to be about 130-140 in each hemisphere. © The Author 2011. Published by Oxford University Press. All rights reserved.

Author Keywords
architectonic;  areas;  maps;  registration;  retinotopy

Document Type: Article
Source: Scopus

 

Behrens, M.I.a b c , Silva, M.b , Salech, F.d , Ponce, D.P.d , Merino, D.e , Sinning, M.a c , Xiong, C.f g , Roe, C.M.f h , Quest, A.F.G.b d
Inverse susceptibility to oxidative death of lymphocytes obtained from Alzheimer's patients and skin cancer survivors: Increased apoptosis in Alzheimer's and reduced necrosis in cancer
(2012) Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 67 A (10), pp. 1036-1040. 

a Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santos Dumont 999, Independencia, Santiago, Chile
b Centro de Estudios Moleculares de la Célula (CEMC), Universidad de Chile, Santiago, Chile
c Clínica Alemana de Santiago, Chile
d Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
e Departamento de Dermatología, Hospital Clínico Universidad de Chile, Santiago, Chile
f Department of Neurology, Chile
g Division of Biostatistics, Chile
h Charles F. and Joanne Knight Alzheimer's Disease Center, Washington University School of Medicine, St Louis, MO, United States

Abstract
A paucity of cancer in individuals with Alzheimer's disease (AD) and low rates of AD in cancer survivors has been reported in epidemiological studies. Deregulation in opposite directions of biological mechanisms, such as susceptibility to cell death, might be shared in the two disorders. We analyzed lymphocytes from AD and skin cancer patients as well as healthy controls and found significantly increased vulnerability of AD lymphocytes to H2O2-induced apoptotic death and higher resistance to death of skin cancer lymphocytes, due to reduced necrosis, as compared with healthy controls by pairwise comparisons adjusted for age and sex. H2O2-induced death in lymphocytes was caspase independent and significantly reduced by PARP-1 inhibition in all three groups. These differences in the susceptibility to cell death observed for lymphocytes from AD and skin cancer patients may be one of the mechanisms that help explain the inverse correlation detected between these diseases in epidemiological studies. © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Author Keywords
Alzheimer;  Apoptosis;  Cancer;  Cell death;  Necrosis

Document Type: Article
Source: Scopus

 

Van Essen, D.C., Glasser, M.F., Dierker, D.L., Harwell, J., Coalson, T.
Parcellations and hemispheric asymmetries of human cerebral cortex analyzed on surface-based atlases
(2012) Cerebral Cortex, 22 (10), pp. 2241-2262. 

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
We report on surface-based analyses that enhance our understanding of human cortical organization, including its convolutions and its parcellation into many distinct areas. The surface area of human neocortex averages 973 cm 2 per hemisphere, based on cortical midthickness surfaces of 2 cohorts of subjects. We implemented a method to register individual subjects to a hybrid version of the FreeSurfer "fsaverage" atlas whose left and right hemispheres are in precise geographic correspondence. Cortical folding patterns in the resultant population-average "fs-LR" midthickness surfaces are remarkably similar in the left and right hemispheres, even in regions showing significant asymmetry in 3D position. Both hemispheres are equal in average surface area, but hotspots of surface area asymmetry are present in the Sylvian Fissure and elsewhere, together with a broad pattern of asymmetries that are significant though small in magnitude. Multiple cortical parcellation schemes registered to the human atlas provide valuable reference data sets for comparisons with other studies. Identified cortical areas vary in size by more than 2 orders of magnitude. The total number of human neocortical areas is estimated to be
150 to 200 areas per hemisphere, which is modestly larger than a recent estimate for the macaque. © The Author 2011. Published by Oxford University Press. All rights reserved.

Author Keywords
architectonic;  areas;  maps;  registration;  retinotopy

Document Type: Article
Source: Scopus

 

Fehr, J.J.a , Honkanen, A.b , Murray, D.J.a
Simulation in pediatric anesthesiology
(2012) Paediatric Anaesthesia, 22 (10), pp. 988-994. 

a Department of Anesthesiology and Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, One Children's Place, 5S31, St Louis, MO 63110, United States
b Department of Anesthesiology, Stanford University, School of Medicine, Palo Alto, CA, United States

Abstract
Summary Simulation-based training, research and quality initiatives are expanding in pediatric anesthesiology just as in other medical specialties. Various modalities are available, from task trainers to standardized patients, and from computer-based simulations to mannequins. Computer-controlled mannequins can simulate pediatric vital signs with reasonable reliability; however the fidelity of skin temperature and color change, airway reflexes and breath and heart sounds remains rudimentary. Current pediatric mannequins are utilized in simulation centers, throughout hospitals in-situ, at national meetings for continuing medical education and in research into individual and team performance. Ongoing efforts by pediatric anesthesiologists dedicated to using simulation to improve patient care and educational delivery will result in further dissemination of this technology. Health care professionals who provide complex, subspecialty care to children require a curriculum supported by an active learning environment where skills directly relevant to pediatric care can be developed. The approach is not only the most effective method to educate adult learners, but meets calls for education reform and offers the potential to guide efforts toward evaluating competence. Simulation addresses patient safety imperatives by providing a method for trainees to develop skills and experience in various management strategies, without risk to the health and life of a child. A curriculum that provides pediatric anesthesiologists with the range of skills required in clinical practice settings must include a relatively broad range of task-training devises and electromechanical mannequins. Challenges remain in defining the best integration of this modality into training and clinical practice to meet the needs of pediatric patients. © 2012 Blackwell Publishing Ltd.

Author Keywords
education;  outcomes;  quality improvement;  simulation

Document Type: Review
Source: Scopus

 

Pollio, D.E.a , North, C.S.b , Hudson, A.M.a , Hong, B.A.c
A Comparison of Enrollees Versus Non-enrollees in a Patient/Family HCV Psychoeducation Study

(2012) Journal of Clinical Psychology in Medical Settings, pp. 1-8. Article in Press. 

a School of Social Work, University of Alabama, Box 870314, Tuscaloosa, 35487-0314, United States
b The VA North Texas Health Care System, Departments of Psychiatry and Surgery/Division of Emergency M, Dallas, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, United States

Abstract
Despite the seriousness of Hepatitis C (HCV), many patients do not receive treatment. One promising means of addressing these issues for medically ill patients is through participation in support group services. This study examined individual-, treatment- and system-level factors associated with enrolling in a support group intervention (psychoeducation) for persons with HCV. A total of 235 research participants were recruited as part of a NIAAA-funded randomized clinical trial for patients with HCV and their family members, with 172 (73.2 %) agreeing to enroll in the psychoeducation trial and 63 (26.8 %) declining. Factors leading to enrollment indicated that individuals without employment, with certain personality structures (low cooperativeness and self-directedness), and traveling greater distance to their group were more likely to agree to participate. Populations being seen in public settings demonstrate a desire for additional support and education, but at the same time these potential participants are faced with challenges to following through and enrolling in the desired services. © 2012 Springer Science+Business Media, LLC.

Author Keywords
Addiction;  Enrollment;  Group;  HCV;  Psychoeducation

Document Type: Article in Press
Source: Scopus

 

Racette, B.A.a , Criswell, S.R.a , Lundin, J.I.b , Hobson, A.a , Seixas, N.b , Kotzbauer, P.T.a , Evanoff, B.A.c , Perlmutter, J.S.a e , Zhang, J.d , Sheppard, L.f , Checkoway, H.b
Increased risk of parkinsonism associated with welding exposure
(2012) NeuroToxicology, . Article in Press. 

a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, USA
b Department of Environmental and Occupational Health Sciences, University of Washington, Box 357234, Seattle, WA 98195, USA
c Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Box 8005, St. Louis, MO 63110, USA
d Department of Pathology, University of Washington School of Medicine, 325 9th Ave., Box 359794, Seattle, WA 98104, USA
e Departments of Radiology, Neurobiology, Physical Therapy, and Occupational Therapy, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, USA
f Department of Biostatistics, University of Washington, F-600, Health Sciences Building, 1705 NE Pacific St., Seattle, WA 98195, USA

Abstract
Objective: Manganese (Mn), an established neurotoxicant, is a common component of welding fume. The neurological phenotype associated with welding exposures has not been well described. Prior epidemiologic evidence linking occupational welding to parkinsonism is mixed, and remains controversial. Methods: This was a cross-sectional and nested case-control study to investigate the prevalence and phenotype of parkinsonism among 811 shipyard and fabrication welders recruited from trade unions. Two reference groups included 59 non-welder trade workers and 118 newly diagnosed, untreated idiopathic PD patients. Study subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism cases were defined as welders with UPDRS3 score ≥15. Normal was defined as UPDRS3 < 6. Exposure was classified as intensity adjusted, cumulative years of welding. Adjusted prevalence ratios for parkinsonism were calculated in relation to quartiles of welding years. Results: The overall prevalence estimate of parkinsonism was 15.6% in welding exposed workers compared to 0% in the reference group. Among welders, we observed a U-shaped dose-response relation between weighted welding exposure-years and parkinsonism. UPDRS3 scores for most domains were similar between welders and newly diagnosed idiopathic Parkinson disease (PD) patients, except for greater frequency of rest tremor and asymmetry in PD patients. Conclusion: This work-site based study among welders demonstrates a high prevalence of parkinsonism compared to nonwelding-exposed workers and a clinical phenotype that overlaps substantially with PD. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Manganese;  Occupational exposures;  Parkinson disease;  Parkinsonism;  Welding

Document Type: Article in Press
Source: Scopus

 

Hintsanen, M.a b , Jokela, M.b , Cloninger, C.R.c , Pulkki-Råback, L.b , Hintsa, T.b , Elovainio, M.d , Josefsson, K.b , Rosenström, T.b , Mullola, S.e , Raitakari, O.T.f g , Keltikangas-Järvinen, L.b
Temperament and character predict body-mass index: A population-based prospective cohort study
(2012) Journal of Psychosomatic Research, . Article in Press. 

a Helsinki Collegium for Advanced Studies, University of Helsinki, Finland
b IBS, Unit of Personality Work and Organizational Psychology, University of Helsinki, Finland
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
d National Institute for Health and Welfare, Helsinki, Finland
e Center for Research on Teaching, Department of Teacher Education, University of Helsinki, Finland
f Department of Clinical Physiology, Turku University Hospital, Finland
g Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland

Abstract
Objective: Personality is a potential factor determining individual differences in body-weight change. The current study examines associations between personality traits and change in body-mass index (BMI) over six years. Method: The participants were 762 women and 648 men aged 24-39 years at the base-line. Personality was assessed with the Temperament and Character Inventory (TCI). For calculating BMI, height and weight were assessed at a clinic. Results: Longitudinal analyses conducted with linear regressions showed that in men and women, higher Novelty seeking predicted higher BMI (p < .05), whereas lower Reward dependence predicted higher BMI in women (p < .05) when baseline BMI was taken into account. In addition, cross-sectional associations for several TCI traits were found in age and education adjusted analyses. In women, higher Self transcendence (p < .05) was associated with higher BMI. In men, higher Novelty seeking (p < .001) and Self transcendence (p < .01) and lower Self directedness (p < .01) and Cooperativeness (p < .05) were associated with higher BMI. In addition, analyses of variance were conducted for multidimensional trait profiles (trait combinations). Significant temperament profile related differences in BMI were found in all analyses in women. Associations with character profiles and in men were less consistent. Conclusion: The results give support for personality playing a role in weight gain. Knowledge on personality may be used for motivating weight loss and designing weight management interventions. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Body-mass index;  Character;  Multidimensional personality profiles;  Over-weight;  Personality;  Temperament

Document Type: Article in Press
Source: Scopus

 

Olfson, E.a , Bierut, L.J.b
Convergence of Genome-Wide Association and Candidate Gene Studies for Alcoholism
(2012) Alcoholism: Clinical and Experimental Research, . Article in Press. 

a Department of Human and Statistical Genetics Washington University School of Medicine St. Louis, Missouri
b Department of Psychiatry Washington University School of Medicine St. Louis, Missouri

Abstract
Background: Genome-wide association (GWA) studies have led to a paradigm shift in how researchers study the genetics underlying disease. Many GWA studies are now publicly available and can be used to examine whether or not previously proposed candidate genes are supported by GWA data. This approach is particularly important for the field of alcoholism because the contribution of many candidate genes remains controversial. Methods: Using the Human Genome Epidemiology (HuGE) Navigator, we selected candidate genes for alcoholism that have been frequently examined in scientific articles in the past decade. Specific candidate loci as well as all the reported single nucleotide polymorphisms (SNPs) in candidate genes were examined in the Study of Addiction: Genetics and Environment (SAGE), a GWA study comparing alcohol-dependent and nondependent subjects. Results: Several commonly reported candidate loci, including rs1800497 in DRD2, rs698 in ADH1C, rs1799971 in OPRM1, and rs4680 in COMT, are not replicated in SAGE (p > 0.05). Among candidate loci available for analysis, only rs279858 in GABRA2 (p = 0.0052, OR = 1.16) demonstrated a modest association. Examination of all SNPs reported in SAGE in over 50 candidate genes revealed no SNPs with large frequency differences between cases and controls, and the lowest p-value of any SNP was 0.0006. Conclusions: We provide evidence that several extensively studied candidate loci do not have a strong contribution to risk of developing alcohol dependence in European and African ancestry populations. Owing to the lack of coverage, we were unable to rule out the contribution of other variants, and these genes and particular loci warrant further investigation. Our analysis demonstrates that publicly available GWA results can be used to better understand which if any of previously proposed candidate genes contribute to disease. Furthermore, we illustrate how examining the convergence of candidate gene and GWA studies can help elucidate the genetic architecture of alcoholism and more generally complex diseases. © 2012 by the Research Society on Alcoholism.

Author Keywords
Alcohol Dependence;  Candidate Genes;  Genetics;  Genome-Wide Association Studies

Document Type: Article in Press
Source: Scopus

 

Baldo, G.a e , Wozniak, D.F.b , Ohlemiller, K.K.c , Zhang, Y.a , Giugliani, R.e , Ponder, K.P.a d
Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits
(2012) Journal of Inherited Metabolic Disease, pp. 1-14. Article in Press. 

a Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, United States
c Department of Otolaryngology, Washington University School of Medicine, St. Louis, United States
d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, United States
e Gene Therapy Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil

Abstract
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to α-L-iduronidase (IDUA) deficiency that results in the accumulation of glycosaminoglycans (GAG). Systemic gene therapy to MPS I mice can reduce lysosomal storage in the brain, but few data are available regarding the effect upon behavioral function. We investigated the effect of gene therapy with a long-terminal-repeat (LTR)-intact retroviral vector or a self-inactivating (SIN) vector on behavioral function in MPS I mice. The LTR vector was injected intravenously to 6-week-old MPS I mice, and the SIN vector was given to neonatal or 6-week-old mice. Adult-LTR, neonatal-SIN, and adult-SIN-treated mice achieved serum IDUA activity of 235 ± 20 (84-fold normal), 127 ± 10, and 71 ± 7 U/ml, respectively. All groups had reduction in histochemical evidence of lysosomal storage in the brain, with the adult-LTR group showing the best response, while adult-LTR mice had reductions in lysosomal storage in the cristae of the vestibular system. Behavioral evaluation was performed at 8 months. Untreated MPS I mice had a markedly reduced ability to hold onto an inverted screen or climb down a pole. LTR-vector-treated mice had marked improvements on both of these tests, whereas neonatal-SIN mice showed improvement in the pole test. We conclude that both vectors can reduce brain disease in MPS I mice, with the LTR vector achieving higher serum IDUA levels and better correction. Vestibular abnormalities may contribute to mobility problems in patients with MPS I, and gene therapy may reduce symptoms. © 2012 SSIEM and Springer.

Document Type: Article in Press
Source: Scopus

 

Fonseca, S.G.a , Urano, F.b , Weir, G.C.c , Gromada, J.a , Burcin, M.a
Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion
(2012) Nature Cell Biology, . Article in Press. 

a Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA
b Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
c Islet Biology and Regenerative Medicine, Joslin Diabetes Center, Boston, Massachusetts 02215, USA

Abstract
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.

Document Type: Article in Press
Source: Scopus

 

Sun, X.a b c , Zaydman, M.A.a b c , Cui, J.a b c
Regulation of voltage-activated K + channel gating by transmembrane β subunits
(2012) Frontiers in Pharmacology, 3 APR, art. no. Article 63, . 
a Department of Biomedical Engineering, Washington University, Saint Louis, MO, United States
b Center for the Investigation of Membrane Excitability Disorders, Washington University, Saint Louis, MO, United States
c Cardiac Bioelectricity and Arrhythmia Center, Washington University, Saint Louis, MO, United States

Abstract
Voltage-activated K + (K V) channels are important for shaping action potentials and maintaining resting membrane potential in excitable cells. K V channels contain a central pore-gate domain (PGD) surrounded by four voltage-sensing domains (VSDs). The VSDs will change conformation in response to alterations of the membrane potential thereby inducing the opening of the PGD. Many K V channels are heteromeric protein complexes containing auxiliary β subunits. These β subunits modulate channel expression and activity to increase functional diversity and render tissue specific phenotypes.This review focuses on the K V β subunits that contain transmembrane (TM) segments including the KCNE family and the β subunits of large conductance, Ca 2+- and voltage-activated K + (BK) channels. These TM β subunits affect the voltage-dependent activation of K V α subunits. Experimental and computational studies have described the structural location of these β subunits in the channel complexes and the biophysical effects on VSD activation, PGD opening, and VSD-PGD coupling.These results reveal some common characteristics and mechanistic insights into K V channel modulation by TM β subunits. © 2012 Sun, Zaydman and Cui.

Author Keywords
β subunit;  BK;  Channel;  K V KCNQ1;  KCNE;  KCNMB;  LRRC

Document Type: Article
Source: Scopus

 

Dikranian, K.a d , Kim, J.b d e , Stewart, F.R.b d e , Levy, M.A.c , Holtzman, D.M.b d e
Ultrastructural studies in APP/PS1 mice expressing human apoe isoforms: Implications for Alzheimer's disease

(2012) International Journal of Clinical and Experimental Pathology, 5 (6), pp. 482-495. 

a Department of Anatomy and Neurobiology, Washington University, Saint Louis, United States
b Department of Neurology, Washington University, Saint Louis, United States
c Department of Cell Biology and Physiology, Washington University, Saint Louis, United States
d Hope Center for Neurological Disorders, Washington University, Saint Louis, United States
e Knight Alzheimer's Disease Research Center, Washington University, Saint Louis, United States

Abstract
Alzheimer's disease is characterized in part by extracellular aggregation of the amyloid-β peptide in the form of diffuse and fibrillar plaques in the brain. Electron microscopy (EM) has made an important contribution in understanding of the structure of amyloid plaques in humans. Classical EM studies have revealed the architecture of the fibrillar core, characterized the progression of neuritic changes, and have identified the neurofibrillary tangles formed by paired helical filaments (PHF) in degenerating neurons. Clinical data has strongly correlated cognitive impairment in AD with the substantial synapse loss observed in these early ultrastructural studies. Animal models of AD-type brain amyloidosis have provided excellent opportunities to study amyloid and neuritic pathology in detail and establish the role of neurons and glia in plaque formation. Transgenic mice overexpressing mutant amyloid precursor protein (APP) alone with or without mutant presenilin 1 (PS1), have shown that brain amyloid plaque development and structure grossly recapitulate classical findings in humans. Transgenic APP/PS1 mice expressing human apolioprotein E isoforms also develop amyloid plaque deposition. However no ultrastructural data has been reported for these animals. Here we show results from detailed EM analysis of amyloid plaques in APP/PS1 mice expressing human isoforms of ApoE and compare these findings with EM data in other transgenic models and in human AD. Our results show that similar to other transgenic animals, APP/PS1 mice expressing human ApoE isoforms share all major cellular and subcellular degenerative features and highlight the identity of the cellular elements involved in Aβ deposition and neuronal degeneration.

Author Keywords
Alzheimer's disease;  Amyloid precursor protein;  APoE;  Electron microscopy;  Presenilin 1

Document Type: Article
Source: Scopus

 

Ragan, D.K.a , McKinstry, R.b , Benzinger, T.b , Leonard, J.R.c , Pineda, J.A.a
Alterations in cerebral oxygen metabolism after traumatic brain injury in children
(2012) Journal of Cerebral Blood Flow and Metabolism, . Article in Press. 

a Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
b Department of Radiology, Washington University School of Medicine, St Louis, Missouri, USA
c Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri, USA

Abstract
Traumatic brain injury (TBI) is the most common cause of acquired disability in children. Metabolic defects, and in particular mitochondrial dysfunction, are important contributors to brain injury after TBI. Studies of metabolic dysfunction are limited, but magnetic resonance methods suitable for use in children are overcoming this limitation. We performed noninvasive measurements of cerebral blood flow and oxygen metabolic index (OMI) to assess metabolic dysfunction in children with severe TBI. Cerebral blood flow is variable after TBI but hypoperfusion and low OMI are predominant, supporting metabolic dysfunction. This finding is consistent with preclinical and adult clinical studies of brain metabolism and mitochondrial dysfunction after TBI.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 September 2012; doi:10.1038/jcbfm.2012.130.

Document Type: Article in Press
Source: Scopus

 

Huang, W.-H.a b , Tupal, S.e , Huang, T.-W.a b , Ward, C.S.b c , Neul, J.L.a b c , Klisch, T.J.b c , Gray, P.A.e , Zoghbi, H.Y.a b c d
Atoh1 Governs the Migration of Postmitotic Neurons that Shape Respiratory Effectiveness at Birth and Chemoresponsiveness in Adulthood
(2012) Neuron, 75 (5), pp. 799-809. 

a Baylor College of Medicine, Houston, TX 77030, United States
b Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States
c Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
d Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, United States
e Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Hindbrain neuronal networks serving respiratory, proprioceptive, and arousal functions share a developmental requirement for the bHLH transcription factor Atoh1. Loss of Atoh1 in mice results in respiratory failure and neonatal lethality; however, the neuronal identity and mechanism by which Atoh1-dependent cells sustain newborn breathing remains unknown. We uncovered that selective loss of Atoh1 from the postmitotic retrotrapezoid nucleus (RTN) neurons results in severely impaired inspiratory rhythm and pronounced neonatal death. Mice that escape neonatal death develop abnormal chemoresponsiveness as adults. Interestingly, the expression of Atoh1 in the RTN neurons is not required for their specification or maintenance, but is important for their proper localization and to establish essential connections with the preBötzinger Complex (preBötC). These results provide insights into the genetic regulation of neonatal breathing and shed light on the labile sites that might contribute to sudden death in newborn infants and altered chemoresponsiveness in adults. Huang et al. show that the bHLH transcription factor Atoh1 governs the migration of embryonic retrotrapezoid neurons so that they can be integrated into the neuronal circuit critical for neonatal inspiratory rhythm generation and adult respiratory chemoresponsiveness. © 2012 Elsevier Inc.

Document Type: Article
Source: Scopus

 

Roh, J.H.a b c , Huang, Y.a , Bero, A.W.a b c , Kasten, T.a , Stewart, F.R.a b c , Bateman, R.J.a b c , Holtzman, D.M.a b c d
Disruption of the sleep-wake cycle and diurnal fluctuation of amyloid-β in mice with Alzheimer's disease pathology
(2012) Science Translational Medicine, 4 (150), art. no. 150ra122, . 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
c Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Aggregation of amyloid-β (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ 42 normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system may be functional and biochemical indicators, respectively, of Aβ-associated pathology.

Document Type: Article
Source: Scopus

 

Eschenbacher, W.H., Song, M., Chen, Y., Bhandari, P., Zhao, P., Jowdy, C.C., Engelhard, J.T., Dorn II, G.W.
Two Rare Human Mitofusin 2 Mutations Alter Mitochondrial Dynamics and Induce Retinal and Cardiac Pathology in Drosophila
(2012) PLoS ONE, 7 (9), art. no. e44296, . 

Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Mitochondrial fusion is essential to organelle homeostasis and organ health. Inexplicably, loss of function mutations of mitofusin 2 (Mfn2) specifically affect neurological tissue, causing Charcot Marie Tooth syndrome (CMT) and atypical optic atrophy. As CMT-linked Mfn2 mutations are predominantly within the GTPase domain, we postulated that Mfn2 mutations in other functional domains might affect non-neurological tissues. Here, we defined in vitro and in vivo consequences of rare human mutations in the poorly characterized Mfn2 HR1 domain. Human exome sequencing data identified 4 rare non-synonymous Mfn2 HR1 domain mutations, two bioinformatically predicted as damaging. Recombinant expression of these (Mfn2 M393I and R400Q) in Mfn2-null murine embryonic fibroblasts (MEFs) revealed incomplete rescue of characteristic mitochondrial fragmentation, compared to wild-type human Mfn2 (hMfn2); Mfn2 400Q uniquely induced mitochondrial fragmentation in normal MEFs. To compare Mfn2 mutation effects in neurological and non-neurological tissues in vivo, hMfn2 and the two mutants were expressed in Drosophila eyes or heart tubes made deficient in endogenous fly mitofusin (dMfn) through organ-specific RNAi expression. The two mutants induced similar Drosophila eye phenotypes: small eyes and an inability to rescue the eye pathology induced by suppression of dMfn. In contrast, Mfn2 400Q induced more severe cardiomyocyte mitochondrial fragmentation and cardiac phenotypes than Mfn2 393I, including heart tube dilation, depressed fractional shortening, and progressively impaired negative geotaxis. These data reveal a central functional role for Mfn2 HR1 domains, describe organ-specific effects of two Mfn2 HR1 mutations, and strongly support prospective studies of Mfn2 400Q in heritable human heart disease of unknown genetic etiology. © 2012 Eschenbacher et al.

Document Type: Article
Source: Scopus

 

Cavazos-Rehg, P.A.a , Krauss, M.J.b , Spitznagel, E.L.c , Chaloupka, F.J.d , Schootman, M.e , Grucza, R.A.a , Bierut, L.J.a
Associations Between Selected State Laws and Teenagers' Drinking and Driving Behaviors
(2012) Alcoholism: Clinical and Experimental Research, 36 (9), pp. 1647-1652. 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States
d Department of Economics, University of Illinois at Chicago, Chicago, IL, United States
e Division of Health Behavior Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: We examined the associations between selected state-level graduated driving licensing (GDL) laws and use-and-lose laws (laws that allow for the suspension of a driver's license for underage alcohol violations including purchase, possession, or consumption) with individual-level alcohol-related traffic risk behaviors among high school youth. Methods: Logistic regression models with fixed effects for state were used to examine the associations between the selected state-level laws and drinking and driving behaviors youth aged 16 to 17 years (obtained from the Youth Risk Behavior Surveillance System (YRBSS); responses dichotomized as "0 times" or "1 or more times") over an extended period of time (1999 to 2009). Results: A total of 11.7% of students reported having driven after drinking any alcohol and 28.2% reported riding in a car with a driver who had been drinking on 1 or more occasions in the past 30 days. Restrictive GDL laws and use-and-lose laws were associated with decreased driving after drinking any alcohol and riding in a car with a driver who had been drinking alcohol. Conclusions: Restrictive GDL and use-and-lose laws may help to bolster societal expectations and values about the hazards of drinking and driving behaviors and are therefore partly responsible for the decline in these alcohol-related traffic risk behaviors. © 2012 by the Research Society on Alcoholism.

Author Keywords
Drinking and driving;  Policy;  Teenage risk behaviors

Document Type: Article
Source: Scopus

 

Kapp-Simon, K.A.a b c d e f g h i , Collett, B.R.a b c d e f g h , Barr-Schinzel, M.A.a b c d e f g h , Cradock, M.M.a b c d e f g h , Buono, L.A.a b c d e f g h , Pietila, K.E.a b c d e f g h , Speltz, M.L.a b c d e f g h
Behavioral adjustment of toddler and preschool-aged children with single-suture craniosynostosis
(2012) Plastic and Reconstructive Surgery, 130 (3), pp. 635-647. 

a Department of Surgery, Northwestern University, United States
b Departments of Psychology and Plastic Surgery, Shriners Hospital for Children, United States
c Psychiatry and Behavioral Medicine, Seattle Children's Hospital, United States
d Departments of Psychiatry and Behavioral Sciences and Epidemiology, University of Washington, United States
e Department of Psychology, Chicago School of Professional Psychology, United States
f Department of Psychology, St. Louis Children's Hospital, United States
g Department of Pediatrics, Washington University School of Medicine, United States
h Craniofacial Team, Children's Healthcare of Atlanta, United States
i Child and Infant Learning Project, 2225 Enterprise Drive, Westchester, IL 60154, United States

Abstract
Background: The purpose of this study was to confirm initial reports of elevated behavior problems in children with single-suture craniosynostosis, using multiple informants, longitudinal analyses, and a control group. The authors hypothesized that children with single-suture craniosynostosis would have higher levels of maladjustment than comparison children, particularly at the older age and in selected areas of previously observed vulnerability: attention and social adjustment. Methods: The Child Behavior Checklist was completed by 436 mothers (219 with single-suture craniosynostosis) and 371 fathers (177 with single-suture craniosynostosis) when children were aged approximately 19 months, and by 361 mothers (175 with single-suture craniosynostosis) and 303 fathers (142 with single-suture craniosynostosis) when children were aged approximately 37 months. A minimum of one caregiver/teacher report was available for 169 of these children (74 with single-suture craniosynostosis) using the Caregiver-Teacher Report Form. Results: Average Child Behavior Checklist/Caregiver-Teacher Report Form externalizing, internalizing, and total scores for all informants were consistently higher (worse) for children with single-suture craniosynostosis than for control group children, but most differences were small and statistically nonsignificant. No differences associated with suture site were found. At the oldest age point, both mothers and fathers (but not teachers) generated higher average scores for patients than for controls on scales measuring attention and social problems, with small to medium effect sizes (0.20 to 0.32). Conclusions: On average, toddlers/preschoolers with single-suture craniosynostosis show behavioral development that is largely indistinguishable from same-aged peers of similar socioeconomic background. The predictive significance of small group differences in attention and social adjustment will be assessed in a follow-up of this cohort at age 7. Clinical Question/Level of Evidence: Risk, I. © 2012 by the American Society of Plastic Surgeons.

Document Type: Article
Source: Scopus

 

Williams, J.L.a c , Richert, B.T.a , Marchant-Forde, J.N.b , Eicher, S.D.b
Behavioral changes in neonatal swine after an 8-hour rest during prolonged transportation
(2012) Journal of Animal Science, 90 (9), pp. 3213-3219. 

a Department of Animal Sciences, Purdue University, 125 S. Russell St, West Lafayette, IN 47907, United States
b United States Department of Agriculture-Agricultural Research Service, 125 S. Russell St, West Lafayette, IN 47907, United States
c Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8051, St, Louis, MO 63110, United States

Abstract
Long distance transportation of weaned piglets (Sus scrofa) is increasingly common in the United States and may result in delayed eating, drinking, or normal social behaviors. A potential solution is a midjourney rest (lairage). The objective of this study was to determine if a lairage altered behavior after a 16-h transport. Pigs that weighed approximately 18 kg each (n = 894) were housed in 16 pens with 8 pens per treatment. Lairaged pigs were transported for 8 h and given an 8-h rest with food and water, whereas control pigs were transported continuously for 16 h. The heaviest, the lightest, and 2 average-BW pigs relative to the average weight of the pen were observed by video recording for 24 h immediately before and after transport, and during d 6 and 13 after transport. Postures (lying, sitting, and standing) were recorded using 10-min-interval scan sampling, and behavioral categories included inactivity, activities (eating, drinking, alert, manipulating pen, rooting, and walking) and social interactions (aggression, belly nosing, playing, tail biting, and positive social behaviors). In both treatments, sitting occurred most before transport (P < 0.01) than at other times, but did not differ between treatments. Standing increased (time effect; P < 0.01) for both treatments immediately after transport through d 6, but returned to pre-transport values by d 13. In contrast, lying decreased (time effect; P < 0.01) after transport, but returned to above pre-transport values by d 13. Time effects were evident for activity (P < 0.01), pen manipulation (P = 0.05), rooting (P < 0.01), initiation of belly-nosing (P = 0.01), and receiving bellynosing (P = 0.03); however, initiation of aggression did not differ for day (P = 0.19) or treatment (P = 0.56). Lairaged pigs initiated more (P = 0.05) play than continuously transported pigs, but no differences (P = 0.84) were seen in receipt of play behavior. Pigs that were to be transported for 16 h continuously walked less pretransport, walked more post-transport (treatment × time interaction; P = 0.02), and drank less pre-transport, but drank more on all days post-transport compared with the lairage group (treatment × time interaction; P = 0.001). This study indicated that extended transport without lairage alters some swine behaviors relevant to production (water consumption) and demonstrated that a longduration transport, regardless of the mid-journey lairage treatment, affects a number of behaviors up to 13 d after transportation. © 2012 American Society of Animal Science. All rights reserved.

Author Keywords
Behavior;  Lairage;  Pig;  Transport

Document Type: Article
Source: Scopus

 

Qin, E.Y.a , Hawkins-Salsbury, J.A.a , Jiang, X.b , Reddy, A.S.a , Farber, N.B.c , Ory, D.S.b , Sands, M.S.a d
Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy

(2012) Molecular Genetics and Metabolism, 107 (1-2), pp. 186-196. 

a Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
b Diabetic Cardiovascular Disease Center, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
d Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, oligodendrocytes. Currently, the only therapy for GLD is hematopoietic stem cell transplantation using bone marrow (BMT) or umbilical cord blood. However, this is only partially effective. Previous studies have shown that enzyme replacement therapy (ERT) provides some therapeutic benefit in the murine model of GLD, the Twitcher mouse. Experiments have also shown that two disparate therapies can produce synergistic effects when combined. The current study tests the hypothesis that BMT will increase the therapeutic effects of ERT when these two treatments are combined. Twitcher mice were treated with either ERT alone or both ERT and BMT during the first 2-4. days of life. Recombinant enzyme was delivered by intracerebroventricular (ICV) and intrathecal (IT) injections. Twitcher mice receiving ERT had supraphysiological levels of GALC activity in the brain 24. h after injection. At 36. days of age, ERT-treated Twitcher mice had reduced psychosine levels, reduced neuroinflammation, improved motor function, and increased lifespan. Twitcher mice receiving both ERT and BMT had significantly increased lifespan, improved motor function, reduced psychosine levels, and reduced neuroinflammation in certain areas of the brain compared to untreated or ERT-treated Twitcher mice. Together, these results indicate that BMT enhances the efficacy of ERT in GLD. © 2012 Elsevier Inc.

Author Keywords
Bone marrow transplantation;  Enzyme replacement therapy;  Globoid cell leukodystrophy;  Lysosomal storage disease;  Neurodegenerative disease;  Twitcher mouse

Document Type: Article
Source: Scopus

 

Shrestha, B.a , Pinto, A.K.a , Green, S.d , Bosch, I.e , Diamond, M.S.a b c
CD8 + T cells use TRAIL to restrict west nile virus pathogenesis by controlling infection in neurons
(2012) Journal of Virology, 86 (17), pp. 8937-8948. 

a Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, United States
e Massachusetts Institute of Technology, Cambridge, MA, United States

Abstract
Previous studies of mice have demonstrated that an orchestrated sequence of innate and adaptive immune responses is required to control West Nile virus (WNV) infection in peripheral and central nervous system (CNS) tissues. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; also known as CD253) has been reported to inhibit infection with dengue virus, a closely related flavivirus, in cell culture. To determine the physiological function of TRAIL in the context of flavivirus infection, we compared the pathogenesis of WNV in wild-type and TRAIL -/- mice. Mice lacking TRAIL showed increased vulnerability and death after subcutaneous WNV infection. Although no difference in viral burden was detected in peripheral tissues, greater viral infection was detected in the brain and spinal cord at late times after infection, and this was associated with delayed viral clearance in the few surviving TRAIL -/- mice. While priming of adaptive B and T cell responses and trafficking of immune and antigen-specific cells to the brain were undistinguishable from those in normal mice, in TRAIL -/- mice, CD8 + T cells showed qualitative defects in the ability to clear WNV infection. Adoptive transfer of WNV-primed wild-type but not TRAIL -/- CD8 + T cells to recipient CD8 -/- mice efficiently limited infection in the brain and spinal cord, and analogous results were obtained when wild-type or TRAIL -/- CD8 + T cells were added to WNV-infected primary cortical neuron cultures ex vivo. Collectively, our results suggest that TRAIL produced by CD8 + T cells contributes to disease resolution by helping to clear WNV infection from neurons in the central nervous system. © 2012, American Society for Microbiology.

Document Type: Article
Source: Scopus

 

Lin, P.a , Hartz, S.M.a , Wang, J.-C.a , Agrawal, A.a , Zhang, T.-X.a , McKenna, N.a , Bucholz, K.a , Brooks, A.I.b , Tischfield, J.A.b , Edenberg, H.J.c , Hesselbrock, V.M.d , Kramer, J.R.e , Kuperman, S.e , Schuckit, M.A.f , Goate, A.M.a , Bierut, L.J.a , Rice, J.P.a
Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence
(2012) Alcoholism: Clinical and Experimental Research, 36 (9), pp. 1512-1518. 

a Department of Psychiatry Washington University, St. Louis, MO, United States
b Department of Genetics, Rutgers University, Piscataway, NJ, United States
c School of Medicine, Indiana University, Indianapolis, IN, United States
d Department of Psychiatry, School of Medicine, University of Connecticut, Farmington, CT, United States
e Department of Psychiatry, School of Medicine, University of Iowa, Iowa City, IA, United States
f Department of Psychiatry, University of California, San Diego, CA, United States

Abstract
Background: Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE). Methods: All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory. Results: CNVs in 6q14.1 (p = 1.04 × 10 -6) and 5q13.2 (p = 3.37 × 10 -4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution. Conclusions: This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence. © 2012 by the Research Society on Alcoholism.

Author Keywords
Alcohol dependence;  CNV accuracy;  Copy number variations

Document Type: Article
Source: Scopus

 

Klawiter, E.C.a b , Xu, J.a , Naismith, R.T.a , Benzinger, T.L.S.c , Shimony, J.S.c , Lancia, S.a , Snyder, A.Z.a c , Trinkaus, K.d , Song, S.-K.c , Cross, A.H.a
Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis
(2012) Multiple Sclerosis, 18 (9), pp. 1259-1268. 

a Department of Neurology, Washington University School of Medicine, St Louis, United States
b Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
c Department of Radiology, Washington University School of Medicine, St Louis, United States
d Division of Biostatistics, Washington University School of Medicine, St Louis, United States

Abstract
Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology. Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions. Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included. Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared with controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and fractional anisotropy within white matter regions upstream and downstream of T2 lesions were different from controls in each disease. Conclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration. © The Author(s) 2012.

Author Keywords
Diffusion tensor imaging;  MRI;  multiple sclerosis (MS);  neuromyelitis optica (NMO);  spinal cord

Document Type: Article
Source: Scopus

 

Eyler, A.A.
Integrating behavioral health services within military health system: A model for opportunities and challenges
(2012) Translational Behavioral Medicine, 2 (3), p. 262. 


Prevention Research Center, Washington University in St. Louis, 660 S. Euclid, #8109, St. Louis, MO 63110, United States

Document Type: Article
Source: Scopus

 

Smyser, C.D.a b , Kidokoro, H.b , Inder, T.E.a b c
Magnetic resonance imaging of the brain at term equivalent age in extremely premature neonates: To scan or not to scan?
(2012) Journal of Paediatrics and Child Health, 48 (9), pp. 794-800. 

a Department of Neurology, Division of Pediatric Neurology, Washington University, 660 South Euclid Avenue, Saint Louis, MO 63110-1093, United States
b Department of Pediatrics, Washington University, Saint Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO, United States

Abstract
In the last decade, the role of magnetic resonance imaging (MRI) in neonatal care for prematurely born infants has rapidly expanded and evolved. Recent investigations addressed many of the practical issues pertaining to image acquisition and interpretation, enabling high-quality MR images to be obtained without sedating medications in preterm infants at any institution. Expanded application has demonstrated that MRI provides superior ability to assess cerebral development and identify and define cerebral injury in comparison to other imaging modalities. Term equivalent MRI results have been shown to correlate with neurodevelopmental outcomes, providing improved predictive ability over other neuroimaging, clinical or physical examination measures. Regular utilisation of MRI in this population is fundamental to gaining the knowledge and expertise necessary for rational, accurate application. Ongoing experiences will continue to shape the nature and type of information available to clinicians and families using MRI, further refining its role as a routine element of neonatal care. © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Author Keywords
magnetic resonance imaging;  neurodevelopmental outcome;  premature infant

Document Type: Review
Source: Scopus

 

Kymes, S.a b , Varma, R.b d , Coleman, A.L.c e f
The economics of the initial preventive physical examination in medicare
(2012) Archives of Ophthalmology, 130 (9), pp. 1232-1233. 

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, United States
b Public Health Committee, American Academy of Ophthalmology, San Francisco, United States
c H. Dunbar Hoskins Jr, MD, Center for Quality Eye Care, San Francisco, United States
d Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
e Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095, United States
f Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, United States

Document Type: Note
Source: Scopus

 

Hu, W.T.a b i , Holtzman, D.M.g h , Fagan, A.M.g h , Shaw, L.M.b d , Perrin, R.h , Arnold, S.E.c e , Grossman, M.a , Xiong, C.h , Craig-Schapiro, R.g h , Clark, C.M.l , Pickering, E.j , Kuhn, M.j , Chen, Y.j , Van Deerlin, V.M.b d , McCluskey, L.a , Elman, L.a , Karlawish, J.f , Chen-Plotkin, A.a b , Hurtig, H.I.a , Siderowf, A.a , Swenson, F.j , Lee, V.M.-Y.b d e , Morris, J.C.g h , Trojanowski, J.Q.b d e , Soares, H.k
Plasma multianalyte profiling in mild cognitive impairment and Alzheimer Disease
(2012) Neurology, 79 (9), pp. 897-905. 

a Department of Neurology, University of Pennsylvania, School of Medicine, Philadelphia, United States
b Center for Neurodegenerative Disease Research, University of Pennsylvania, School of Medicine, Philadelphia, United States
c Department of Psychiatry, University of Pennsylvania, School of Medicine, Philadelphia, United States
d Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, Philadelphia, United States
e Institute on Aging, University of Pennsylvania, School of Medicine, Philadelphia, United States
f Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, United States
g Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
h Knight Alzheimer's Disease Research Center, Washington University, School of Medicine, St. Louis, MO, United States
i Department of Neurology, Emory University, School of Medicine, Atlanta, GA, United States
j Pfizer Global Research and Development, Groton, CT, United States
k Bristol-Myers Squibb, New London, CT, United States

Abstract
Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study Copyright © 2012 by AAN Enterprises, Inc.

Document Type: Article
Source: Scopus

 

Thangarajh, M., Mar, S.S.
Teaching neuroimages: CNS involvement in systemic anaplastic large-cell lymphoma
(2012) Neurology, 79 (8), pp. e74-e75. 

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

Document Type: Note
Source: Scopus

 

Lee, J.K.a , Mathews, K.b c , Schlaggar, B.d e f g , Perlmutter, J.d e f g h , Paulsen, J.S.a c i , Epping, E.a , Burmeister, L.j , Nopoulos, P.a b c
Measures of growth in children at risk for Huntington disease

(2012) 
Neurology, 79 (7), pp. 668-674. 

a Department of Psychiatry, University of Iowa Carver, College of Medicine, Iowa City, United States
b Department of Pediatrics, University of Iowa Carver, College of Medicine, Iowa City, United States
c Department of Neurology, University of Iowa Carver, College of Medicine, Iowa City, United States
d Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States
g Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
h Program in Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
i Department of Psychology, University of Iowa, Iowa City, United States
j University of Iowa, College of Public Health Administration, Iowa City, United States

Abstract
Objective: The effect of mHTT on human development was examined by evaluating measures of growth in children at risk for Huntington disease (HD). Methods: Children at risk for HD with no manifest symptoms (no juvenile HD included) were enrolled and tested for gene expansion for research purposes only. Measurements of growth (height, weight, body mass index [BMI], and head circumference) in children tested as geneexpanded (n = 20, 7-18 years of age, CAG repeats ≥39) were compared to those of a large database of healthy children (n = 152, 7-18 years of age). Results: Gene-expanded children had significantly lower measures of head circumference, weight, and BMI. Head circumference was abnormally low even after correcting for height, suggesting a specific deficit in brain growth, rather than a global growth abnormality. Conclusions: These results indicate that, compared to a control population, children who were estimated to be decades from HD diagnosis have significant differences in growth. Further, they suggest that mHTT may play a role in atypical somatic, and in particular, brain development. Copyright © 2012 by AAN Enterprises, Inc.

Document Type: Article
Source: Scopus

 

Kim, S., DiAntonio, A.
A role for the membrane Golgi protein Ema in autophagy
(2012) Autophagy, 8 (8), pp. 1269-1270. 

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

Abstract
Autophagy is a cellular homeostatic response that involves degradation of self-components by the doublemembraned autophagosome. The biogenesis of autophagosomes has been well described, but the ensuing processes after autophagosome formation are not clear. In our recent study, we proposed a model in which the Golgi complex contributes to the growth of autophagic structures, and that the Drosophila melanogaster membrane protein Ema promotes this process. In fat body cells of the D. melanogaster ema mutant, the recruitment of the Golgi complex protein Lava lamp (Lva) to autophagic structures is impaired and autophagic structures are very small. In addition, in the ema mutant autophagic turnover of SQSTM1/p62 and mitophagy are impaired. Our study not only identifies a role for Ema in autophagy, but also supports the hypothesis that the Golgi complex may be a potential membrane source for the biogenesis and development of autophagic structures. © 2012 Landes Bioscience.

Author Keywords
Autophagy;  Clec16A;  Drosophila;  Ema;  Fat body;  Golgi;  Growth

Document Type: Short Survey
Source: Scopus

 

Postuma, R.B.a c , Montplaisir, J.Y.b c , Pelletier, A.a e , Dauvilliers, Y.f , Oertel, W.g , Iranzo, A.j , Ferini-Strambi, L.i , Arnulf, I.h , Hogl, B.k , Manni, R.l , Miyamoto, T.m , Mayer, G.n , Stiasny-Kolster, K.g , Puligheddu, M.o , Ju, Y.p , Jennum, P.q , Sonka, K.r , Santamaria, J.h , Fantini, M.L.i , Zucconi, M.i , Leu-Semenescu, S.j , Frauscher, B.k , Terzaghi, M.l , Miyamoto, M.s , Unger, M.M.g , De Cock, V.C.f , Wolfson, C.d e
Environmental risk factors for REM sleep behavior disorder: A multicenter case-control study
(2012) Neurology, 79 (5), pp. 428-434. 

a Departments of Neurology, McGill University, Montreal General Hospital, Montreal, Canada
b Departments of Epidemiology and Biostatistics and Occupational Health, McGill University, Montreal General Hospital, Montreal, Canada
c Centre D'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, Canada
d Research Institute of the McGill University Health Center, Montreal, Canada
e Department of Psychiatry, Université de Montréal, Montreal, Canada
f Department of Neurology, Hôpital Gui de Chauliac, Montpellier, INSERM U1061, Montpellier, France
g Philipps-Universität, Marburg, Germany
h Neurology Service, Hospital Clinic de Barcelona, CIBERNED, Barcelona, Spain
i Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy
j Unité des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Pierre and Marie Curie University, Paris, France
k Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
l Unit of Sleep Medicine, National Institute of Neurology, IRCCS C. Mondino Foundation, Pavia, Italy
m Department of Neurology, Dokkyo Medical University, Koshigaya Hospital, Saitama, Japan
n Hephata Klinik, Schwalmstadt-Treysa, Germany
o Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy
p Washington University, Multidisciplinary Sleep Center, St. Louis, MO, United States
q Danish Center for Sleep Medicine, University of Copenhagen, Denmark
r Department of Neurology, Charles University, General University Hospital, Prague, Czech Republic
s Department of Neurology, Dokkyo Medical University, School of Medicine, Tochigi, Japan

Abstract
Objective: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. Methods: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. Results: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR=1.59, p=0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked Abstract: farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). Conclusions: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder. Copyright © 2012 by AAN Enterprises, Inc.

Document Type: Article
Source: Scopus

 

Xiong, C.a , Luo, J.a , Gao, F.a , Chen, L.a , Yan, Y.b
Optimum Design of Disease-Modifying Trials on Alzheimer's Disease
(2012) Statistics in Biopharmaceutical Research, 4 (3), pp. 216-227. 

a Division of Biostatistics, Washington University, St. Louis, MO, 63110, United States
b Department of Surgery and Division of Biostatistics, Washington University, St. Louis, MO, 63110, United States

Abstract
Randomized start and withdrawal designs have been recently proposed to test the disease-modifying agents on Alzheimer's disease (AD). This article provides methods to determine the optimum parameters for these designs. A general linear mixed-effects model is proposed. This model employs a piecewise linear growth pattern for those in the delayed treatment or early withdrawal arm and incorporates a potential correlation between the rates of change in efficacy outcome before and after the treatment switch. Based on this model, we formulate the disease-modifying hypothesis by comparing the rate of change in efficacy outcome between treatment arms with and without a treatment switch and develop a methodology to optimally determine the sample size allocations to different treatment arms as well as the time of treatment switch for subjects whose treatment is changed. We then propose an intersection-union test (IUT) to assess the disease-modifying efficacy and study the size and the power of the IUT. Finally, we employ two recently published symptomatic trials on AD to obtain pilot estimates to model parameters and provide the optimum design parameters, including total and individual sample size to different arms as well as the time of treatment switch, for future disease-modifying trials on AD. © 2012 Copyright Taylor and Francis Group, LLC.

Author Keywords
Delayed treatment;  Intersection-union test;  Randomized start design;  Rate of cognitive progression

Document Type: Article
Source: Scopus

 

Savine, A.C., McDaniel, M.A., Shelton, J.T., Scullin, M.K.
A characterization of individual differences in prospective memory monitoring using the Complex Ongoing Serial Task.
(2012) Journal of experimental psychology. General, 141 (2), pp. 337-362. 

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

Abstract
Prospective memory--remembering to retrieve and execute future goals--is essential to daily life. Prospective remembering is often achieved through effortful monitoring; however, potential individual differences in monitoring patterns have not been characterized. We propose 3 candidate models to characterize the individual differences present in prospective memory monitoring: attentional focus, secondary memory retrieval, and information thresholding. Two experiments using a novel paradigm, the Complex Ongoing Serial Task (COST), investigated the resource allocation patterns underlying individual differences in monitoring. Individuals exhibited differential resource allocation patterns, and the differences remained relatively stable across experimental sessions. Resource allocation patterns associated with information thresholding (high prospective memory, preserved ongoing task performance) and attentional focus (high prospective memory, inefficient ongoing task performance) were superior to secondary memory retrieval (low prospective memory, very inefficient ongoing task performance). Importantly, personality (openness, prevention focus) and cognitive (primary, working, and secondary memory) individual differences influenced monitoring patterns. This research represents the first explicit attempt to elucidate individual differences in prospective memory monitoring patterns.

Document Type: Article
Source: Scopus

 

Jaeger, A., Cox, J.C., Dobbins, I.G.
Recognition confidence under violated and confirmed memory expectations.
(2012) Journal of experimental psychology. General, 141 (2), pp. 282-301. 

Department of Psychology, Washington University in St Louis, St. Louis, MO 63130-4899, USA.

Abstract
Individuals' memory experiences typically covary with those of others' around them, and on average, an item is more likely to be familiar if a companion recommends it as such. Although it would be ideal if observers could use the external recommendations of others' as statistical priors during recognition decisions, it is currently unclear how or if they do so. Furthermore, understanding the sensitivity of recognition judgments to such external cues is critical for understanding memory conformity and eyewitness suggestibility phenomena. To address this we examined recognition accuracy and confidence following cues from an external source (e.g., "Likely Old") that forecast the likely status of upcoming memory probes. Three regularities emerged. First, hit and correct-rejection rates expectedly fell when participants were invalidly versus validly cued. Second, hit confidence was generally higher than correct-rejection confidence, regardless of cue validity. Finally, and most noteworthy, cue validity interacted with judgment confidence such that validity heavily influenced the confidence of correct rejections but had no discernible influence on the confidence of hits. Bootstrap-informed Monte Carlo simulation supported a dual process recognition model under which familiarity and recollection processes counteract to heavily dampen the influence of external cues on average reported confidence. A 3rd experiment tested this model using source memory. As predicted, because source memory is heavily governed by contextual recollection, cue validity again did not affect confidence, although as with recognition it clearly altered accuracy.

Document Type: Article
Source: Scopus

 

September 19, 2012

Aravamuthan, B.R.a , Angelaki, D.E.a b
Vestibular responses in the macaque pedunculopontine nucleus and central mesencephalic reticular formation
(2012) Neuroscience, 223, pp. 183-199. Article in Press. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States

Abstract
The pedunculopontine nucleus (PPN) and central mesencephalic reticular formation (cMRF) both send projections and receive input from areas with known vestibular responses. Noting their connections with the basal ganglia, the locomotor disturbances that occur following lesions of the PPN or cMRF, and the encouraging results of PPN deep brain stimulation in Parkinson's disease patients, both the PPN and cMRF have been linked to motor control. In order to determine the existence of and characterize vestibular responses in the PPN and cMRF, we recorded single neurons from both structures during vertical and horizontal rotation, translation, and visual pursuit stimuli. The majority of PPN cells (72.5%) were vestibular-only (VO) cells that responded exclusively to rotation and translation stimuli but not visual pursuit. Visual pursuit responses were much more prevalent in the cMRF (57.1%) though close to half of cMRF cells were VO cells (41.1%). Directional preferences also differed between the PPN, which was preferentially modulated during nose-down pitch, and cMRF, which was preferentially modulated during ipsilateral yaw rotation. Finally, amplitude responses were similar between the PPN and cMRF during rotation and pursuit stimuli, but PPN responses to translation were of higher amplitude than cMRF responses. Taken together with their connections to the vestibular circuit, these results implicate the PPN and cMRF in the processing of vestibular stimuli and suggest important roles for both in responding to motion perturbations like falls and turns. © 2012 IBRO.

Author Keywords
Central mesencephalic reticular formation;  Pedunculopontine nucleus;  Vestibular system

Document Type: Article in Press
Source: Scopus

 

Leonard, J.C., Mao, J., Jaffe, D.M.
Potential adverse effects of spinal immobilization in children
(2012) Prehospital Emergency Care, 16 (4), pp. 513-518. 

Department of Pediatrics, Washington University School of Medicine, Division of Emergency Medicine, One Children's Place, St. Louis, MO 63110, United States

Abstract
Objective. The purpose of our study was to describe potential adverse effects associated with spinal immobilization following trauma among children. Methods. We conducted a prospective cohort study of children presenting to the emergency department (ED) for evaluation following trauma over a 13-month period. Children were eligible if they underwent spinal immobilization prior to physician evaluation or if they met the American College of Surgeons (ACS) guidelines for spinal immobilization but were not immobilized. We compared children who were immobilized with those who were not immobilized for self-reported pain, use of radiography to evaluate the cervical spine, ED length of stay, and ED disposition. We also report the characteristics of the cohort. Results. One hundred seventy-three spine-immobilized children and 112 children who met ACS criteria but were not immobilized were enrolled. There were differences between the two study groups, which included age, mechanism of injury, and proportion transported by emergency medical services. However, the comparison groups had comparable Pediatric Trauma Scores (PTSs) and Glasgow Coma Scale scores (GCSs). Immobilized children had a higher median pain score (3 versus 2) and were more likely to undergo cervical radiography (56.6 versus 13.4) and be admitted to the hospital (41.6 versus 14.3). The comparison groups had similar lengths of stay in the ED. Conclusion. Despite presenting with comparable PTSs and GCSs, children who underwent spinal immobilization following trauma had a higher degree of self-reported pain, and were much more likely to undergo radiographic cervical spine clearance and be admitted to the hospital than those who were not immobilized. Future studies are warranted to determine whether these differences are related to spinal immobilization or differences in the mechanisms of injury, injury patterns, or other variables. © 2012 National Association of EMS Physicians.

Author Keywords
Cervical spine clearance;  Injury;  Pain;  Pediatric;  Spinal immobilization;  Trauma

Document Type: Article
Source: Scopus

 

Zempel, J.M.a b , Politte, D.G.c , Kelsey, M.c , Verner, R.c d , Nolan, T.S.c , Babajani-Feremi, A.e , Prior, F.c , Larson-Prior, L.J.a c
Characterization of scale-free properties of human electrocorticography in awake and slow wave sleep states
(2012) Frontiers in Neurology, JUN, art. no. Article 76, . 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, 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 Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Like many complex dynamic systems, the brain exhibits scale-free dynamics that follow power-law scaling. Broadband power spectral density (PSD) of brain electrical activity exhibits state-dependent power-law scaling with a log frequency exponent that varies across frequency ranges. Widely divergent naturally occurring neural states, awake and slow wave sleep (SWS), were used to evaluate the nature of changes in scale-free indices of brain electrical activity. We demonstrate two analytic approaches to characterizing electro-corticographic (ECoG) data obtained during awake and SWS states. A data-driven approach was used, characterizing all available frequency ranges. Using an equal error state discriminator (EESD), a single frequency range did not best characterize state across data from all six subjects, though the ability to distinguish awake and SWS ECoG data in individual subjects was excellent. Multi-segment piecewise linear fits were used to characterize scale-free slopes across the entire frequency range (0.2-200 Hz). These scale-free slopes differed between awake and SWS states across subjects, particularly at frequencies below 10 Hz and showed little difference at frequencies above 70 Hz. A multivariate maximum likelihood analysis (MMLA) method using the multi-segment slope indices successfully categorized ECoG data in most subjects, though individual variation was seen. In exploring the differences between awake and SWS ECoG data, these analytic techniques show that no change in a single frequency range best characterizes differences between these two divergent biological states. With increasing computational tractability, the use of scale-free slope values to characterize ECoG and EEG data will have practical value in clinical and research studies. © 2012 Zempel, Politte, Kelsey, Verner, Nolan, Babajani-Feremi, Prior and Larson-Prior.

Author Keywords
Electrocorticography;  Epilepsy;  Scale-free;  Sleep

Document Type: Article
Source: Scopus

 

Schroer, R.J.a , Beaudet, A.L.b , Shinawi, M.c , Sahoo, T.b , Patel, A.b , Sun, Q.b , Skinner, C.a , Stevenson, R.E.a
Duplication of OCRL and adjacent genes associated with autism but not Lowe syndrome
(2012) American Journal of Medical Genetics, Part A, . Article in Press. 

a Greenwood Genetic Center, Greenwood, South Carolina
b Baylor College of Medicine, Houston, Texas
c Washington University School of Medicine, St. Louis, Missouri

Abstract
Disturbances in the form of microduplications and microdeletions have been found throughout the genome and have been associated with autism, intellectual disability, and recognizable malformation syndromes. In our study of 187 probands with autism, we have identified a duplication in Xq25 including full gene duplication of OCRL and six flanking genes. Activity of the enzyme gene product in fibroblasts was elevated to over twice the level in control fibroblasts. The boy had no somatic or neurological findings reminiscent of Lowe syndrome. © 2012 Wiley Periodicals, Inc.

Author Keywords
Autism;  Lowe syndrome;  Microduplication;  OCRL;  X chromosome

Document Type: Article in Press
Source: Scopus

 

Milchenko, M., Marcus, D.
Obscuring Surface Anatomy in Volumetric Imaging Data
(2012) Neuroinformatics, pp. 1-11. Article in Press. 

Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri, 4525 Scott Ave, St Louis, 63110, United States

Abstract
The identifying or sensitive anatomical features in MR and CT images used in research raise patient privacy concerns when such data are shared. In order to protect human subject privacy, we developed a method of anatomical surface modification and investigated the effects of such modification on image statistics and common neuroimaging processing tools. Common approaches to obscuring facial features typically remove large portions of the voxels. The approach described here focuses on blurring the anatomical surface instead, to avoid impinging on areas of interest and hard edges that can confuse processing tools. The algorithm proceeds by extracting a thin boundary layer containing surface anatomy from a region of interest. This layer is then "stretched" and "flattened" to fit into a thin "box" volume. After smoothing along a plane roughly parallel to anatomy surface, this volume is transformed back onto the boundary layer of the original data. The above method, named normalized anterior filtering, was coded in MATLAB and applied on a number of high resolution MR and CT scans. To test its effect on automated tools, we compared the output of selected common skull stripping and MR gain field correction methods used on unmodified and obscured data. With this paper, we hope to improve the understanding of the effect of surface deformation approaches on the quality of de-identified data and to provide a useful de-identification tool for MR and CT acquisitions. © 2012 Springer Science+Business Media, LLC.

Author Keywords
3D;  Biomedical imaging;  CT imaging;  Facial recognition;  MR imaging;  Privacy

Document Type: Article in Press
Source: Scopus

 

Salt, A.N.a , Hartsock, J.J.a , Gill, R.M.a , Piu, F.b , Plontke, S.K.c
Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal
(2012) JARO - Journal of the Association for Research in Otolaryngology, pp. 1-13. Article in Press. 

a Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, United States
b Otonomy Inc., San Diego, United States
c Department of Otorhinolaryngology, Head and Neck Surgery, University of Halle, Halle, Germany

Abstract
Perilymph pharmacokinetics was investigated by a novel approach, in which solutions containing drug or marker were injected from a pipette sealed into the perilymphatic space of the lateral semi-circular canal (LSCC). The cochlear aqueduct provides the outlet for fluid flow so this procedure allows almost the entire perilymph to be exchanged. After wait times of up to 4 h the injection pipette was removed and multiple, sequential samples of perilymph were collected from the LSCC. Fluid efflux at this site results from cerebrospinal fluid (CSF) entry into the basal turn of scala tympani (ST) so the samples allow drug levels from different locations in the ear to be defined. This method allows the rate of elimination of substances from the inner ear to be determined more reliably than with other delivery methods in which drug may only be applied to part of the ear. Results were compared for the markers trimethylphenylammonium (TMPA) and fluorescein and for the drug dexamethasone (Dex). For each substance, the concentration in fluid samples showed a progressive decrease as the delay time between injection and sampling was increased. This is consistent with the elimination of substance from the ear with time. The decline with time was slowest for fluorescein, was fastest for Dex, with TMPA at an intermediate rate. Simulations of the experiments showed that elimination occurred more rapidly from scala tympani (ST) than from scala vestibuli (SV). Calculated elimination half-times from ST averaged 54.1, 24.5 and 22.5 min for fluorescein, TMPA and Dex respectively and from SV 1730, 229 and 111 min respectively. The elimination of Dex from ST occurred considerably faster than previously appreciated. These pharmacokinetic parameters provide an important foundation for understanding of drug treatments of the inner ear. © 2012 Association for Research in Otolaryngology.

Author Keywords
cochlea;  fluorescein;  intratympanic drug delivery;  perilymph;  round window;  steroids;  TMPA;  trimethylphenylammonium

Document Type: Article in Press
Source: Scopus

 

Wang, L.H.a b , Bucelli, R.C.a , Patrick, E.a c , Rajderkar, D.d , Alvarez III, E.a , Lim, M.M.a e , DeBruin, G.a , Sharma, V.a , Dahiya, S.f , Schmidt, R.E.f , Benzinger, T.S.d , Ward, B.A.a , Ances, B.M.a
Role of magnetic resonance imaging, cerebrospinal fluid, and electroencephalogram in diagnosis of sporadic Creutzfeldt-Jakob disease

 

(2012) Journal of Neurology, pp. 1-9. Article in Press. 
a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, 63110, United States
b Department of Neurology, University of Washington School of Medicine, Seattle, United States
c Department of Neurology, University of Rochester, Rochester, United States
d Department of Radiology, Washington University School of Medicine, Saint Louis, United States
e Departments of Medicine and Neuroscience, University of Pennsylvania, Philadelphia, United States
f Department of Pathology, Washington University School of Medicine, Saint Louis, United States

Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive dementia (RPD) that can be difficult to identify antemortem, with definitive diagnosis requiring tissue confirmation. We describe the clinical, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and electroencephalogram (EEG) measures of a small cohort of 30 patients evaluated for RPD. Clinical and diagnostic measures were cross-sectionally obtained from 17 sCJD patients (15 definite, two probable), 13 non-prion rapidly progressive dementia patients (npRPD), and 18 unimpaired controls. In a subset of patients (nine sCJD and nine npRPD) diffusion tensor imaging (DTI) measures [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)] were also obtained for the caudate, corpus callosum, posterior limb of the internal capsule, pulvinar, precuneus, and frontal lobe. Differences among groups were assessed by an analysis of variance. Compared to npRPD individuals, sCJD patients had cerebellar dysfunction, significantly higher CSF tau, "positive" CSF 14-3-3, and hyperintensities on diffusion-weighted imaging (DWI) that met previously established imaging criteria for sCJD. EEG changes were similar for the two groups. In addition, sCJD patients had significant decreases in DTI measures (MD, AD, RD but not FA) within the caudate and pulvinar compared to either npRPD patients or unimpaired controls. Our results confirm that CSF abnormalities and MRI (especially DWI) can assist in distinguishing sCJD patients from npRPD patients. Future longitudinal studies using multiple measures (including CSF and MRI) are needed for evaluating pathological changes seen in sCJD patients. © 2012 Springer-Verlag.

Author Keywords
Cerebrospinal fluid;  Creutzfeldt-Jakob disease;  Diffusion magnetic resonance imaging

Document Type: Article in Press
Source: Scopus

 

Lang, C.E., Bland, M.D., Bailey, R.R., Schaefer, S.Y., Birkenmeier, R.L.
Assessment of Upper Extremity Impairment, Function, and Activity After Stroke: Foundations for Clinical Decision Making
(2012) Journal of Hand Therapy, . Article in Press. 

Program in Physical Therapy, Program in Occupational Therapy, and Department of Neurology, Washington University, St. Louis, Missouri

Abstract
The purpose of this review is to provide a comprehensive approach for assessing the upper extremity (UE) after stroke. First, common UE impairments and how to assess them are briefly discussed. Although multiple UE impairments are typically present after stroke, the severity of one's impairment, paresis, is the primary determinant of UE functional loss. Second, UE function is operationally defined and a number of clinical measures are discussed. It is important to consider how impairment and loss of function affect UE activity outside of the clinical environment. Thus, this review also identifies accelerometry as an objective method for assessing UE activity in daily life. Finally, the role that each of these levels of assessment should play in clinical decision making is discussed to optimize the provision of stroke rehabilitation services. © 2012 Hanley & Belfus.

Document Type: Article in Press
Source: Scopus

 

Craver, C.F.
A preliminary case for amnesic selves: Toward a clinical moral psychology
(2012) Social Cognition, 30 (4), pp. 449-473. 

Washington University, St. Louis, United States

Abstract
Does episodic memory make us who we are? Scholars from Aristotle to the present claim that episodic memory is necessary for one to be a self, a person, or an agent. A consequence of the episodic necessity hypothesis (N) is that individuals with episodic amnesia fail to qualify as selves, persons, or agents. This ethical demotion requires empirical justification. I show that established dissociations in individuals with episodic amnesia falsify many initially plausible formulations of N. The task going forward is to formulate a hypothesis that avoids falsification or to conclude that no plausible formulation succeeds. This method of clinical moral psychology affords incremental progress in the difficult task of showing how selves, persons, and agents are implemented in cognitive mechanisms. © 2012 Guilford Publications, Inc.

Document Type: Article
Source: Scopus

 

Dobbins, I.G.a , Jaeger, A.a , Studer, B.b c , Simons, J.S.b c
Use of explicit memory cues following parietal lobe lesions
(2012) Neuropsychologia, . Article in Press. 

a Department of Psychology, Washington University, St. Louis, MO, USA
b Department of Experimental Psychology, University of Cambridge, Cambridge, UK
c Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

Abstract
The putative role of the lateral parietal lobe in episodic memory has recently become a topic of considerable debate, owing primarily to its consistent activation for studied materials during functional magnetic resonance imaging studies of recognition. Here we examined the performance of patients with parietal lobe lesions using an explicit memory cueing task in which probabilistic cues ("Likely Old" or "Likely New"; 75% validity) preceded the majority of verbal recognition memory probes. Without cues, patients and control participants did not differ in accuracy. However, group differences emerged during the "Likely New" cue condition with controls responding more accurately than parietal patients when these cues were valid (preceding new materials) and trending towards less accuracy when these cues were invalid (preceding old materials). Both effects suggest insufficient integration of external cues into memory judgments on the part of the parietal patients whose cued performance largely resembled performance in the complete absence of cues. Comparison of the parietal patients to a patient group with frontal lobe lesions suggested the pattern was specific to parietal and adjacent area lesions. Overall, the data indicate that parietal lobe patients fail to appropriately incorporate external cues of novelty into recognition attributions. This finding supports a role for the lateral parietal lobe in the adaptive biasing of memory judgments through the integration of external cues and internal memory evidence. We outline the importance of such adaptive biasing through consideration of basic signal detection predictions regarding maximum possible accuracy with and without informative environmental cues. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
Decision biasing;  Episodic memory;  Parietal cortex;  Prefrontal cortex;  Signal detection

Document Type: Article in Press
Source: Scopus

 

Shah, M.N.a , Botros, J.A.a , Pilgram, T.K.b , Moran, C.J.a b , Cross III, D.T.a b , Chicoine, M.R.a , Rich, K.M.a b , Dacey Jr., R.G.a , Derdeyn, C.P.a b , Zipfel, G.J.a c
Borden-Shucart Type I dural arteriovenous fistulas: Clinical course including risk of conversion to higher-grade fistulas
(2012) Journal of Neurosurgery, 117 (3), pp. 539-545. 

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

Abstract
Object. The goal of this study was to determine the clinical course of Borden-Shucart Type I cranial dural arteriovenous fistulas (DAVFs) and to calculate the annual rate of conversion of these lesions to more aggressive fistulas that have cortical venous drainage (CVD). Methods. A retrospective chart review was conducted of all patients harboring DAVFs who were seen at the authors' institution between 1997 and 2009. Twenty-three patients with Type I DAVFs who had available clinical follow-up were identified. Angiographic and clinical data from these patients were reviewed. Neurological outcome and status of presenting symptoms were assessed during long-term follow-up. Results. Of the 23 patients, 13 underwent endovascular treatment for intolerable tinnitus or ophthalmological symptoms, and 10 did not undergo treatment. Three untreated patients died of unrelated causes. In those who were treated, complete DAVF obliteration was achieved in 4 patients, and palliative reduction in DAVF flow was achieved in 9 patients. Of the 19 patients without radiographic cure, no patient developed intracranial hemorrhage or nonhemorrhagic neurological deficits (NHNDs), and no patient died of DAVF-related causes over a mean follow-up of 5.6 years. One patient experienced a spontaneous, asymptomatic obliteration of a partially treated DAVF in late follow-up, and 2 patients experienced a symptomatic conversion of their DAVF to a higher-grade fistula with CVD in late follow-up. The annual rate of conversion to a higher-grade DAVF based on Kaplan-Meier cumulative event-free survival analysis was 1.0%. The annual rate of intracranial hemorrhage, NHND, and DAVF-related death was 0.0%. Conclusions. A small number of Type I DAVFs will convert to more aggressive DAVFs with CVD over time. This conversion to a higher-grade DAVF is typically heralded by a change in patient symptoms. Follow-up vascular imaging is important, particularly in the setting of recurrent or new symptoms.

Author Keywords
Benign;  Conversion;  Dural arteriovenous fistula;  Natural history;  Vascular disorders

Document Type: Article
Source: Scopus

 

Ray, W.Z.a , Yarbrough, C.K.a , Yee, A.b , Mackinnon, S.E.b
Clinical outcomes following brachialis to anterior interosseous nerve transfers: Report of 4 cases
(2012) Journal of Neurosurgery, 117 (3), pp. 604-609. 

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

Abstract
The surgical management of lower brachial plexus injuries remains a challenging problem. Although nerve transfers have improved clinical outcomes following brachial plexus injuries, the majority of work has focused on upper trunk injuries. Complete lower plexus injuries often lack suitable donors for either nerve or tendon transfers. The authors describe their experience with isolated lower trunk injuries utilizing the nerve to the brachialis to reinnervate the anterior interosseous nerve.

Author Keywords
Anterior interosseous nerve;  Brachial plexus;  Brachialis;  Nerve transfer;  Peripheral nerve injury

Document Type: Article
Source: Scopus

 

Chin, K.R.a , Ricchetti, E.T.b , Yu, W.D.c , Riew, K.D.d
Less exposure surgery for multilevel anterior cervical fusion using 2 transverse incisions

(2012) Journal of Neurosurgery: Spine, 17 (3), pp. 194-198.
a Institute for Modern and Innovative Surgery, Fort Lauderdale, FL, United States
b Department of Orthopaedic Surgery, University of Pennsylvania, School of Medicine, Philadelphia, PA, United States
c Department of Orthopaedic Surgery, George Washington University, School of Medicine, Washington, DC, United States
d Departments of Neurological Surgery and Surgery, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Multilevel anterior cervical fusion often necessitates a large extensile incision for exposure and substantial retraction of the esophagus for placing long plates, potentially predisposing patients to complications such as dysphagia, dysphonia, and neurovascular injury. To the authors' knowledge, the use of 2 incisions as an option has not been published, and so it is not intuitive to young surgeons or widely practiced. In this report, the authors discuss the advantages and raise awareness of using 2 incisions for multilevel anterior cervical fusion, and they document a safe skin bridge length. They also describe the advantages of using 2 incisions for performing multilevel anterior cervical fusion either at contiguous or noncontiguous levels as in adjacent-segment disease. By using the 2-incision technique, the authors made the surgery technically easier and diminished the amount of esophageal retraction otherwise needed through 1 long transverse or longitudinal incision. A skin bridge of 3 cm was safe.

Author Keywords
Cervical spine;  Dysphagia;  Fusion;  Incision;  Less exposure surgery;  Minimally invasive surgery;  Plate

Document Type: Article
Source: Scopus

 

Stein, J.D.a , Niziol, L.M.a , Musch, D.C.a b , Lee, P.P.c , Kotak, S.V.d , Peters, C.M.e f , Kymes, S.M.e f
Longitudinal trends in resource use in an incident cohort of open-angle glaucoma patients: Resource use in open-angle glaucoma
(2012) American Journal of Ophthalmology, 154 (3), pp. 452-459.e2. 

a Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United States
b Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
c Department of Ophthalmology, Duke University, Durham, NC, United States
d Pfizer, Inc., New York, NY, United States
e Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States
f Center for Economic Evaluation in Medicine, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States

Abstract
Purpose: To characterize the costs of caring for patients with open-angle glaucoma (OAG) in the United States over time and to identify factors that influence these costs. Design: Longitudinal cohort study. Methods: Claims data from 19 927 newly diagnosed OAG patients enrolled in a large United States managed care network were reviewed to identify glaucoma-related charges for all incident OAG patients from 2001 through 2009. Average glaucoma-related charges for enrollees with OAG were characterized in 6-month blocks from the date of initial OAG diagnosis through the ensuing 5 years. Factors associated with being an enrollee in the costliest 5% for glaucoma-related charges (accruing $5810 or more in charges in the first 2 years) were identified using logistic regression. Results: The costliest 5% of enrollees were responsible for $10 202 871 (24%) of all glaucoma-related charges. By comparison, those whose costs fell within the lower 50% of the cost distribution collectively amassed only $7 986 582 (19%) of all glaucoma-related charges. A spike in glaucoma-related charges occurred in the 6-month period around the time of OAG diagnosis, stabilized by 1 year after diagnosis, and remained relatively constant over time. Risk factors associated with being in the costliest 5% for glaucoma-related care included younger age, Northeastern United States state residence, undergoing cataract surgery, and possessing ocular comorbidities (P <.006 for all comparisons). Conclusions: A small subset of enrollees account for a large proportion of all glaucoma-related charges. Understanding the characteristics of these individuals and finding ways to reduce disease burden and costs associated with their care can result in substantial cost savings. © 2012 Elsevier Inc. All rights reserved.

Document Type: Article
Source: Scopus

 

Khanna, S.a , Sharma, A.b , Huecker, J.a , Gordon, M.a , Naismith, R.T.c , Van Stavern, G.P.a c
Magnetic resonance imaging of optic neuritis in patients with neuromyelitis optica versus multiple sclerosis
(2012) Journal of Neuro-Ophthalmology, 32 (3), pp. 216-220. 

a Departments of Ophthalmology and Visual Sciences and Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
b Department of Neuroradiology, Washington University School of Medicine, St Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
BACKGROUND:: Patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) both can present with acute optic neuritis (ON), while differing considerably in their prognosis and management. The clinical course, serologic testing results, and brain and spinal cord imaging of these diseases have been well documented. The purpose of this study was to look systematically for any differences in the imaging appearance of the optic nerve in NMO and MS-related ON. METHODS:: Magnetic resonance imaging (MRI) of brain and orbits obtained within 6 weeks of acute ON in patients with securely diagnosed NMO (n = 6) and MS (n = 11) were retrospectively analyzed by a neuroradiologist masked to the clinical diagnosis. Standardized scoring system was used to assess and analyze the extent and nature of optic pathway involvement. RESULTS:: No significant differences were observed in the presence, degree, or the type of signal alteration and contrast enhancement of the affected nerve segments between NMO and MS groups. There was a trend toward more posterior involvement of the optic nerve in the NMO group with chiasmatic enhancement exclusively seen in NMO patients. CONCLUSION:: We found a higher propensity of NMO-related ON to affect more posterior parts of the optic nerve, including chiasm, and have simultaneous bilateral disease. Further study with larger sample sizes is needed. Copyright © 2012 North American Neuro-Ophthalmology Society.

Document Type: Article
Source: Scopus

 

Halliday, G.a , Bigio, E.H.b , Cairns, N.J.c , Neumann, M.d , MacKenzie, I.R.A.e , Mann, D.M.A.f g
Mechanisms of disease in frontotemporal lobar degeneration: Gain of function versus loss of function effects
(2012) Acta Neuropathologica, 124 (3), pp. 373-382. 

a Neuroscience Research Australia, University of New South Wales, Sydney, Australia
b Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neuropathology, German Center for Neurodegenerative Diseases Tuebingen, University of Tuebingen, Tuebingen, Germany
e Department of Pathology, University of British Columbia, Vancouver, Canada
f Institute of Brain, Behaviour and Mental Health, School of Community Based Medicine, University of Manchester, Manchester, United Kingdom
g Salford Royal Hospital, University of Manchester, Stott Lane, Salford M6 8HD, United Kingdom

Abstract
Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5-10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease. © 2012 Springer-Verlag.

Author Keywords
Frontotemporal lobar degeneration;  FUS;  Gain of function;  Loss of function;  Microtubule associated protein;  Motor neurone disease;  Tau;  TDP-43

Document Type: Review
Source: Scopus

 

Han, S.a d , Kim, S.a , Bahl, S.a , Li, L.a , Burande, C.F.a , Smith, N.a , James, M.a , Beauchamp, R.L.a , Bhide, P.b , DiAntonio, A.c , Ramesh, V.a
The E3 ubiquitin ligase protein associated with Myc (Pam) regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling in vivo through N- and C-terminal domains
(2012) Journal of Biological Chemistry, 287 (36), pp. 30063-30072. 

a Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Bldg., 185 Cambridge St., Boston, MA 02114, United States
b Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States
c Department of Molecular Biology and Pharmacology, Washington University, St. Louis, MO 63110, United States
d Bio Lab., Samsung Advanced Institute of Technology, Yongin, Gyeonggi 446-712, South Korea

Abstract
Pam and its homologs (the PHR protein family) are large E3 ubiquitin ligases that function to regulate synapse formation and growth in mammals, zebrafish, Drosophila, and Caenorhabditis elegans. Phr1-deficient mouse models (Phr1 Δ8,9 and Phr1 Magellan, with deletions in the N-terminal putative guanine exchange factor region and the C-terminal ubiquitin ligase region, respectively) exhibit axon guidance/outgrowth defects and striking defects of major axon tracts in the CNS. Our earlier studies identified Pam to be associated with tuberous sclerosis complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic target of rapamycin (mTOR) signaling. Here, we examine the potential involvement of the TSC/mTOR complex 1(mTORC1) signaling pathway in Phr1-deficient mouse models. We observed attenuation of mTORC1 signaling in the brains of both Phr1 Δ8,9 and Phr1 Magellan mouse models. Our results establish that Pam regulates TSC/mTOR signaling in vitro and in vivo through two distinct domains. To further address whether Pam regulates mTORC1 through two functionally independent domains, we undertook heterozygous mutant crossing between Phr1 Δ8,9 and Phr1 Magellan mice to generate a compound heterozygous model to determine whether these two domains can complement each other. mTORC1 signaling was not attenuated in the brains of double mutants (Phr1 Δ8,9/Mag), confirming that Pam displays dual regulation of the mTORC1 pathway through two functional domains. Our results also suggest that although dysregulation of mTORC1 signaling may be responsible for the corpus callosum defects, other neurodevelopmental defects observed with Phr1 deficiency are independent of mTORC1 signaling. The ubiquitin ligase complex containing Pam-Fbxo45 likely targets additional synaptic and axonal proteins, which may explain the overlapping neurodevelopmental defects observed in Phr1 and Fbxo45 deficiency. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

 

Simon-thomas, E.R.a , Godzik, J.b , Castle, E.c , Antonenko, O.d , Ponz, A.d , Kogan, A.d , Keltner, D.J.d
An fmri study of caring vs self-focus during induced compassion and pride
(2012) Social Cognitive and Affective Neuroscience, 7 (6), art. no. nsr045, pp. 635-648. 

a The Center for Compassion and Altruism Research and Education, Stanford University, Stanford, CA, United States
b Department of Medicine, Washington University, St. Louis, MO, United States
c Department of Psychology, University of California, Los Angeles, CA, United States
d Department of Psychology, University of California, Berkeley, CA, United States

Abstract
This study examined neural activation during the experience of compassion, an emotion that orients people toward vulnerable others and prompts caregiving, and pride, a self-focused emotion that signals individual strength and heightened status. Functional magnetic resonance images (fMRI) were acquired as participants viewed 55 s continuous sequences of slides to induce either compassion or pride, presented in alternation with sequences of neutral slides. Emotion self-report data were collected after each slide condition within the fMRI scanner. Compassion induction was associated with activation in the midbrain periaqueductal gray (PAG), a region that is activated during pain and the perception of others' pain, and that has been implicated in parental nurturance behaviors. Pride induction engaged the posterior medial cortex, a region that has been associated with self-referent processing. Self-reports of compassion experience were correlated with increased activation in a region near the PAG, and in the right inferior frontal gyrus (IFG). Self-reports of pride experience, in contrast, were correlated with reduced activation in the IFG and the anterior insula. These results provide preliminary evidence towards understanding the neural correlates of important interpersonal dimensions of compassion and pride. Caring (compassion) and self-focus (pride) may represent core appraisals that differentiate the response profiles of many emotions. © The Author (2011). Published by Oxford University Press.

Author Keywords
Caregiving;  Midbrain periaqueductal gray;  Nurturing;  Posterior medial cortex;  Self-focus

Document Type: Article
Source: Scopus

 

Chole, R.A., Allison Ogden, M.
Predictors of future success in otolaryngology residency applicants
(2012) Archives of Otolaryngology - Head and Neck Surgery, 138 (8), pp. 707-712. 

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Campus Box 8115, 660 S Euclid Ave, St Louis, MO 63110, United States

Abstract
Objective: To evaluate the information available about otolaryngology residency applicants for factors that may predict future success as an otolaryngologist. Design: Retrospective review of residency applications; survey of resident graduates and otolaryngology clinical faculty. Setting: Otolaryngology residency program. Participants: Otolaryngology program graduates from 2001 to 2010 and current clinical faculty from Barnes-Jewish Hospital/Washington University School of Medicine. Main Outcome Measure: Overall ratings of the otolaryngology graduates by clinical faculty (on a 5-point scale) were compared with the resident application attributes that might predict success. The application factors studied are United States Medical Licensing Examination part 1 score, Alpha Omega Alpha Honor Medical Society election, medical school grades, letter of recommendation, rank of the medical school, extracurricular activities, residency interview, experience with acting intern, and extracurricular activities. Results: Forty-six graduates were included in the study. The overall faculty rating of the residents showed good interrater reliability. The objective factors, letters of recommendation, experience as an acting intern, and musical excellence showed no correlation with higher faculty rating. Rank of the medical school and faculty interview weakly correlated with faculty rating. Having excelled in a team sport correlated with higher faculty rating. Conclusions: Many of the application factors typically used during otolaryngology residency candidate selection may not be predictive of future capabilities as a clinician. Prior excellence in a team sport may suggest continued success in the health care team. ©2012 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

 

Zaleta, A.K.a , Carpenter, B.D.a , Porensky, E.K.a , Xiong, C.b , Morris, J.C.c
Agreement on diagnosis among patients, companions, and professionals after a dementia evaluation
(2012) Alzheimer Disease and Associated Disorders, 26 (3), pp. 232-237. 

a Department of Psychology, Campus Box 1125, Washington University, St Louis, MO 63130, United States
b Division of Biostatistics, Alzheimer's Disease Research Center, Washington University, St Louis, MO, United States
c Department of Neurology, Alzheimer's Disease Research Center, Washington University, St Louis, MO, United States

Abstract
A diagnosis of dementia is challenging to deliver and to hear; yet, agreement on diagnosis is essential for effective treatment for dementia. We examined consensus on the results of an evaluation of dementia in 90 patients assessed at an Alzheimer's Disease Research Center. Diagnostic impressions were obtained from 5 sources: (1) the physician's chart; (2) the patient who was evaluated; (3) a companion present at the evaluation; (4) a diagnostic summary written by a nurse present during the evaluation; and (5) raters who watched a video of the diagnostic disclosure conversation. Overall, diagnostic consensus was only moderate. Patients and companions exhibited just fair agreement with one another. Agreement was better between physicians and companions compared with that between physicians and patients, although it was imperfect between physicians and video raters and the written summary. Agreement among sources varied by dementia severity, with the lowest agreement occurring in instances of very mild dementia. This study documents discrepancies that can arise in diagnostic communication, which could influence adjustment to a diagnosis of dementia and decisions regarding future planning and care. Copyright © 2012 by Lippincott Williams & Wilkins.

Author Keywords
Alzheimer disease;  dementia;  diagnostic disclosure;  doctor-patient communication;  patient education

Document Type: Article
Source: Scopus

 

September 12, 2012

Sun, H.H., Saheb-Al-Zamani, M., Yan, Y., Hunter, D.A., Mackinnon, S.E., Johnson, P.J.
Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo
(2012) Neuroscience, 223, pp. 114-123. Article in Press. 

Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8238, St. Louis, MO 63110, USA

Abstract
FK-506 accelerates nerve regeneration and improves functional recovery in vivo; its immunosuppressive properties, however, limit its clinical utility. Geldanamycin (GA), a non-immunosuppressive agent, shares a common binding target (heat shock protein 90) with FK-506 and may accelerate nerve regeneration through a similar mechanism. GA has been shown to augment neurite outgrowth in vitro but has not been tested in vivo. The current study investigated the effect of GA on the rate of axonal regeneration and functional recovery following peripheral nerve injury. In the first experiment, Thy1-GFP transgenic rats underwent serial transmuscular imaging to quantify the rate of axonal regeneration following saphenous nerve crush injury. In subsequent experiments, Lewis rats underwent tibial nerve crush or transection-and-repair injuries and were assessed for functional recovery by walking track analysis. All animals were randomized to receive daily administration of FK-506 (2. mg/kg), GA (0.2. mg/kg), or a control vehicle (dimethyl sulfoxide, 1. mL/kg) starting 3. days prior to injury. Both GA and FK-506 significantly increased the rate of axonal regeneration following crush injury in Thy1-GFP rats. In Lewis rats undergoing tibial nerve crush injury, earlier functional recovery occurred at day 5 and day 6 in animals treated with FK-506 and GA respectively, vs. day 13 for controls. Over a truncated 21-day timeframe, Lewis rats undergoing tibial nerve transection-and-repair injury and treated with FK-506 regained function at day 16, whereas those treated with GA or the control vehicle did not regain normal function. GA-treated animals, however, did exhibit significant functional improvement vs. controls. The current study demonstrated that GA accelerates axonal regeneration and enhances functional recovery in vivo. Its ability to increase the rate at which peripheral axons regenerate is comparable to that of FK-506. GA, however, did not match the performance of FK-506 in injury models where Wallerian degeneration (WD) is ongoing in the distal stump. This provides evidence that FK-506 accelerates axonal regeneration through two parallel mechanisms: the first being its well-established effect on neurons; the second is likely a newly described, as-yet poorly defined mechanism that affects WD. Finally, given the decrease in observed toxicity with GA administration, it might be a suitable non-immunosuppressive alternative to FK-506 for accelerating peripheral nerve regeneration in cases of clinical nerve injury. © 2012 IBRO.

Author Keywords
FK-506;  Geldanamycin;  Live imaging;  Nerve regeneration;  Tacrolimus;  Thy1-GFP rat

Document Type: Article in Press
Source: Scopus

 

Cavazos-Rehg, P.A.a , Krauss, M.J.b , Spitznagel, E.L.c , Schootman, M.d , Cottler, L.B.a , Bierut, L.J.a
Brief report: Pregnant by age 15 years and substance use initiation among US adolescent girls
(2012) Journal of Adolescence, 35 (5), pp. 1393-1397. 

a Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 South Euclid, St. Louis, MO 63110, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63130, United States
d Division of Health Behavior Research, Washington University School of Medicine, St. Louis, MO 63108, United States

Abstract
We examined substance use onset and associations with pregnancy by age 15 years. Participants were girls ages 15 years or younger (weighted n = 8319) from the 1999-2003 Youth Risk Behavior Surveillance System (YRBS). Multivariable logistic regression examined pregnancy as a function of substance use onset (i.e., age 10 years or younger, 11-12, 13-14, and age 15 years) for alcohol, cigarettes and marijuana, controlling for race/ethnicity and metropolitan location. Of girls pregnant by age 15 years (3% of the sample, weighted n = 243), 16% had smoked marijuana by age 10 years and over 20% had smoked cigarettes and initiated alcohol use by age 10 years. In the multivariable analysis, marijuana use by age 14 years and/or cigarette smoking by age 12 years clearly distinguished girls who became pregnant by age 15 years and is perhaps due to a common underlying risk factor. © 2012 The Foundation for Professionals in Services for Adolescents.

Author Keywords
Adolescent risk behaviors;  Sexual intercourse;  Substance use;  Teenage pregnancy

Document Type: Article
Source: Scopus

 

Yang, K.-C.a , Tseng, Y.-T.b , Nerbonne, J.M.a
Exercise training and PI3Kα-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling
(2012) Journal of Molecular and Cellular Cardiology, 53 (4), pp. 532-541. 

a Department of Developmental Biology, Washington University Medical School, St. Louis, MO, United States
b Department of Pediatrics, Women and Infant's Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, United States

Abstract
In contrast with pathological hypertrophy, exercise-induced physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk. Recent studies have shown that increased cardiac-specific expression of phosphoinositide-3-kinase-α (PI3Kα), the key mediator of physiological hypertrophy, results in transcriptional upregulation of ion channel subunits in parallel with the increase in myocyte size (cellular hypertrophy) and the maintenance of myocardial excitability. The experiments here were undertaken to test the hypothesis that Akt1, which underlies PI3Kα-induced cellular hypertrophy, mediates the effects of augmented PI3Kα signaling on the transcriptional regulation of cardiac ion channels. In contrast to wild-type animals, chronic exercise (swim) training of mice (Akt1 -/-) lacking Akt1 did not result in ventricular myocyte hypertrophy. Ventricular K + current amplitudes and the expression of K + channel subunits, however, were increased markedly in Akt1 -/- animals with exercise training. Expression of the transcripts encoding inward (Na + and Ca 2+) channel subunits were also increased in Akt1 -/- ventricles following swim training. Additional experiments in a transgenic mouse model of inducible cardiac-specific expression of constitutively active PI3Kα (icaPI3Kα) revealed that short-term activation of PI3Kα signaling in the myocardium also led to the transcriptional upregulation of ion channel subunits. Inhibition of cardiac Akt activation with triciribine in this (inducible caPI3Kα expression) model did not prevent the upregulation of myocardial ion channel subunits. These combined observations demonstrate that chronic exercise training and enhanced PI3Kα expression/activity result in transcriptional upregulation of myocardial ion channel subunits independent of cellular hypertrophy and Akt signaling. © 2012 Elsevier Ltd.

Author Keywords
Akt;  Electrical remodeling;  Ion channel;  PI3Kα signaling

Document Type: Article
Source: Scopus

 

Reynolds, M.R.a , Vega, R.A.a , Murphy, R.K.J.a , Miller-Thomas, M.M.b , Zipfel, G.J.a c
Perimesencephalic subarachnoid hemorrhage associated with a painless, pupillary-involving third cranial nerve palsy: Case report and literature review
(2012) Clinical Neurology and Neurosurgery, 114 (8), pp. 1168-1171. 

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

Author Keywords
Non-aneurysmal;  Painless;  Perimesencephalic;  Pupil-involving;  Subarachnoid hemorrhage;  Third nerve palsy

Document Type: Article
Source: Scopus

 

Nichols, C.G., Remedi, M.S.
The diabetic β-cell: Hyperstimulated vs. hyperexcited
(2012) Diabetes, Obesity and Metabolism, 14 (SUPPL.3), pp. 129-135. 

Department of Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Hyperglycaemia has multiple effects on β-cells, some clearly prosecretory, including hyperplasia and elevated insulin content, but eventually, a 'glucotoxic' effect which leads to pancreatic β-cell dysfunction, reduced β-cell mass and insulin deficiency, is an important part of diabetes pathophysiology. Myriad underlying cellular and molecular processes could lead to such dysfunction. High glucose will stimulate glycolysis and oxidative phosphorylation, which will in turn increase β-cell membrane excitability through K ATP channel closure. Chronic hyperexcitability will then lead to persistently elevated [Ca 2+] i, a key trigger to insulin secretion. Thus, at least a part of the consequence of 'hyperstimulation' by glucose has been suggested to be a result of 'hyperexcitability' and chronically elevated [Ca 2+] i. This link is lost when the [glucose], K ATP-channel activity link is broken, either pharmacologically or genetically. In isolated islets, such studies reveal that hyperexcitability causes a largely reversible chronic loss of insulin content, but in vivo chronic hyperexcitability per se does not lead to β-cell death or loss of insulin content. On the other hand, chronic inexcitability in vivo leads to systemic diabetes and consequential β-cell death, even while [Ca 2+] i remains low. © 2012 Blackwell Publishing Ltd.

Author Keywords
Apoptosis;  Diabetes;  Excitability;  Function;  Glucose;  Glucotoxicity;  Insulin;  Islets;  K ATP ;  Membrane;  Mice;  Neonatal

Document Type: Review
Source: Scopus

 

Setton, L.A.a , Yin, F.C.b , Margulies, S.S.c , Sakiyama-Elbert, S.E.b , Beizer, D.d
Getting Your Research Out There: Open Access & More
(2012) Annals of Biomedical Engineering, pp. 1-2. Article in Press. 

a Department of Biomedical Engineering and Orthopaedic Surgery, Duke University, Durham, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States
c Department of Bioengineering, University of Pennsylvania, Philadelphia, United States
d Biomedical Engineering Society, Landover, United States

Document Type: Article in Press
Source: Scopus

 

Macare, C.a , Bates, T.C.b , Heath, A.C.c , Martin, N.G.d , Ettinger, U.a
Substantial Genetic Overlap Between Schizotypy and Neuroticism: A Twin Study
(2012) Behavior Genetics, pp. 1-11. Article in Press. 

a Department of Psychology, University of Bonn, Kaiser-Karl-Ring 9, Bonn, 53111, Germany
b Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
c Department of Psychiatry, Washington University Medical School, St Louis, United States
d Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia

Abstract
Schizotypy is phenotypically associated with neuroticism. To reveal the origin of this association, we assessed 3,349 (1,449 monozygotic, 1,105 dizygotic [DZ] same-sex and 795 DZ opposite-sex) twins on a 12-item version of Chapman's Psychosis-Proneness Scales and the short form of the Eysenck Personality Questionnaire-Revised as measures of schizotypy and neuroticism. A substantial proportion (0.51 with 95 % CI from 0.38 to 0.64) of the phenotypic correlation of 0.37 between neuroticism and the perceptual and ideational components of schizotypy was accounted for by shared genetic influences on these two traits. Moreover, a Cholesky decomposition including anhedonia, hypomania and impulsivity fully accounted for the heritable variance in perceptual and ideational components of schizotypy. These findings suggest a shared genetic etiology between neuroticism and perceptual and ideational components of schizotypy and affect future investigations on the etiology of these phenotypically overlapping traits and affective and psychotic disorders. © 2012 Springer Science+Business Media, LLC.

Author Keywords
Behavior genetics;  Magical ideation;  Neuroticism;  Perceptual aberration;  Phenotypic correlation;  Schizotypy

Document Type: Article in Press
Source: Scopus

 

Kelly, H.W.a , Sternberg, A.L.b , Lescher, R.c d , Fuhlbrigge, A.L.e , Williams, P.f , Zeiger, R.S.g , Raissy, H.H.a , Van Natta, M.L.b , Tonascia, J.b , Strunk, R.C.c
Effect of inhaled glucocorticoids in childhood on adult height

(2012) New England Journal of Medicine, 367 (10), pp. 904-912. 
a University of New Mexico, Albuquerque, NM, United States
b Johns Hopkins University, Baltimore, United States
c Washington University, St. Louis, WA, United States
d Alaska Native Medical Center, Anchorage, AK, United States
e Brigham and Women's Hospital, Boston, United States
f University of Washington, Seattle, WA, United States
g University of California, San Diego, Kaiser Permanente Southern California Region, San Diego, CA, United States

Abstract
BACKGROUND: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. METHODS:We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. RESULTS: Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P = 0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P = 0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P = 0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. CONCLUSIONS: The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.

Document Type: Article
Source: Scopus

 

Portelius, E.a , Zetterberg, H.a , Dean, R.A.b , Marcil, A.c , Bourgeois, P.c , Nutu, M.a , Andreasson, U.a , Siemers, E.b , Mawuenyega, K.G.d , Sigurdson, W.C.d e , May, P.C.b , Paul, S.M.b , Holtzman, D.M.d e f , Blennow, K.a , Bateman, R.J.d e f
Amyloid-β 1-15/16 as a marker for γ-secretase inhibition in Alzheimer's disease
(2012) Journal of Alzheimer's Disease, 31 (2), pp. 335-341. 

a Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, M¨olndal, Sweden
b Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Headquarters, Indianapolis, IN, United States
c PerkinElmer Biosignal, Inc., Montreal, QC, Canada
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
f Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ 1-15 is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ 1-15/16 represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ 1-15/16, Aβ x-38, Aβ x-40, Aβ x-42, sAβPPα, and sAβPPβ. The CSF concentration of Aβ 1-15/16 showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ x-38, Aβ x-40, and Aβ x-42 decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ 1-15/16 increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing. © 2012-IOS Press and the authors. All rights reserved.

Author Keywords
γ-secretase;  Alzheimer's disease;  amyloid-β

Document Type: Article
Source: Scopus

 

McNamara, A.a , Booth, T.b , Sridharan, S.b , Caffey, S.a , Grimm, C.c , Bailey, R.b
Directing gaze in narrative art
(2012) Proceedings, SAP 2012 - ACM Symposium on Applied Perception, pp. 63-70. 

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

Abstract
Narrative art tells a story, either as a moment in an ongoing story or as a sequence of events unfolding over time. In many works of art separate panels within the same frame are used to depict the sequence of events. Often, there is no clear delineation between these panels, or any indication of the optimal viewing order. To improve visual literacy we propose using Subtle Gaze Direction (SGD) to direct the viewers gaze across an image in a manner which reveals the story. SGD uses small image space modulations in the luminance channel to guide a viewer's gaze about an image without disrupting their normal visual experience. Using a simple ordering task we compared performance using no modulation and using subtle modulation with the correct order of narrative episodes as intended by the artist. Results from experiments show improved performance when SGD is employed. This experiment establishes the potential of the method as an aid to visual navigation in images where the viewing order is unclear. © 2012 ACM.

Author Keywords
art history education;  eye-tracking;  gaze direction

Document Type: Conference Paper
Source: Scopus

 

Leavey, A.a b , Zwaigenbaum, L.c , Heavner, K.b , Burstyn, I.b
Gestational Age at Birth and Risk of Autism Spectrum Disorders in Alberta, Canada
(2012) Journal of Pediatrics, . Article in Press. 

a Aerosol and Air Quality Research Laboratory, Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, St. Louis, MO
b Department of Environmental and Occupational Health, School of Public Health, Drexel University, Philadelphia, PA
c Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

Abstract
Objective: To examine the association between autism spectrum disorders (ASD) and each completed week of gestation using a graphical method of presenting results at all possible categorizations of gestational age (GA). Study design: The risk of ASD in a total of 218 110 singleton live births with complete data from Alberta, Canada between 1998 and 2004 was examined through linkage to health insurance records. The relative risk of developing ASD according to the 21 dichotomizations of shorter gestation (GA ≤23 weeks vs >23 weeks to ≤43 weeks vs >43 weeks, in 1-week increments) was calculated using log-binomial regression and adjusted for fetal sex, socioeconomic status, and birth year. Results: We observed a gradual increased risk of ASD with shorter gestation. Cutoffs only between 29 and 40 weeks clearly denoted an elevated risk of developing ASD compared with longer gestation, and the risk increased with earlier GA cutoff. The results were not affected by sex or measures of fetal growth. Conclusion: Our data confirm the role of shortened gestation in ASD risk. We warn against the use of prespecified or a data-driven GA cutoff, however; instead, we recommend systematically examining all plausible cutoffs for GA to avoid overstating the homogeneity of risk in children on either side of a given cutoff, as well as to increase the comparability of studies. © 2012 Mosby, Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

 

Kibby, T., Halcomb, S.E.
Toxicology observation: Nystagmus after marijuana use
(2012) Journal of Forensic and Legal Medicine, . Article in Press. 

Toxicology Section, Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Traditional teaching has held that horizontal-gaze nystagmus is a sign of intoxication by sedatives such as alcohol but not marijuana. This is a case report of an adult male who presents with 3 days of visual disturbance and dizziness following marijuana use. The exam was notable for gaze-evoked nystagmus and ataxia. Lab testing was normal except that urine drug screening was positive for marijuana only. Imaging included computed tomography (CT) and magnetic resonance imaging (MRI) scans of the head. Prior studies showing a negative association of nystagmus with marijuana are reviewed. This case is presented as a possible exception to the generalisation that marijuana is not associated with nystagmus. © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine.

Author Keywords
Forensic science;  Humans;  Marijuana abuse/detection;  Nystagmus;  Pathologic/aetiology;  Psychomotor performance/drug effects;  Substance abuse detection

Document Type: Article in Press
Source: Scopus

 

Jiang, Y.a b , Brody, D.L.b c
Administration of COG1410 reduces axonal amyloid precursor protein immunoreactivity and microglial activation after controlled cortical impact in mice
(2012) Journal of Neurotrauma, 29 (13), pp. 2332-2341. 

a Department of Neurosurgery, Affiliated Hospital, Luzhou Medical College, Luzhou, China
b Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Traumatic axonal injury (TAI) accounts for at least 35% of the morbidity and mortality in traumatic brain injury (TBI) patients without space-occupying lesions. It is also believed to be a key determinant of adverse outcomes such as cognitive dysfunction across the spectrum of TBI severity. Previous studies have shown that COG1410, a synthetic peptide derived from the apolipoprotein E (apoE) receptor binding region, has anti-inflammatory effects after experimental TBI, with improvements in cognitive recovery. However, the effects of COG1410 on axonal injury following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously starting 30 min after controlled cortical impact (CCI) injury on pericontusional TAI in young, wild-type C57BL6/J male mice. We found that COG1410 did not affect the number of amyloid precursor protein (APP)-immunoreactive axonal varicosities in the pericontusional corpus callosum and external capsule at 24 h, but reduced APP-immunoreactive varicosities by 31% at 3 days (p=0.0023), and 36% at 7 days (p=0.0009). COG1410 significantly reduced the number of Iba1-positive cells with activated microglial morphology at all three time points by 21-30%. There was no effect of COG1410 on pericontusional white matter volume or silver staining at any time point. This indicates a possible effect of COG1410 on delayed but not immediate TAI. Future studies are needed to investigate the underlying mechanisms, therapeutic time window, and physiological implications of this effect. © Copyright 2012, Mary Ann Liebert, Inc. 2012.

Author Keywords
COG1410;  controlled cortical impact injury;  microglia;  neuroprotection;  traumatic axonal injury

Document Type: Article
Source: Scopus

 

Agarwal, P.K.
Advances in Cognitive Psychology Relevant to Education: Introduction to the Special Issue
(2012) Educational Psychology Review, 24 (3), pp. 353-354. 

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

Document Type: Editorial
Source: Scopus

 

Schuur, J.D.a c , Brown, M.D.d , Cheung, D.S.e , Graff IV, L.f m , Griffey, R.T.g , Hamedani, A.G.h , Kelly, J.J.i , Klauer, K.j n , Phelan, M.k , Sierzenski, P.R.l , Raja, A.S.a b c
Assessment of medicare's imaging efficiency measure for emergency department patients with atraumatic headache
(2012) Annals of Emergency Medicine, 60 (3), pp. 280-290.

a Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, United States
b Center for Evidence-Based Imaging, Brigham and Women's Hospital, Boston, MA, United States
c Harvard Medical School, Boston, MA, United States
d Department of Emergency Medicine, Spectrum Health and Michigan State University, College of Human Medicine, Grand Rapids, MI, United States
e Carepoint P.C., Denver, CO, United States
f Department of Emergency Medicine, Hospital of Central Connecticut, New Britain, CT, United States
g Washington University School of Medicine, Washington University Institute for Public Health, Barnes-Jewish Hospital, St. Louis, MO, United States
h University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States
i Department of Emergency Medicine, Albert Einstein Medical Center, Jefferson Medical College, Philadelphia, PA, United States
j Emergency Medicine Physicians. Ltd, Canton, OH, United States
k Emergency Services Institute, Quality and Patients Safety Institute, Cleveland Clinic, Cleveland, OH, United States
l Department of Emergency Medicine, Christiana Care Health System, Newark/Wilmington, DE, United States
m University of Connecticut School of Medicine, Farmington, CT, United States
n Michigan State University, College of Osteopathic Medicine, Summa Health System, Barberton and Wadsworth, OH, United States

Abstract
Computed tomography (CT) use has increased rapidly, raising concerns about radiation exposure and cost. The Centers for Medicare & Medicaid Services (CMS) developed an imaging efficiency measure (Outpatient Measure 15 [OP-15]) to evaluate the use of brain CT in the emergency department (ED) for atraumatic headache. We aim to determine the reliability, validity, and accuracy of OP-15. This was a retrospective record review at 21 US EDs. We identified 769 patient visits that CMS labeled as including an inappropriate brain CT to identify clinical indications for CT and reviewed the 748 visits with available records. The primary outcome was the reliability of OP-15 as determined by CMS from administrative data compared with medical record review. Secondary outcomes were the measure's validity and accuracy. Outcome measures were defined according to the testing protocol of the American Medical Association's Physician Consortium for Performance Improvement. On record review, 489 of 748 ED brain CTs identified as inappropriate by CMS had a measure exclusion documented that was not identified by administrative data; the measure was 34.6% reliable (95% confidence interval [CI] 31.2% to 38.0%). Among the 259 patient visits without measure exclusions documented in the record, the measure's validity was 47.5% (95% CI 41.4% to 53.6%), according to a consensus list of indications for brain CT. Overall, 623 of the 748 ED visits had either a measure exclusion or a consensus indication for CT; the measure's accuracy was 16.7% (95% CI 14% to 19.4%). Hospital performance as reported by CMS did not correlate with the proportion of CTs with a documented clinical indication (r=0.11; P=.63). The CMS imaging efficiency measure for brain CTs (OP-15) is not reliable, valid, or accurate and may produce misleading information about hospital ED performance. © 2012 American College of Emergency Physicians.

Document Type: Review
Source: Scopus

 

Hoffman, B.M.a , Blumenthal, J.A.a , Carney, R.C.b , O'Hayer, C.V.F.a , Freedland, K.b , Smith, P.J.a , Babyak, M.A.a , Davis, R.D.c , Mathew, J.P.d , Martinu, T.e , Palmer, S.e
Changes in neurocognitive functioning following lung transplantation
(2012) American Journal of Transplantation, 12 (9), pp. 2519-2525. 

a Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States
b Department of Psychiatry, Washington University, St. Louis, MO, United States
c Department of Surgery, Duke University Medical Center, Durham, NC, United States
d Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
e Department of Medicine, Duke University Medical Center, Durham, NC, United States


Abstract
Although neurocognitive impairment is relatively common among patients with advanced lung disease, little is known regarding changes in neurocognition following lung transplantation. We therefore administered 10 tests of neurocognitive functioning before and 6 months following lung transplantation and sought to identify predictors of change. Among the 49 study participants, native diseases included chronic obstructive pulmonary disease (n = 22), cystic fibrosis (n = 12), nonfibrotic diseases (n = 11) and other (n = 4). Although composite measures of executive function and verbal memory scores were generally within normal limits both before and after lung transplantation, verbal memory performance was slightly better posttransplant compared to baseline (p < 0.0001). Executive function scores improved in younger patients but worsened in older patients (p = 0.03). A minority subset of patients (29%) exhibited significant cognitive decline (i.e. >1 standard deviations on at least 20% of tests) from baseline to posttransplant. Patients who declined were older (p < 0.004) and tended to be less educated (p = 0.07). Lung transplantation, like cardiac revascularization procedures, appears to be associated with cognitive decline in a subset of older patients, which could impact daily functioning posttransplant. Data provided by 49 patients who completed neuropsychological tests before and 6 months following lung transplantation suggest that verbal memory may improve after lung transplantation, whereas executive function may improve for younger patients but decline for older patients. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Author Keywords
Lung transplantation;  neurocognition;  neuropsychological testing;  outcomes

Document Type: Article
Source: Scopus

 

Depta, J.P.a , Fowler, J.b , Novak, E.a , Katzan, I.b , Bakdash, S.b , Kottke-Marchant, K.b , Bhatt, D.L.c
Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack
(2012) Stroke, 43 (9), pp. 2376-2381. 

a Washington University School of Medicine, St Louis, MO, United States
b Cleveland Clinic, Cleveland, OH, United States
c VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, 1400 VFW Parkway, Boston, MA 02132, United States

Abstract
BACKGROUND AND PURPOSE-: Antiplatelet therapy nonresponse is associated with worse clinical outcomes. We studied the clinical outcomes associated with platelet function-guided modifications in antiplatelet therapy in patients with ischemic stroke or transient ischemic attack. METHODS-: From January 2005 to August 2007, 324 patients with ischemic stroke underwent platelet function testing using platelet aggregometry. Aspirin nonresponse was defined as a mean platelet aggregation ≥20% with 0.5 mg/mL arachidonic acid and/or ≥70% with 5 μmol/L adenosine diphosphate. Clopidogrel nonresponse was defined as a mean platelet aggregation ≥40% with 5 μmol/L adenosine diphosphate. A modification was any increase in antiplatelet therapy occurring after testing. Clinical outcomes were compared between patients with and without platelet function-guided antiplatelet therapy modifications using univariate and propensity score-adjusted analyses. RESULTS-: In patients with ischemic stroke or transient ischemic attack, 43% (n=128) and 35% (n=54) were nonresponders to aspirin and clopidogrel, respectively. After platelet function testing, antiplatelet therapy was increased in 23% of patients (n=73). After propensity score matching (n=61 in each group), antiplatelet therapy modification was associated with significantly increased rates of death, ischemic events, or bleeding (hazard ratio, 2.24; 95% CI, 1.12-4.47; P=0.02) compared with no modification in antiplatelet therapy and a trend toward increased bleeding (hazard ratio, 3.56; 95% CI, 0.98-12.95; P=0.05). No differences in ischemic events were observed. CONCLUSIONS-: Platelet function-guided modification in antiplatelet therapy after an ischemic stroke or transient ischemic attack was associated with significantly higher rates of adverse clinical outcomes. © 2012 American Heart Association, Inc.

Author Keywords
aspirin;  clopidogrel;  ischemic stroke;  nonresponse;  platelet function testing;  resistance;  transient ischemic attack

Document Type: Article
Source: Scopus

 

Osei, D.A.a , Williams, A.A.b , Weiland, A.J.c
Concomitant compressive neuropathy of the ulnar and median nerves in the hand by midpalmar ganglion

(2012) Hand, 7 (3), pp. 317-319. 


a Department of Orthopaedic Surgery, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Orthopaedic Surgery, Johns Hopkins University, 601 North Caroline Street, JHOC #5215, Baltimore, MD 21287, United States
c Department of Orthopaedic Surgery, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, United States

Document Type: Article
Source: Scopus

 

Gaffrey, M.S.a , Luby, J.L.a , Botteron, K.a c , Repovš, G.b d , Barch, D.M.a b c
Default mode network connectivity in children with a history of preschool onset depression
(2012) Journal of Child Psychology and Psychiatry and Allied Disciplines, 53 (9), pp. 964-972. 

a Campus Box: 8134, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Psychology, Washington University in St. Louis, Saint Louis, MO, United States
c Department of Radiology, Washington University in St. Louis, Saint Louis, MO, United States
d Department of Psychology, University of Ljubljana, Ljubljana, Slovenia

Abstract
Background: Atypical Default Mode Network (DMN) functional connectivity has been previously reported in depressed adults. However, there is relatively little data informing the developmental nature of this phenomenon. The current case-control study examined the DMN in a unique prospective sample of school-age children with a previous history of preschool depression. Methods: DMN functional connectivity was assessed using resting state functional connectivity magnetic resonance imaging data and the posterior cingulate (PCC) as a seed region of interest. Thirty-nine medication naïve school age children (21 with a history of preschool depression and 18 healthy peers) and their families who were ascertained as preschoolers and prospectively assessed over at least 4 annual waves as part of a federally funded study of preschool depression were included. Results: Decreased connectivity between the PCC and regions within the middle temporal gyrus (MTG), inferior parietal lobule, and cerebellum was found in children with known depression during the preschool period. Increased connectivity between the PCC and regions within the subgenual and anterior cingulate cortices and anterior MTG bilaterally was also found in these children. Additionally, a clinically relevant 'brain-behavior' relationship between atypical functional connectivity of the PCC and disruptions in emotion regulation was identified. Conclusions: To our knowledge, this is the first study to examine the DMN in children known to have experienced the onset of a clinically significant depressive syndrome during preschool. Results suggest that a history of preschool depression is associated with atypical DMN connectivity. However, longitudinal studies are needed to clarify whether the current findings of atypical DMN connectivity are a precursor or a consequence of preschool depression. © 2012 Association for Child and Adolescent Mental Health.

Author Keywords
default mode network;  Depression;  functional connectivity;  preschool

Document Type: Article
Source: Scopus

 

Shah, K.M.a , Mueller, M.J.b
Effect of selected exercises on in-shoe plantar pressures in people with diabetes and peripheral neuropathy
(2012) Foot, 22 (3), pp. 130-134. 

a Movement Science Program, Washington University, School of Medicine, St. Louis, United States
b Washington University School of Medicine, Department of Radiology, St. Louis, United States

Abstract
Background: In people with diabetes and peripheral neuropathy (DM. +. PN), injury risk is not clearly known for weight bearing (WB) vs. non-weight bearing (NWB) exercise. In-shoe peak plantar pressures (PPP) often are used as a surrogate indicator of injury to the insensitive foot. Objective: Compare PPPs in people with DM. +. PN during selected WB and NWB exercises. Methods: Fifteen subjects with DM. +. PN participated. PPPs were recorded for the forefoot, midfoot, and heel during level walking and compared to; WB exercises - treadmill walking, heel and toe raises, sit to stands, stair climbing, single leg standing; and NWB exercises - stationary bicycling, balance ball exercise and plantar flexion exercise. Results: Compared to level walking; mean forefoot PPP during treadmill walking was 13% higher, but this difference was eliminated when walking speed was used as a covariate. Mean PPPs were similar or substantially lower for other exercises, except for higher forefoot PPP with heel raise exercises. Conclusions: Slow progression and regular monitoring of insensitive feet are recommended for all exercises, but especially for heel raises, and increases in walking speed. The remaining WB and NWB exercises pose no greater risk to the insensitive foot due to increases in PPP compared to level walking. © 2012 Elsevier Ltd.

Author Keywords
Diabetes;  Exercise;  Peripheral neuropathy;  Plantar pressure

Document Type: Article
Source: Scopus

 

Sylvester, C.M.a , Corbetta, M.b c d , Raichle, M.E.b c d , Rodebaugh, T.L.e , Schlaggar, B.L.b c d f , Sheline, Y.I.a b d , Zorumski, C.F.a c , Lenze, E.J.a
Functional network dysfunction in anxiety and anxiety disorders
(2012) Trends in Neurosciences, 35 (9), pp. 527-535. 

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

Abstract
A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. We propose here that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies. © 2012 Elsevier Ltd.

Author Keywords
Anxiety;  Anxiety disorder;  Brain network;  FMRI;  Functional network

Document Type: Review
Source: Scopus

 

Diringer, M.N.a , Zazulia, A.R.a b
Hemostatic therapy should be used for acute treatment of anticoagulation-related intracerebral hemorrhage
(2012) Stroke, 43 (9), pp. 2535-2536. 

a Department of Neurology, Neurosurgery Intensive Care Unit, Washington University School of Medicine, St Louis, MO, United States
b Department of Radiology, Neurosurgery Intensive Care Unit, Washington University School of Medicine, St Louis, MO, United States

Document Type: Note
Source: Scopus

 

Sobrin, L.a , Ripke, S.b , Yu, Y.c z , Fagerness, J.b , Bhangale, T.R.d , Tan, P.L.e , Souied, E.H.f g , Buitendijk, G.H.S.h , Merriam, J.E.i , Richardson, A.J.j , Raychaudhuri, S.k , Reynolds, R.c , Chin, K.A.c , Lee, A.Y.l , Leveziel, N.f g , Zack, D.J.m n o , Campochiaro, P.m n , Smith, R.T.i , Barile, G.R.i , Hogg, R.E.p , Chakravarthy, U.p , Behrens, T.W.q , Uitterlinden, A.G.r , Van Duijn, C.M.s , Vingerling, J.R.h , Brantley Jr., M.A.t , Baird, P.N.j , Klaver, C.C.W.h , Allikmets, R.i u , Katsanis, N.e , Graham, R.R.q , Ioannidis, J.P.A.v w x , Daly, M.J.b , Seddon, J.M.c y
Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes
(2012) Ophthalmology, 119 (9), pp. 1874-1885. 

a Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States
b Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States
c Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts University School of Medicine, Boston, MA, United States
d Department of Bioinformatics and Computational Biology, Genentech, Inc, South San Francisco, CA, United States
e Center for Human Disease Modeling, Departments of Cell Biology and Pediatrics, Duke University, Durham, NC, United States
f Department of Ophthalmology, University Paris Est Creteil, Hôpital Intercommunal de Creteil, Creteil, France
g Department of Ophthalmology, Faculté de Médecine Henri Mondor, UPEC, Créteil, France
h Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
i Department of Ophthalmology, Columbia University, New York, NY, United States
j Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia
k Divisions of Genetics and Rheumatology, Brigham and Women's Hospital, Boston, MA, United States
l Ophthalmology and Visual Sciences, Washington University School of Medicine, Barnes Retina Institute, St. Louis, MO, United States
m McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
n Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
o Department of Molecular Biology, Genetics and Institut de la Vision, UPMC, Paris, France
p Center for Vision and Vascular Science, Queen's University, Belfast, United Kingdom
q Immunology Tissue Growth and Repair (ITGR), Human Genetics Group, Genentech, Inc., South San Francisco, CA, United States
r Department Epidemiology, Department Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
s Department Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
t Deparment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, United States
u Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
v Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
w Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
x Center for Genetic Epidemiology and Modeling, Institute for Clinical Research and Health Policy Studies (ICRHPS), Tufts University School of Medicine, Boston, MA, United States
y Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, United States
z Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States

Abstract
Purpose: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. Design: Sibling correlation study and genome-wide association study (GWAS). Participants: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. Methods: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. Main Outcome Measures: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. Results: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2×10 -5), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3×10 -9), which was confirmed in the replication samples (OR, 1.38; P = 7.4×10 -14 for combined discovery and replication analysis). Conclusions: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. © 2012 American Academy of Ophthalmology.

Document Type: Article
Source: Scopus

 

Willey, J.Z.a , Ortega-Gutierrez, S.a , Petersen, N.a , Khatri, P.b , Ford, A.L.c , Rost, N.S.d , Ali, L.K.e , Gonzales, N.R.f , Merino, J.G.g , Meyer, B.C.h , Marshall, R.S.a
Impact of acute ischemic stroke treatment in patients >80 years of age: The specialized program of translational research in acute stroke (SPOTRIAS) consortium experience
(2012) Stroke, 43 (9), pp. 2369-2375. 

a Department of Neurology, Columbia University, Box 30, 710 West 168th Street, New York, NY 10032, United States
b Department of Neurology, University of Cincinnati, Cincinnati, OH, United States
c Department of Neurology, Washington University, St Louis, MO, United States
d Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
e Department of Neurology, UCLA, Los Angeles, CA, United States
f Department of Neurology, University of Texas Houston, Houston, TX, United States
g Division of Intramural Research, National Institutes of Health, Bethesda, MD, United States
h Department of Neurology, University of California, San Diego, San Diego, CA, United States

Abstract
BACKGROUND AND PURPOSE-: Few studies have addressed outcomes among patients ≥80 years treated with acute stroke therapy. In this study, we outline in-hospital outcomes in (1) patients ≥80 years compared with their younger counterparts; and (2) those over >80 years receiving intra-arterial therapy (IAT) compared with those treated with intravenous recombinant tissue-type plasminogen activator (IV rtPA). METHODS-: Stroke centers within the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) prospectively collected data on all patients treated with IV rtPA or IAT from January 1, 2005, to December 31, 2010. IAT was defined as receiving any endovascular therapy; IAT was further divided into bridging therapy when the patient received both IAT and IV rtPA and endovascular therapy alone. In-hospital mortality was compared in (1) all patients aged ≥80 years versus younger counterparts; and (2) IAT, bridging therapy, and endovascular therapy alone versus IV rtPA only among those age ≥80 years using multivariable logistic regression. An age-stratified analysis was also performed. RESULTS-: A total of 3768 patients were included in the study; 3378 were treated with IV rtPA alone and 808 with IAT (383 with endovascular therapy alone and 425 with bridging therapy). Patients ≥80 years (n=1182) had a higher risk of in-hospital mortality compared with younger counterparts regardless of treatment modality (OR, 2.13; 95% CI, 1.60-2.84). When limited to those aged ≥80 years, IAT (OR, 0.95; 95% CI, 0.60-1.49), bridging therapy (OR, 0.82; 95% CI, 0.47-1.45), or endovascular therapy alone (OR, 1.15; 95% CI, 0.64-2.08) versus IV rtPA were not associated with increased in-hospital mortality. CONCLUSIONS-: IAT does not appear to increase the risk of in-hospital mortality among those aged >80 years compared with IV thrombolysis alone. © 2012 American Heart Association, Inc.

Author Keywords
acute Rx;  acute stroke;  interventional neuroradiology

Document Type: Article
Source: Scopus

 

Lieu, J.E.C.a , Tye-Murray, N.a , Fu, Q.b
Longitudinal study of children with unilateral hearing loss
(2012) Laryngoscope, 122 (9), pp. 2088-2095. 

a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Campus Box 8115, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Department of Biostatistics, St. Louis University, School of Public Health, St. Louis, MO, United States

Abstract
Objectives/Hypothesis: Children with unilateral hearing loss (UHL) have been found to have lower language scores, and increased rate of speech therapy, grade failures, or needing Individualized Education Plans (IEPs). The objective of this study was to determine whether language skills and educational performance improved or worsened over time in a cohort of children with UHL. Study Design: Prospective longitudinal cohort study. Methods: Forty-six children with permanent UHL, ages 6 to 12 years, were studied using standardized cognitive, achievement, and language testing at yearly intervals for 3 years. Using standardized test scores allowed implicit comparison to norms established by national cross-sectional samples. Secondary outcomes included behavioral issues, IEPs, receipt of speech therapy, or teacher report of problems at school. Analysis utilized repeated measures analysis of variance and multilevel random regression modeling. Results: Several cognitive and language mean standardized scores increased over time. Possible predictors of increase with time included higher baseline cognitive levels and receipt of interventions through an IEP. However, standardized achievement scores and indicators of school performance did not show concomitant improvements. Rates of IEPs remained >50% throughout, and rates of speech therapy were consistently about 20%. Conclusions: Children with UHL demonstrated improvement in oral language and verbal intelligence quota scores over time, but not improvements in school performance. Parents and teachers reported persistent behavioral problems and academic weaknesses or areas of concern in about 25%. The provision of IEPs for children with UHL, and acknowledging UHL as a hearing disability, may be an effective intervention to improve language skills over time. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

Author Keywords
children;  speech or language delay;  Unilateral hearing loss

Document Type: Article
Source: Scopus

 

Gilbert, O.M.a , Kuzdzal-Fick, J.J.b , Queller, D.C.c , Strassmann, J.E.c
Mind the gap: A comparative study of migratory behavior in social amoebae

(2012) Behavioral Ecology and Sociobiology, 66 (9), pp. 1291-1296. 
a 6046 Penrose Avenue, Dallas, TX 75206, United States
b Department of Systems Biology-Unit 950, The University of Texas MD Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77054, United States
c Department of Biology, Washington University in St. Louis, Campus Box 1137, One Brookings Drive, St. Louis, MO 63130-4899, United States

Abstract
Social amoebae aggregate to form a multicellular slug that migrates some distance. Most species produce a stalk during migration, but some do not. We show that Dictyostelium giganteum, a species that produces stalk during migration, is able to traverse small gaps and utilize bacterial resources following gap traversal by shedding live cells. In contrast, we found that Dictyostelium discoideum, a species that does not produce stalk during migration, can traverse gaps only when in the presence of other species' stalks or other thin filaments. These findings suggest that production of stalk during migration allows traversal of gaps that commonly occurs in soil and leaf litter. Considering the functional consequences of a stalked migration may be important for explaining the evolutionary maintenance or loss of a stalked migration. © 2012 Springer-Verlag.

Author Keywords
Cellular slime mold;  Development;  Dictyostelium;  Inclusive fitness

Document Type: Article
Source: Scopus

 

Mansberger, S.L.a , Gordon, M.O.b , Jampel, H.c , Bhorade, A.b , Brandt, J.D.d , Wilson, B.c , Kass, M.A.b
Reduction in intraocular pressure after cataract extraction: The ocular hypertension treatment study
(2012) Ophthalmology, 119 (9), pp. 1826-1831. 

a Devers Eye Institute/Discoveries in Sight, Legacy Health System, 1040 NW 22nd Avenue, Portland, OR 97210, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c John Hopkins University, Baltimore, MD, United States
d University of California, Davis Eye Center, Davis, CA, United States

Abstract
Purpose: To determine the change in intraocular pressure (IOP) after cataract extraction in the observation group of the Ocular Hypertension Treatment Study. Design: Comparative case series. Participants: Forty-two participants (63 eyes) who underwent cataract surgery in at least 1 eye during the study and a control group of 743 participants (743 eyes) who did not undergo cataract surgery. Methods: We defined the "split date" as the study visit date at which cataract surgery was reported in the cataract surgery group and a corresponding date in the control group. Preoperative IOP was defined as the mean IOP of up to 3 visits before the split date. Postoperative IOP was the mean IOP of up to 3 visits including the split date (0, 6, and 12 months' with "0 months" equaling the split date). In both groups, we censored data after initiation of ocular hypotensive medication or glaucoma surgery of any kind. Main Outcome Measures: Difference in preoperative and postoperative IOP. Results: In the cataract group, postoperative IOP was significantly lower than the preoperative IOP (19.8±3.2 mmHg vs. 23.9±3.2 mmHg; P<0.001). The postoperative IOP remained lower than the preoperative IOP for at least 36 months. The average decrease in postoperative IOP from preoperative IOP was 16.5%, and 39.7% of eyes had postoperative IOP <20% below preoperative IOP. A greater reduction in postoperative IOP occurred in the eyes with the highest preoperative IOP. In the control group, the corresponding mean IOPs were 23.8±3.6 before the split date and 23.4±3.9 after the split date. Conclusions: Cataract surgery decreases IOP in patients with ocular hypertension over a long period of time. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. © 2012 American Academy of Ophthalmology.

Document Type: Article
Source: Scopus

 

Stein, P.K.
Sleep apnea: What does that really mean? A commentary on Baranchuk: "Sleep apnea, cardiac arrhythmias, and conduction disorders"
(2012) Journal of Electrocardiology, 45 (5), pp. 513-514. 

Heart Rate Variability Laboratory, School of Medicine, Washington University, Saint Louis, MO, United States

Document Type: Note
Source: Scopus

 

Stein, L.R., Imai, S.-I.
The dynamic regulation of NAD metabolism in mitochondria
(2012) Trends in Endocrinology and Metabolism, 23 (9), pp. 420-428. 

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

Abstract
Mitochondria are intracellular powerhouses that produce ATP and carry out diverse functions for cellular energy metabolism. Although the maintenance of an optimal NAD/NADH ratio is essential for mitochondrial function, it has recently become apparent that the maintenance of the mitochondrial NAD pool is also of crucial importance. The biosynthesis, transport, and catabolism of NAD and its key intermediates play an important role in the regulation of NAD-consuming mediators, such as sirtuins, poly-ADP-ribose polymerases, and CD38/157 ectoenzymes, in intra- and extracellular compartments. Mitochondrial NAD biosynthesis is also modulated in response to nutritional and environmental stimuli. In this article, we discuss this dynamic regulation of NAD metabolism in mitochondria to shed light on the intimate connection between NAD and mitochondrial function. © 2012 Elsevier Ltd.

Document Type: Article
Source: Scopus

 

Acosta, M.T.a b , Bearden, C.E.c , Castellanos, X.F.d , Cutting, L.e , Elgersma, Y.f , Gioia, G.a , Gutmann, D.H.g , Lee, Y.-S.h , Legius, E.i , Muenke, M.b , North, K.i , Parada, L.F.j , Ratner, N.k , Hunter-Schaedle, K.l , Silva, A.J.c
The Learning Disabilities Network (LeaDNet): Using neurofibromatosis type 1 (NF1) as a paradigm for translational research
(2012) American Journal of Medical Genetics, Part A, 158 A (9), pp. 2225-2232. 

a The Gilbert Neurofibromatosis Institute, Children's National Medical Center, Washington District of Columbia, United States
b National Human Genome Research Institute, National Institute of Health, Bethesda, MD, United States
c University of California, Los Angeles, CA, United States
d New York University, New York, NY, United States
e Vanderbilt University, Nashville, TN, United States
f Erasmus University, Rotterdam, Netherlands
g Washington University School of Medicine, St. Louis, MO, United States
h University of Leuven, Leuven, Belgium
i Children's Hospital at Westmead, University of Sydney, Sydney, Australia
j University of Texas Southwestern, Dallas, TX, United States
k Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
l Children's Tumor Foundation, New York, NY, United States

Abstract
Learning disabilities and other cognitive disorders represent one of the most important unmet medical needs and a significant source of lifelong disability. To accelerate progress in this area, an international consortium of researchers and clinicians, the Learning Disabilities Network (LeaDNet), was established in 2006. Initially, LeaDNet focused on neurofibromatosis type 1 (NF1), a common single gene disorder with a frequency of 1:3,000. Although NF1 is best recognized as an inherited tumor predisposition syndrome, learning, cognitive, and neurobehavioral deficits account for significant morbidity in this condition and can have a profound impact on the quality of life of affected individuals. Recently, there have been groundbreaking advances in our understanding of the molecular, cellular, and neural systems underpinnings of NF1-associated learning deficits in animal models, which precipitated clinical trials using a molecularly targeted treatment for these deficits. However, much remains to be learned about the spectrum of cognitive, neurological, and psychiatric phenotypes associated with the NF1 clinical syndrome. In addition, there is a pressing need to accelerate the identification of specific clinical targets and treatments for these phenotypes. The successes with NF1 have allowed LeaDNet investigators to broaden their initial focus to other genetic disorders characterized by learning disabilities and cognitive deficits including other RASopathies (caused by changes in the Ras signaling pathway). The ultimate mission of LeaDNet is to leverage an international translational consortium of clinicians and neuroscientists to integrate bench-to-bedside knowledge across a broad range of cognitive genetic disorders, with the goal of accelerating the development of rational and biologically based treatments. © 2012 Wiley Periodicals, Inc.

Author Keywords
Learning disabilities;  Learning Disabilities Network;  Neurodevelopmental disorders;  Neurofibromatosis type 1;  RAS/MAPK pathway

Document Type: Review
Source: Scopus

 

Agarwal, P.K.a , Bain, P.M.b , Chamberlain, R.W.c
The Value of Applied Research: Retrieval Practice Improves Classroom Learning and Recommendations from a Teacher, a Principal, and a Scientist
(2012) Educational Psychology Review, 24 (3), pp. 437-448. 

a Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, United States
b Columbia Middle School, Columbia, IL 62236, United States
c College of Education, Roosevelt University, Chicago, IL 60605, United States

Abstract
Over the course of a 5-year applied research project with more than 1,400 middle school students, evidence from a number of studies revealed that retrieval practice in authentic classroom settings improves long-term learning (Agarwal et al. 2009; McDaniel et al., Journal of Educational Psychology 103:399-414, 2011; McDaniel et al. 2012; Roediger et al., Journal of Experimental Psychology: Applied 17:382-395, 2011a). Retrieval practice, or the use of quizzes and exams to engage and enhance retrieval processes, has been widely established as an effective strategy for facilitating learning in laboratory settings (e. g., Roediger et al. 2011c). In this article, we review recent findings from applied research that demonstrate that retrieval practice enhances long-term classroom learning, delayed quizzes are particularly potent for retention, quizzes benefit students' transfer to novel quiz items, and quizzes with feedback improve students' learning and metacognitive awareness. In addition to generating evidence to support retrieval-based learning, these applied research studies also enhanced the professional development of the teachers, administrators, and scientists involved in the project. In this article, it is our hope that by sharing what we have learned from a variety of perspectives, applied scientific research in K-12 classrooms will continue to be explored and generated at local, state, and national levels, improving student learning and educational decision-making. © 2012 Springer Science+Business Media, LLC.

Author Keywords
Applied research;  Education;  Quizzing;  Retrieval practice;  Teaching;  Testing effect

Document Type: Review
Source: Scopus

 

Bateman, R.J.a , Xiong, C.b , Benzinger, T.L.S.d , Fagan, A.M.a , Goate, A.c , Fox, N.C.f , Marcus, D.S.d , Cairns, N.J.e , Xie, X.b , Blazey, T.M.d , Holtzman, D.M.a , Santacruz, A.a , Buckles, V.a , Oliver, A.a , Moulder, K.a , Aisen, P.S.g , Ghetti, B.h , Klunk, W.E.i j , McDade, E.j , Martins, R.N.k , Masters, C.L.l , Mayeux, R.n , Ringman, J.M.o , Rossor, M.N.f , Schofield, P.R.m , Sperling, R.A.p , Salloway, S.q , Morris, J.C.a
Clinical and biomarker changes in dominantly inherited Alzheimer's disease
(2012) New England Journal of Medicine, 367 (9), pp. 795-804. 

a Washington University School of Medicine, Department of Neurology, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, United States
b Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
f University College London Institute of Neurology, London, United Kingdom
g Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
h Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
i Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
j Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
k Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia
l Mental Health Research Institute, University of Melbourne, Melbourne, VIC, Australia
m Neuroscience Research Australia and the School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
n Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University College of Physicians and Surgeons, New York, United States
o Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
p Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
q Department of Neurology and the Memory and Aging Program, Butler Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States

Abstract
BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ) 42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.

Document Type: Article
Source: Scopus

 

Loo, L.a , Shepherd, A.J.a , Mickle, A.D.a , Lorca, R.A.a c , Shutov, L.P.a , Usachev, Y.M.a b , Mohapatra, D.P.a b
The C-type natriuretic peptide induces thermal hyperalgesia through a noncanonical Gβγ-dependent modulation of TRPV1 channel
(2012) Journal of Neuroscience, 32 (35), pp. 11942-11955. 

a Departments of Pharmacology, Roy J. and Lucile A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, United States
b Departments of Anesthesia, Roy J. and Lucile A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, United States
c Department of Obstetrics and Gynecology, Center for Women's Reproductive Sciences Research, BJC Institute of Health, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain essentially unknown. Many biological effects of NPs are mediated by guanylate cyclase (GC)-coupled NP receptors, NPR-A and NPR-B, whereas the third NP receptor, NPR-C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR-C can couple to specific Gα i-Gβγ-mediated intracellular signaling cascades in numerous cell types. We found that NPR-C is coexpressed in transient receptor potential vanilloid-1 (TRPV1)-expressing mouse dorsal root ganglia (DRG) neurons. NPR-C can be coimmunoprecipitated with Gα i, and C-type natriuretic peptide (CNP) treatment induced translocation of protein kinase Ce (PKCe) to the plasma membrane of these neurons, which was inhibited by pertussis toxin pretreatment. Application of CNP potentiated capsaicin- and proton-activated TRPV1 currents in cultured mouse DRG neurons and increased their firing frequency, an effect that was absent in DRG neurons from TRPV1 -/- mice. CNP-induced sensitization of TRPV1 activity was attenuated by pretreatment of DRG neurons with the specific inhibitors of Gβγ, phospholipase C-/3 (PLCβ), or PKC, but not of protein kinase A, and was abolished by mutations at two PKC phosphorylation sites in TRPV1. Furthermore, CNP injection into mouse hindpaw led to the development of thermal hyperalgesia that was attenuated by administration of specific inhibitors of Gβγ or TRPV1 and was also absent in TRPV1 -/- mice. Thus, our work identifies the Gβγ-PLCβ-PKC-dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Yablonskiy, D.A.a b , Luo, J.c , Sukstanskii, A.L.a , Iyer, A.a , Cross, A.H.d
Biophysical mechanisms of MRI signal frequency contrast in multiple sclerosis
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (35), pp. 14212-14217. 

a Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, United States
c Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Neurology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Phase images obtained with gradient echo MRI provide image contrast distinct from T1- and T2-weighted images. It is commonly assumed that the local contribution to MRI signal phase directly relates to local bulk tissue magnetic susceptibility. Here, we use Maxwell's equations and Monte Carlo simulations to provide theoretical background to the hypothesis that the local contribution to MRI signal phase does not depend on tissue bulk magnetic susceptibility but tissue magnetic architecture - distribution of magnetic susceptibility inclusions (lipids, proteins, iron, etc.) at the cellular and subcellular levels. Specifically, we show that the regular longitudinal structures forming cylindrical axons (myelin sheaths and neurofilaments) can be locally invisible in phase images. Contrary to an expectation that the phase contrast in multiple sclerosis lesions should always increase in degree along with worsening of lesion severity (which happens for all known MR magnitude-based contrast mechanisms), we show that phase contrast can actually disappear with extreme tissue destruction. We also show that the phase contrast in multiple sclerosis lesions could be altered without loss of nervous system tissue, which happens in mild injury to the myelin sheaths or axonal neurofilaments. Moreover, we predict that the sign of phase contrast in multiple sclerosis lesions indicates the predominant type of tissue injury - myelin damage (positive sign) vs. axonal neurofilament damage (negative sign). Therefore, our theoretical and experimental results shed light on understanding the relationship between gradient echo MRI signal phase and multiple sclerosis pathology.

Author Keywords
CNS;  Demyelination;  Generalized lorentzian approach;  Neuronal integrity;  Phase imaging

Document Type: Article
Source: Scopus

 

Carrasquillo, Y.a , Burkhalter, A.b , Nerbonne, J.M.a
A-type K + channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons
(2012) Journal of Physiology, 590 (16), pp. 3877-3890. 
a Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, United States
b Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Rapidly activating and rapidly inactivating voltage-gated A-type K + currents, I A, are key determinants of neuronal excitability and several studies suggest a critical role for the Kv4.2 pore-forming α subunit in the generation of I A channels in hippocampal and cortical pyramidal neurons. The experiments here demonstrate that Kv4.2, Kv4.3 and Kv1.4 all contribute to the generation of I A channels in mature cortical pyramidal (CP) neurons and that Kv4.2-, Kv4.3- and Kv1.4-encoded I A channels play distinct roles in regulating the intrinsic excitability and the firing properties of mature CP neurons. In vivo loss of Kv4.2, for example, alters the input resistances, current thresholds for action potential generation and action potential repolarization of mature CP neurons. Elimination of Kv4.3 also prolongs action potential duration, whereas the input resistances and the current thresholds for action potential generation in Kv4.3 -/- and WT CP neurons are indistinguishable. In addition, although increased repetitive firing was observed in both Kv4.2 -/- and Kv4.3 -/- CP neurons, the increases in Kv4.2 -/- CP neurons were observed in response to small, but not large, amplitude depolarizing current injections, whereas firing rates were higher in Kv4.3 -/- CP neurons only with large amplitude current injections. In vivo loss of Kv1.4, in contrast, had minimal effects on the intrinsic excitability and the firing properties of mature CP neurons. Comparison of the effects of pharmacological blockade of Kv4-encoded currents in Kv1.4 -/- and WT CP neurons, however, revealed that Kv1.4-encoded I A channels do contribute to controlling resting membrane potentials, the regulation of current thresholds for action potential generation and repetitive firing rates in mature CP neurons. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.

Document Type: Article
Source: Scopus

 

Disabato, B.M.a , Sheline, Y.I.b
Biological basis of late life depression

(2012) Current Psychiatry Reports, 14 (4), pp. 273-279. 
a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Departments of Psychiatry, Washington University, School of Medicine, 660 South Euclid, St. Louis, MO 63110, United States

Abstract
Late life depression (LLD) is an important area of research given the growing elderly population. The purpose of this review is to examine the available evidence for the biological basis of LLD. Structural neuroimaging shows specific gray matter structural changes in LLD as well as ischemic lesion burden via white matter hyperintensities. Similarly, specific neuropsychological deficits have been found in LLD. An inflammatory response is another possible underlying contributor to the pathophysiology of LLD. We review the available literature examining these multiple facets of LLD and how each may affect clinical outcome in the depressed elderly. © Springer Science+Business Media, LLC 2012.

Author Keywords
Cognitive deficits;  Elderly;  Inflammatory markers;  Ischemic lesion burden;  Late life depression;  LLD;  Neuropsychological factors;  Structural neuroimaging;  Treatment outcome;  White matter hyperintensities

Document Type: Article
Source: Scopus

 

Carlson, B.A.
Diversity matters: The importance of comparative studies and the potential for synergy between neuroscience and evolutionary biology
(2012) Archives of Neurology, 69 (8), pp. 987-993. 

Department of Biology, Washington University, Campus Box 1137, 1 Brookings Dr, St Louis, MO 63130, United States

Abstract
Basic research in neuroscience and clinical research on neurological disorders synergistically increase our understanding of the human brain. Traditionally, functional and clinical studies of the human brain were limited to postmortem histology, "natural experiments"(eg, lesions to brain areas caused by trauma or disease), and crude measures of electrical activity such as electroencephalography. More recently, the development of transcranial magnetic stimulation and rapid advances in imaging technology have greatly facilitated human brain research. In rare cases in which treating a neurological disorder involves implanting electrodes, researchers can even record the electrical activity of individual neurons. Although these approaches have led to important insights, they do not allow for a precise dissection of the underlying mechanisms by which the brain mediates perception, cognition, and behavior. Thus, neuroscientists and neurologists remain severely limited in the types of experiments they can perform on human subjects and much of our understanding of brain structure and function is based on research in animal models. In this article, I highlight the enormous potential for synergy between neuroscience and evolutionary biology. Nervous systems have been shaped by evolution, and comparative approaches take advantage of the resulting diversity to gain insight into the neural mechanisms of behavior. On the other hand, nervous systems and the behaviors and perceptions they mediate can play a fundamental role in the evolutionary processes that generate this diversity. To emphasize these points, I describe recent findings from research on African fishes that use electricity to communicate and navigate in their dark underwater world. ©2012 American Medical Association. All rights reserved.

Document Type: Review
Source: Scopus

 

Hartz, S.M.a , Short, S.E.b , Saccone, N.L.a , Culverhouse, R.a , Chen, L.a , Schwantes-An, T.-H.a , Coon, H.c , Han, Y.d , Stephens, S.H.e , Sun, J.f , Chen, X.g , Ducci, F.h i , Dueker, N.j , Franceschini, N.k , Frank, J.l , Geller, F.m , Guobjartsson, D.n , Hansel, N.N.o , Jiang, C.p , Keskitalo-Vuokko, K.q , Liu, Z.u , Lyytikäinen, L.-P.r , Michel, M.v , Rawal, R.w , Rosenberger, A.t , Scheet, P.d , Shaffer, J.R.x , Teumer, A.y , Thompson, J.R.z , Vink, J.M.aa , Vogelzangs, N.ab , Wenzlaff, A.S.ac , Wheeler, W.ad , Xiao, X.d , Yang, B.-Z.p , Aggen, S.H.g , Balmforth, A.J.ae , Baumeister, S.E.y , Beaty, T.o , Bennett, S.af , Bergen, A.W.v , Boyd, H.A.m , Broms, U.q aq , Campbell, H.ag , Chatterjee, N.at , Chen, J.g , Cheng, Y.-C.j , Cichon, S.ah ai , Couper, D.k , Cucca, F.aj , Dick, D.M.g ak , Foroud, T.al , Furberg, H.am , Giegling, I.an , Gu, F.at , Hall, A.S.ae , Hällfors, J.q bt , Han, S.p , Hartmann, A.M.an , Hayward, C.ao , Heikkilä, K.q , Hewitt, J.K.e , Hottenga, J.J.aa , Jensen, M.K.ap , Jousilahti, P.aq , Kaakinen, M.ar , Kittner, S.J.as , Konte, B.an , Korhonen, T.q , Landi, M.-T.at , Laatikainen, T.aq , Leppert, M.c , Levy, S.M.aw , Mathias, R.A.o , McNeil, D.W.ax , Medland, S.E.ay , Montgomery, G.W.ay , Muley, T.az , Murray, T.o , Nauck, M.y , North, K.k , Pergadia, M.a , Polasek, O.ba , Ramos, E.M.au , Ripatti, S.bb , Risch, A.bc , Ruczinski, I.o , Rudan, I.ag , Salomaa, V.aq , Schlessinger, D.av , Styrkársdóttir, U.n , Terracciano, A.av , Uda, M.bd , Willemsen, G.aa , Wu, X.d , Abecasis, G.be , Barnes, K.o , Bickeböller, H.t , Boerwinkle, E.bf , Boomsma, D.I.aa , Caporaso, N.at , Duan, J.bg , Edenberg, H.J.al , Francks, C.bh , Gejman, P.V.bg , Gelernter, J.p , Grabe, H.J.y , Hops, H.bi , Jarvelin, M.-R.ar bj bk , Viikari, J.bl , Kähönen, M.r s , Kendler, K.S.g , Lehtimäki, T.r , Levinson, D.F.bo , Marazita, M.L.x , Marchini, J.u , Melbye, M.m , Mitchell, B.D.j , Murray, J.C.aw , Nöthen, M.M.ai , Penninx, B.W.ab , Raitakari, O.bm bn , Rietschel, M.l , Rujescu, D.an , Samani, N.J.z , Sanders, A.R.bg , Schwartz, A.G.ac , Shete, S.d , Shi, J.at , Spitz, M.d , Stefansson, K.n , Swan, G.E.v , Thorgeirsson, T.n , Völzke, H.y , Wei, Q.d , Wichmann, H.-E.w bp , Amos, C.I.d , Breslau, N.bq , Cannon, D.S.c , Ehringer, M.e , Grucza, R.a , Hatsukami, D.br , Heath, A.a , Johnson, E.O.bs , Kaprio, J.q aq bt , Madden, P.a , Martin, N.G.ay , Stevens, V.L.f , Stitzel, J.A.e , Weiss, R.B.c , Kraft, P.ap , Bierut, L.J.a
Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers
(2012) Archives of General Psychiatry, 69 (8), pp. 854-861. 

a Washington University School of Medicine, Campus Box 8134, 660 S Euclid Ave, St Louis, MO 63110, United States
b Brown University, Providence, RI, United States
c University of Utah School of Medicine, Salt Lake City, UT, United States
d University of Texas MD Anderson Cancer Center, Houston, TX, United States
e University of Colorado, Boulder, CO, United States
f American Cancer Society, Atlanta, GA, United States
g Virginia Commonwealth University, Richmond, VA, United States
h Institute of Psychiatry Kings College, Department of Psychiatry, St. George's University, London, United Kingdom
i University of Pisa, Pisa, Italy
j University of Maryland School of Medicine, Baltimore, MD, United States
k University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
l Central Institute of Mental Health, Mannheim, Germany
m Statens Serum Institut, Copenhagen, Denmark
n DeCODE Genetics, Reykjavik, Iceland
o Johns Hopkins University, Baltimore, MD, United States
p Yale University School of Medicine, New Haven, CT, United States
q University of Helsinki, Hjelt Institute, Helsinki, Finland
r Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
s Department of Clinical Physiology, Tampere University Hospital, University of Tampere School of Medicine, Tampere, Finland
t University Medical Center, Georg-August- University Goettingen, Goettingen, Germany
u Department of Statistics, University of Oxford, Oxford, United Kingdom
v SRI International, Menlo Park, CA, United States
w Helmholtz Zentrum Mu Nchen, German Research Center for Environmental Health, Neuherberg, Germany
x University of Pittsburgh, Pittsburgh, PA, United States
y University of Greifswald, Greifswald, Germany
z University of Leicester, Leicester, United Kingdom
aa VU University Amsterdam, Amsterdam, Netherlands
ab VU University Medical Center, Amsterdam, Netherlands
ac Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
ad Information Management Services Inc, Rockville, MD, United States
ae University of Leeds, Leeds, United Kingdom
af University of Washington, Seattle, WA, United States
ag University of Edinburgh, Edinburgh, United Kingdom
ah Research Center Jülich, Jülich, Germany
ai Life and Brain Center, Institute of Human Genetics, University of Bonn, Bonn, Germany
aj Istituto di Ricerca Genetica e Biomedica, CNR, Rome, Italy
ak Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
al Indiana University School of Medicine, Indianapolis, IN, United States
am Memorial Sloan-Kettering Cancer Center, New York, NY, United States
an Ludwig Maximilians University Munich, Munich, Germany
ao Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom
ap Harvard School of Public Health, Boston, MA, United States
aq National Institute for Health and Welfare, Helsinki, Finland
ar Institute of Health Sciences, University of Oulu, Oulu, Finland
as Baltimore Veterans Administration Medical Center, University of Maryland, Baltimore, MD, United States
at Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
au National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
av National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
aw University of Iowa, Iowa City, IA, United States
ax West Virginia University, Morgantown, WV, United States
ay Queensland Institute of Medical Research, Herston, QLD, Australia
az Thoraxklinik am Universitätsklinikum Heidelberg, Heidelberg, Germany
ba Medical School, University of Split, Split, Croatia
bb University of Helsinki, Finland
bc DKFZGerman Cancer Research Center, Heidelberg, Germany
bd Translational Lung Research Centre Heidelberg, Consiglio Nazionale Delle Ricerche, Rome, Italy
be University of Michigan, Ann Arbor, MI, United States
bf University of Texas Health Science Center at Houston, Houston, TX, United States
bg NorthShore University HealthSystem Research Institute, University of Chicago, Evanston, IL, United States
bh Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
bi Oregon Research Institute, Eugene, OR, United States
bj Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
bk Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland
bl Department of Medicine, Turku University Hospital, Turku, Finland
bm Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
bn Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
bo Stanford University, Stanford, CA, United States
bp Institute of Epidemiology I, German Research Center for Environmental Health, Ludwig- Maximilians-Universität, Germany
bq Michigan State University, East Lansing, MI, United States
br University of Minnesota, Minneapolis, MN, United States
bs RTI International, Durham, NC, United States
bt Institute for Molecular Medicine Finland, Helsinki, Finland

Abstract
Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. Data Sources: Primary data. Study Selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DataExtraction: Uniform statistical analysis scripts were runlocally. Startingwith94 050ever-smokersfrom43studies, we extracted the heavy smokers (CPD>20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavyvs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. Data Synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36-1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR=1.27; 95% CI, 1.21-1.33, n=19 505) (P=.01). Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers. ©2012 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

 

Ryther, R.C.C., Wong, M., Ryther, R.C.C.
Mammalian target of rapamycin (mtor) inhibition: Potential for antiseizure, antiepileptogenic, and epileptostatic therapy
(2012) Current Neurology and Neuroscience Reports, 12 (4), pp. 410-418. 

Department of Neurology, Washington University School of Medicine, Hope Center for Neurological Disorders, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
New epilepsy treatments are needed that not only inhibit seizures symptomatically (antiseizure) but also prevent the development of epilepsy (antiepileptogenic). The mammalian target of rapamycin (mTOR) pathway may mediate mechanisms of epileptogenesis and serve as a rational therapeutic target. mTOR inhibitors have antiepileptogenic and antiseizure effects in animal models of the genetic disease, tuberous sclerosis complex. The mTOR pathway is also implicated in epileptogenesis in animal models of acquired epilepsy and infantile spasms, although the effects of mTOR inhibitors are variable depending on the specific conditions and model. Furthermore, beneficial effects on seizures are lost when treatment is withdrawn, suggesting that mTOR inhibitors are "epileptostatic" in only stalling epilepsy progression during treatment. Clinical studies of rapamycin in human epilepsy are limited, but suggest that mTOR inhibitors at least have antiseizure effects in tuberous sclerosis patients. Further studies are needed to assess the full potential of mTOR inhibitors for epilepsy treatment. © Springer Science+Business Media, LLC 2012.

Author Keywords
Antiepileptogenic;  Antiseizure;  Epilepsy;  Epileptogenesis;  Epileptostatic;  Everolimus;  Mice;  mTOR;  Rapamycin;  Rat;  Seizure;  Status epilepticus;  Therapy;  Traumatic brain injury;  Tuberous sclerosis complex

Document Type: Article
Source: Scopus

 

Tang, J.a b , Yang, W.a , Suga, N.a
Modulation of thalamic auditory neurons by the primary auditory cortex
(2012) Journal of Neurophysiology, 108 (3), pp. 935-942. 

a Department of Biology, Washington University, St. Louis, MO, United States
b Department of Physiology, Southern Medical University, Guangzhou, China

Abstract
The central auditory system consists of the lemniscal and nonlemniscal pathways or systems, which are anatomically and physiologically different from each other. In the thalamus, the ventral division of the medial geniculate body (MGBv) belongs to the lemniscal system, whereas its medial (MGBm) and dorsal (MGBd) divisions belong to the nonlemniscal system. Lemniscal neurons are sharply frequency-tuned and provide highly frequency-specific information to the primary auditory cortex (AI), whereas nonlemniscal neurons are generally broadly frequency-tuned and project widely to cortical auditory areas including AI. These two systems are presumably different not only in auditory signal processing, but also in eliciting cortical plastic changes. Electric stimulation of narrowly frequency-tuned MGBv neurons evokes the shift of the frequency-tuning curves of AI neurons toward the tuning curves of the stimulated MGBv neurons (tone-specific plasticity). In contrast, electric stimulation of broadly frequency-tuned MGBm neurons augments the auditory responses of AI neurons and broadens their frequency-tuning curves (nonspecific plasticity). In our current studies, we found that electric stimulation of AI evoked tone-specific plastic changes of the MGBv neurons, whereas it degraded the frequency tuning of MGBm neurons by inhibiting their auditory responses. AI apparently modulates the lemniscal and nonlemniscal thalamic neurons in quite different ways. High MGBm activity presumably makes AI neurons less favorable for fine auditory signal processing, whereas high MGBv activity makes AI neurons more suitable for fine processing of specific auditory signals and reduces MGBm activity. © 2012 the American Physiological Society.

Author Keywords
Corticofugal modulation;  Frequency tuning;  Medial geniculate body;  Nonspecific plasticity;  Tone-specific plasticity

Document Type: Article
Source: Scopus

 

Lueder, G.T., Galli, M.
Oblique muscle surgery for treatment of nystagmus with head tilt

(2012) Journal of AAPOS, 16 (4), pp. 322-326. 
Departments of Ophthalmology and Visual Sciences and Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, One Children's Place, St. Louis, MO 63110, United States

Abstract
Background: Patients with nystagmus may adopt an abnormal head posture if they have a null zone in eccentric gaze. These patients uncommonly present with torticollis due to a null zone when the head is tilted. We describe the results of surgery on the oblique muscles to improve the abnormal head posture in this condition. Methods: This was a retrospective review of patients who had head tilts due to null zones of nystagmus. Surgery consisted of an anterior 50% tenectomy of the superior oblique tendon on one side and recession of the inferior oblique muscle to a position 6 mm posterior to the insertion of the inferior rectus muscle on the contralateral side. The patients' clinical histories and outcomes were reviewed. Results: Six patients underwent the procedure. Of these, four had infantile nystagmus syndrome and two were born prematurely and had histories of intraventricular hemorrhages. Five of the patients had previous Kestenbaum surgery that corrected the horizontal component of their abnormal head postures. Age at time of surgery for the head tilt ranged from 3 to 13 years. Postoperative follow-up ranged from 1.5 to 3 years. The preoperative head tilts ranged from 25° to 45°(mean, 39°). The postoperative improvement ranged from 20°to 40°(mean, 28°). One of the patients with a history of intraventricular hemorrhage required additional surgery for strabismus unrelated to nystagmus. Conclusions: Anterior tenectomy of the superior oblique tendon combined with contralateral recession of the inferior oblique muscle improved head tilts related to a null zone of nystagmus. © 2012 by the American Association for Pediatric Ophthalmology and Strabismus.

Document Type: Article
Source: Scopus

 

Johnson, L.B.a , Florence, J.M.b , Abresch, R.T.c
Physical therapy evaluation and management in neuromuscular diseases
(2012) Physical Medicine and Rehabilitation Clinics of North America, 23 (3), pp. 633-651. 

a Physical Therapy Department, University of California Davis, Suite 1100, 4860 Y Street, Sacramento, CA 95817, United States
b Neuromuscular Division, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid, St Louis, MO 63110, United States
c Department of Physical Medicine and Rehabilitation, Rehabilitation Research and Training Center, University of California Davis, MED:PM and R, TB191, One Shields Avenue, Davis, CA 95616, United States

Abstract
Neuromuscular disorders (NMDs) are a group of myopathic or neuropathic diseases that directly or indirectly affect the functioning of muscle. Physical therapists (PTs) have extensive specialized training in musculoskeletal evaluation and assessment that gives them the tools to meet the significant needs of this population. This article reviews the role of PTs in treating the NMD population with a discussion of available evaluation techniques and interventions and with an effort to differentiate between treatments known to apply to this population and conventional practice of PTs. The status of currently available outcome measures used for research and their applicability to clinics are presented. © 2012 Elsevier Inc.

Author Keywords
Exercise;  Neuromuscular diseases;  Outcome measures;  Physical therapy

Document Type: Review
Source: Scopus

 

Lichenstein, R.a , Glass, T.F.b , Quayle, K.S.c , Wootton-Gorges, S.L.d , Wisner, D.H.e , Miskin, M.i , Muizelaar, J.P.f , Badawy, M.j , Atabaki, S.k , Holmes, J.F.g , Kuppermann, N.g h
Presentations and outcomes of children with intraventricular hemorrhages after blunt head trauma
(2012) Archives of Pediatrics and Adolescent Medicine, 166 (8), pp. 725-731. 

a Department of Pediatrics, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21201, United States
b Department of Pediatric Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
c Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
d Department of Radiology, University of California-Davis School of Medicine, Davis, CA, United States
e Department of Surgery, University of California-Davis School of Medicine, Davis, CA, United States
f Department of Neurological Surgery, University of California-Davis School of Medicine, Davis, CA, United States
g Department of Emergency Medicine, University of California-Davis School of Medicine, Davis, CA, United States
h Department of Pediatrics, University of California-Davis School of Medicine, Davis, CA, United States
i Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
j Department of Emergency Medicine, University of Rochester School of Medicine, Rochester, NY, United States
k Department of Pediatrics, George Washington School of Medicine, Washington, DC, United States

Abstract
Objective: To describe the clinical presentations and outcomes of children with intraventricular hemorrhages (IVHs) after blunt head trauma (BHT). Design: Subanalysis of a large, prospective, observational cohort study performed from June 1, 2004, through September 31, 2006. Setting: Twenty-five emergency departments participating in the Pediatric Emergency Care Applied Research Network. Patients: Children presenting with IVH after BHT. Exposure: Blunt head trauma. Main Outcome Measures: Clinical presentations and outcomes, including the Pediatric Overall Performance Category (POPC) and Pediatric Cerebral Performance Category (PCPC) scores at hospital discharge. Results: Of 15 907 patients evaluated with computed tomography, 1156 (7.3%) had intracranial injuries. Fortythree of the 1156 (3.7%; 95% CI, 2.7%-5.0%) had nonisolated IVHs (ie, with intracranial injuries on computed tomography), and 10 of 1156 (0.9%; 95% CI, 0.4%-1.6%) had isolated IVHs. Only 4 of 43 (9.3%) of those with nonisolated IVHs had Glasgow Coma Scale (GCS) scores of 14 to 15, and all 10 (100.0%) with isolated IVHs had GCS scores of 15. No patients with isolated IVHs required neurosurgery or died. One patient had moderate overall disability (by the POPC score), and no patient had moderate or severe disability at discharge (by the PCPC score). Of the 43 patients with nonisolated IVHs, however, 16 (37.2%) died and 18 (41.9%) required neurosurgery. In 27 patients (62.8%), injuries ranged from moderate overall disability to brain death by the POPC score. Conclusions: Children with nonisolated IVHs after BHT typically present with GCS scores of less than 14, frequently require neurosurgery, and have high mortality rates. In contrast, those with isolated IVHs typically present with normal mental status and are at low risk for acute adverse events and poor outcomes. ©2012 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

 

Iacovino, J.M.a , Gredysa, D.M.a , Altman, M.b , Wilfley, D.E.b
Psychological treatments for binge eating disorder
(2012) Current Psychiatry Reports, 14 (4), pp. 432-446. 

a Department of Psychology, Washington University in St. Louis, Campus Box 1125, One Brookings Drive, St. Louis, MO 63130, United States
b Department of Psychiatry, Washington University, School of Medicine, Campus Box 8134, St. Louis, MO 63110, United States

Abstract
Bin ge eating disorder (BED) is the most prevalent eating disorder in adults, and individuals with BED report greater general and specific psychopathology than noneating disordered individuals. The current paper reviews research on psychological treatments for BED, including the rationale and empirical support for cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), dialectical behavior therapy (DBT), behavioral weight loss (BWL), and other treatments warranting further study. Research supports the effectiveness of CBT and IPT for the treatment of BED, particularly for those with higher eating disorder and general psychopathology. Guided self-help CBT has shown efficacy for BED without additional pathology. DBT has shown some promise as a treatment for BED, but requires further study to determine its long-term efficacy. Predictors and moderators of treatment response, such as weight and shape concerns, are highlighted and a steppedcare model proposed. Future directions include expanding the adoption of efficacious treatments in clinical practice, testing adapted treatments in diverse samples (e.g., minorities and youth), improving treatment outcomes for nonresponders, and developing efficient and cost-effective stepped-care models. © Springer Science+Business Media, LLC 2012.

Author Keywords
Behavioral weight loss;  Binge eating disorder;  Cognitive behavioral therapy;  Dialectical behavior therapy;  Eating disorders;  Guided self-help;  Interpersonal psychotherapy;  Loss of control;  Psychological treatments;  Randomized controlled trials;  Treatment review

Document Type: Article
Source: Scopus

 

Tychsen, L.
The cause of infantile strabismus lies upstairs in the cerebral cortex, not downstairs in the brainstem
(2012) Archives of Ophthalmology, 130 (8), pp. 1060-1061. 

Department of Ophthalmology and Visual Sciences, St. Louis Children's Hospital, Washington University School of Medicine, 1 Children's Pl, Ste 2S-89, St Louis, MO 63110, United States

Document Type: Editorial
Source: Scopus

 

Fagan, A.M.a b c , Perrin, R.J.c d
Upcoming candidate cerebrospinal fluid biomarkers of Alzheimers disease
(2012) Biomarkers in Medicine, 6 (4), pp. 455-476. 

a Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Ave., St Louis, MO 63110, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Ave., St Louis, MO 63110, United States
c Knight Alzheimers Disease Research Center, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Ave., St Louis, MO 63110, United States
d Division of Neuropathy, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., St Louis, MO 63110, United States

Abstract
Dementia due to Alzheimers disease (AD) is estimated to reach epidemic proportions by the year 2030. Given the limited accuracy of current AD clinical diagnosis, biomarkers of AD pathologies are currently being sought. Reductions in cerebrospinal fluid levels of -amyloid 42 (a marker of amyloid plaques) and elevations in tau species (markers of neurofibrillary tangles and/or neurodegeneration) are well-established as biomarkers useful for AD diagnosis and prognosis. However, novel markers for other features of AD pathophysiology (e.g., -amyloid processing, neuroinflammation and neuronal stress/dysfunction) and for other non-AD dementias are required to improve the accuracy of AD disease diagnosis, prognosis, staging and therapeutic monitoring (theragnosis). This article discusses the potential of several promising novel cerebrospinal fluid analytes, highlights the next steps critical for advancement in the field, and provides a prediction on how the field may evolve in 5-10 years. © 2012 Future Medicine Ltd.

Author Keywords
Alzheimers disease;  amyloid;  biomarker;  cerebrospinal fluid;  diagnostic accuracy;  neurodegeneration;  neurofibrillary tangles;  neuroinflammation;  prognosis;  theragnosis

Document Type: Review
Source: Scopus

 

Fennema-Notestine, C.a b , Panizzon, M.S.a , Thompson, W.R.a , Chen, C.-H.a , Eyler, L.T.a c , Fischl, B.d e f , Franz, C.E.a , Grant, M.D.g , Jak, A.J.a c , Jernigan, T.L.a b h i , Lyons, M.J.g , Neale, M.C.j , Seidman, L.J.g , Tsuang, M.T.a k l , Xian, H.m , Dale, A.M.b n , Kremen, W.S.a c k
Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age
(2011) Advances in Alzheimer's Disease, 2, pp. 77-88. 

a Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
b Department of Radiology, University of California, San Diego, San Diego, CA, United States
c Veterans' Administration San Diego Healthcare System, San Diego, CA, United States
d Department of Radiology, Massachusetts General Hospital, Boston, MA, United States
e Harvard Medical School, Boston, MA, United States
f Computer Science and AI Lab, Massachusetts Institute of Technology, Cambridge, MA, United States
g Department of Psychology, Boston University, Boston, MA, United States
h Department of Cognitive Science, University of California, San Diego, San Diego, CA, United States
i Center for Human Development, University of California, San Diego, San Diego, CA, United States
j Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
k Center for Behavioral Genomics, University of California, San Diego, San Diego, CA, United States
l Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School and School of Public Health, Boston, MA, United States
m Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
n Department of Neurosciences, University of California, San Diego, San Diego, CA, United States

Abstract
The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51-59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of ε4-related effects. The presence of the ε2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age-and disease-related mediation of the influence of ApoE allele status. © 2011 The authors and IOS Press. All rights reserved.

Author Keywords
aging;  apolipoprotein E2;  apolipoprotein E3;  apolipoprotein E4;  apolipoproteins E;  brain;  cerebral cortex;  frontal lobe;  genetic association studies;  Magnetic resonance imaging

Document Type: Article
Source: Scopus

 

September 5, 2012  

Tammimäki, A.a d , Herder, P.a , Li, P.b , Esch, C.b , Laughlin, J.R.a , Akk, G.b , Stitzel, J.A.a c
Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by α3β4α5 nicotinic acetylcholine receptors
(2012) Neuropharmacology, 63 (6), pp. 1002-1011. 

a Institute for Behavioral Genetics, University of Colorado at Boulder, UCB 447, Boulder, CO 80309, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO, United States
d Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, POB 56, 00014, Helsinki, Finland

Abstract
The human CHRNA5 D398N polymorphism (rs16969968) causes an aspartic acid to asparagine change in the nicotinic acetylcholine receptor (nAChR) α5 subunit gene. The N398 variant of CHRNA5 is linked to increased risk for nicotine dependence. In this study, we explored the effect of the CHRNA5 D398N polymorphism on the properties of human α3β4* nicotinic acetylcholine receptors in human embryonic kidney (HEK) cells. Addition of either D398 or N398 variant of α5 subunit in the α3β4* receptor did not affect total [ 125I]-epibatidine binding or surface expression of the receptor. However, addition of α5 D398 into α3β4* receptor decreased the maximal response to agonist without significantly affecting EC 50 in aequorin intracellular calcium assay. α3β4α5 N398 nAChRs showed further decreased maximal response. The differences in agonist efficacy between the receptor subtypes were found to be dependent upon the concentration of external calcium but independent of external sodium. Moreover, activation of α3β4α5 nAChRs led to significantly greater intracellular calcium release from IP 3 stores relative to α3β4 nAChRs although no effect of the α5 polymorphism was observed. Finally, inclusion of the α5 variant caused a small shift to the left in IC 50 for some of the antagonists tested, depending upon α5 variant but did not affect sensitivity of α3β4* receptors to desensitization in response to incubation with nicotine. In conclusion, addition of either variant of α5 into an α3β4α5 receptor similarly effects receptor pharmacology and function. However, the N398 variant exhibits a reduced response to agonists when extracellular calcium is high and it may lead to distinct downstream cellular signaling. Highlights: Addition of α5 subunit in the α3β4* receptor does not affect surface expression. The maximal agonist-induced calcium response: α3β4α5N &lt; α3β4α5D &lt; α3β4. The differences in the agonist response dependent upon [Ca 2+] ext, not [Na +] ext. Activation of α3β4α5 nAChRs induces greater Ca 2+ release from IP 3 stores than α3β4. Inclusion of the α5 variant did not affect sensitivity of α3β4* nAChRs. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
Alpha5 subunit;  CHRNA5;  Intracellular calcium;  Nicotinic acetylcholine receptors;  Polymorphism;  Rs16969968

Document Type: Article
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, 2 (4), pp. 396-408. 

a Washington University School of Medicine, Campus Box: 8134, Department of Radiology, 660 S. Euclid St., St Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, United States
c Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, United States
d Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, United States
f Department of Psychology, Washington University, One Brookings Drive, St Louis, MO 63130, United States
g Department of Biomedical Engineering, Washington University, One Brookings Drive, St Louis, MO 63130, United States

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.

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

Document Type: Article
Source: Scopus

 

Van Essen, D.C.a , Ugurbil, K.b , Auerbach, E.b , Barch, D.c , Behrens, T.E.J.d , Bucholz, R.e , Chang, A.h i , Chen, L.h i , Corbetta, M.f , Curtiss, S.W.a , Della Penna, S.g , Feinberg, D.h i , Glasser, M.F.a , Harel, N.b , Heath, A.C.j , Larson-Prior, L.k , Marcus, D.k , Michalareas, G.l , Moeller, S.b , Oostenveld, R.m , Petersen, S.E.f , Prior, F.k , Schlaggar, B.L.f , Smith, S.M.d , Snyder, A.Z.k , Xu, J.b , Yacoub, E.b
The Human Connectome Project: A data acquisition perspective
(2012) NeuroImage, 62 (4), pp. 2222-2231.
a Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
b Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States
c Department of Psychology, Washington University, St. Louis, MO, United States
d Centre for Functional MRI of the Brain (FMRIB), Oxford University, Oxford, United Kingdom
e Department of Neurosurgery, St. Louis University, St. Louis, MO, United States
f Department of Neurology, Washington University, St. Louis, MO, United States
g Department of Neuroscience and Imaging and Institute for Advanced Biomedical Technologies, University G. D'Annunzio, Chieti, Italy
h Advanced MRI Technologies, Sebastopol, CA, United States
i University of California, Berkeley, CA, United States
j Department of Psychiatry, Washington University, St. Louis, MO, United States
k Department of Radiology, Washington University, St. Louis, MO, United States
l Ernst Strüngmann Institute (ESI) in Cooperation with Max Planck Society, Frankfurt, Germany
m Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Netherlands

Abstract
The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences. © 2012 Elsevier Inc.

Author Keywords
Behavior;  Connectivity;  Diffusion imaging;  FMRI;  MEG/EEG;  Twins

Document Type: Review
Source: Scopus

 

Carter, A.R.a , Shulman, G.L.a , Corbetta, M.a b c
Why use a connectivity-based approach to study stroke and recovery of function?
(2012) NeuroImage, 62 (4), pp. 2271-2280. 

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

Abstract
The brain is organized into a set of widely distributed networks. Therefore, although structural damage from stroke is focal, remote dysfunction can occur in regions connected to the area of lesion. Historically, neuroscience has focused on local processing due in part to the absence of tools to study the function of distributed networks. In this article we discuss how a more comprehensive understanding of the effects of stroke can be attained using resting state functional connectivity BOLD magnetic resonance imaging (resting state fcMRI). Resting state fcMRI has a number of advantages over task-evoked fMRI for studying brain network reorganization in response to stroke, including the ability to image subjects with a broad range of impairments and the ability to study multiple networks simultaneously. We describe our rationale for using resting state connectivity as a tool for investigating the neural substrates of stroke recovery in a heterogeneous population of stroke patients and discuss the main questions we hope to answer, in particular whether resting state fcMRI measures in the acute phase of stroke can predict subsequent recovery. Early results suggest that disruption of inter-hemispheric connectivity in the somatomotor network and the dorsal attention network is more strongly associated with behavioral impairment in those domains than is intra-hemispheric connectivity within either the lesioned or unaffected hemisphere. We also observe in the somatomotor network an interesting interaction between corticospinal tract damage and decreased inter-hemispheric connectivity that suggests that both processes combine to contribute to neuromotor impairment after stroke. A connectivity-based approach will provide greater insight into network reorganization in the acute and chronic phases after stroke and will contribute to improving prognostic ability and the development of therapeutic interventions. © 2012 Elsevier Inc.

Author Keywords
Connectivity;  FMRI;  Inter-hemispheric;  Recovery;  Resting state;  Stroke

Document Type: Review
Source: Scopus

 

Tamez, E., Myerson, J., Hale, S.
Contributions of associative learning to age and individual differences in fluid intelligence
(2012) Intelligence, 40 (5), pp. 518-529. 

Department of Psychology, Washington University, One Brookings Drive, Campus Box 1125, St. Louis, MO 63130, United States

Abstract
According to the cognitive cascade hypothesis, age-related slowing results in decreased working memory, which in turn affects higher-order cognition. Because recent studies show complex associative learning correlates highly with fluid intelligence, the present study examined the role of complex associative learning in cognitive cascade models of data from adults aged 30-80. years. Path analyses revealed that an extended cascade model, in which associative learning mediated the relation between working memory and fluid intelligence, provided an adequate fit to the data. Moreover, an alternative extended cascade model, one with an additional path from speed to fluid intelligence and separate learning and secondary memory components, provided an excellent fit. These findings establish a role for complex associative learning in the extended cognitive cascade underlying age and individual differences in fluid intelligence. © 2012 Elsevier Inc.

Author Keywords
Aging;  Associative learning;  Cognitive cascade;  Extended cascade;  Fluid intelligence;  Working memory

Document Type: Article
Source: Scopus

 

Widiger, T.A.a , Lynam, D.R.b , Miller, J.D.c , Oltmanns, T.F.d
Measures to assess maladaptive variants of the five-factor model
(2012) Journal of Personality Assessment, 94 (5), pp. 450-455. 

a Department of Psychology, University of Kentucky, 115 Kastle Hall, Lexington, KY 40506-0044, United States
b Department of Psychological Sciences, Purdue University, United States
c Department of Psychology, University of Georgia, United States
d Department of Psychology, Washington University, St. Louis, United States

Abstract
The five-factor model (FFM) is the predominant dimensional model of general personality structure. A considerable body of research supports the hypothesis that personality disorders can be conceptualized as extreme or maladaptive variants of the domains and facets of the FFM. However, existing measures of the FFM are confined largely to the normal variants. The purpose of this special section of the Journal of Personality Assessment is to provide the development and initial validation of self-report inventory scales to assess obsessive-compulsive, borderline, narcissistic, avoidant, and dependent personality traits from the perspective of the FFM, which complement the similarly constructed existing measures for psychopathic, histrionic, and schizotypal personality traits. © 2012 Taylor and Francis Group, LLC.

Document Type: Article
Source: Scopus

 

Chen, Z.-W.a , Manion, B.a , Townsend, R.R.b c , Reichert, D.E.e , Covey, D.F.d , Steinbach, J.H.a , Sieghart, W.f , Fuchs, K.f , Evers, A.S.a b d
Neurosteroid analog photolabeling of a site in the third transmembrane domain of the β3 subunit of the GABA A receptor
(2012) Molecular Pharmacology, 82 (3), pp. 408-419. 
a Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, United States
e Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
f Department of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria

 

Abstract
Accumulated evidence suggests that neurosteroids modulate GABAA receptors through binding interactions with transmembrane domains. To identify these neurosteroid binding sites directly, a neurosteroid-analog photolabeling reagent, (3α,5β)-6-azipregnanolone (6-AziP), was used to photolabel membranes from Sf9 cells expressing high-density, recombinant, His8-β3 homomeric GABAA receptors. 6-AziP inhibited 35S-labeled t- butylbicyclophosphorothionate binding to the His8-β3 homomeric GABAAreceptors in a concentration-dependent manner (IC50 = 9 ± 1 μM), with a pattern consistent with a single class of neurosteroid binding sites. [3H]6-AziP photolabeled proteins of 30, 55, 110, and 150 kDa, in a concentration-dependent manner. The 55-, 110-, and 150-kDa proteins were identified as His8-β3 subunits through immunoblotting and through enrichment on a nickel affinity column. Photolabeling of the β3 subunits was stereoselective, with [3H]6-AziP producing substantially greater labeling than an equal concentration of its diastereomer [3H](3β,5β)-6-AziP. High-resolution mass spectrometric analysis of affinity-purified, 6-AziP-labeled His8-β3 subunits identified a single photolabeled peptide, ALLEYAF-6-AziP, in the third transmembrane domain. The identity of this peptide and the site of incorporation on Phe301 were confirmed through high-resolution tandem mass spectrometry. No other sites of photoincorporation were observed despite 90% sequence coverage of the whole β3 subunit protein, including 84% of the transmembrane domains. This study identifies a novel neurosteroid binding site and demonstrates the feasibility of identifying neurosteroid photolabeling sites by using mass spectrometry. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus

 

Wang, K.-S.a , Zhang, Q.b , Liu, X.a , Wu, L.c , Zeng, M.a
PKNOX2 is associated with formal thought disorder in schizophrenia: A meta-analysis of two genome-wide association studies
(2012) Journal of Molecular Neuroscience, 48 (1), pp. 265-272. 

a Department of Biostatistics and Epidemiology, Lamb Hall, East Tennessee State University, PO Box 70259, Johnson City, TN 37614-1700, United States
b Division of Statistical Genomics, Washington University, School of Medicine, St. Louis, MO 63108, United States
c Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON, Canada

Abstract
Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia; however, little is known about the etiology of FTD. To identify new genetic loci associated with FTD, we conducted the first genome-wide association meta-analysis of two datasets of 835 cases of FTD and 2,694 controls with 729,454 single-nucleotide polymorphisms (SNPs). Logistic regression analysis of FTD as a binary trait, adjusted for age and sex, was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 61 SNPs associated with FTD with p &lt; 10 -4. The most significant association with FTD was observed with rs1783925 (p = 4.4 × 10 -7) within PKNOX2 gene at 11q24.2 while the second interesting locus was rs2277644 (p = 1.18 × 10 -5) within MYH13 at 17p13. Haplotype analyses of PKNOX2 and MYH13 loci further supported the associations with FTD. The third locus was PHF2 at 9q22.31 (the top SNP was rs12238738 with p = 2.08 × 10 -5) while the fourth locus was GPC6 at 13q32 (the top SNP was rs17196161 with p = 3.12 × 10 -5). In conclusion, we identified four new loci (PKNOX2, MYH13, PHF2, and GPC6) associated with FTD. These findings offer the potential for new insights into the pathogenesis of FTD and schizophrenia. © 2012 Springer Science+Business Media, LLC.


Author Keywords
Formal thought disorder;  Genome-wide association;  Haplotype;  Meta-analysis;  PKNOX2;  Schizophrenia


Document Type: Article
Source: Scopus

 

Matava, M.a , Brater, D.C.b , Gritter, N.c , Heyer, R.d , Rollins, D.e , Schlegel, T.f , Toto, R.g , Yates, A.h
Recommendations of the National Football League Physician Society Task Force on the Use of Toradol® Ketorolac in the National Football League
(2012) Sports Health, 4 (5), pp. 377-383. 

a Washington University, St. Louis, MO, United States
b Indiana University, Indianapolis, IN, United States
c Metrolina Nephrology Associates, Charlotte, NC, United States
d Carolinas Medical Center, Charlotte, NC, United States
e University of Utah, Salt Lake City, UT, United States
f Steadman-Hawkins Clinic, Greenwood Village, CO, United States
g University of Texas, Southwestern Dallas, TX, United States
h University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Ketorolac tromethamine (Toradol®) is a non-steroidal anti-inflammatory drug that has potent analgesic and anti-inflammatory properties. It can be administered orally, intravenously, intramuscularly, or via a nasal route. Ketorolac injections have been used for several years in the National Football League (NFL), in both the oral and injectable forms, to treat musculoskeletal injuries and to prevent post-game soreness. In an attempt to determine the appropriate use of this medication in NFL players, the NFL Team Physician Society appointed a Task Force to consider the best available evidence as to how ketorolac should be used for pain management in professional football players. These treatment recommendations were established based on the available medical literature taking into consideration the pharmacokinetic properties of ketorolac, its accepted indications and contraindications, and the unique clinical challenges of the NFL. The Task Force recommended that 1) ketorolac should only be administered under the direct supervision and order of a team physician; 2) ketorolac should not be used prophylactically as a means of reducing anticipated pain either during or after participation in NFL games or practices and should be limited to those players diagnosed with an injury or condition and listed on the teams' injury report; 3) ketorolac should be given in the lowest effective therapeutic dose and should not be used in any form for more than 5 days; 4) ketorolac should be given in its oral preparation under typical circumstances; 5) ketorolac should not be taken concurrently with other NSAIDs or by those players with a history of allergic reaction to ketorolac, other NSAIDs or aspirin; and 6) ketorolac should not be used by a player with a history of significant gastrointestinal bleeding, renal compromise, or a past history of complications related to NSAIDs. © 2012 The Author(s).

Author Keywords
Football;  Ketorolac;  NFL;  Toradol


Document Type: Article
Source: Scopus

 

Belden, A.C., Gaffrey, M.S., Luby, J.L.
Relational aggression in children with preschool-onset psychiatric disorders
(2012) Journal of the American Academy of Child and Adolescent Psychiatry, 51 (9), pp. 889-901. 

Early Emotional Development Program (EEDP), Washington University School of Medicine, St. Louis, United States

Abstract
The role of preschool-onset (PO) psychiatric disorders as correlates and/or risk factors for relational aggression during kindergarten or first grade was tested in a sample of 146 preschool-age children (age 3 to 5.11 years). Axis-I diagnoses and symptom scores were derived using the Preschool Age Psychiatric Assessment. Children's roles in relational aggression as aggressor, victim, aggressive-victim, or nonaggressor/nonvictim were determined at preschool and again 24 months later at elementary school entry. Preschoolers diagnosed with PO psychiatric disorders were three times as likely as the healthy preschoolers to be classified aggressors, victims, or aggressive-victims. Children diagnosed with PO disruptive, depressive, and/or anxiety disorders were at least six times as likely as children without PO psychiatric disorders to become aggressive-victims during elementary school after covarying for other key risk factors. Findings suggested that PO psychiatric disorders differentiated preschool and school-age children's roles in relational aggression based on teacher report. Recommendations for future research and preventative intervention aimed at minimizing the development of relational aggression in early childhood by identifying and targeting PO psychiatric disorders are made. © 2012 American Academy of Child and Adolescent Psychiatry.


Author Keywords
aggressive-victim;  bullying;  preschool psychiatric disorders;  relational aggression


Document Type: Article
Source: Scopus


Viteri, E.a , Barnoya, J.a b , Hudmon, K.S.c , Solorzano, P.J.a
Smoking cessation medications and cigarettes in Guatemala pharmacies
(2012) Tobacco Control, 21 (5), pp. 477-481. 

a Department of Research, Cardiovascular Unit of Guatemala, Guatemala City, Guatemala
b Division of Public Health Sciences, Department of Surgery, Washington University in St Louis, School of Medicine, St Louis, MO, United States
c Department of Pharmacy Practice, Purdue University College of Pharmacy, Indianapolis, IN, United States

Abstract
Background: Guatemala, a party to the Framework Convention on Tobacco Control (FCTC), is obliged to promote the wider availability of smoking cessation treatment and to restrict tobacco advertising. Pharmacies are fundamental in providing smoking cessation medications but also might increase the availability of cigarettes. Purpose: To assess availability of cessation medications and cigarettes and their corresponding advertising in Guatemala pharmacies. Methods: In Guatemala City a representative sample was selected from a list of registered pharmacies classified by type (non-profit, chain, independent). In addition, all pharmacies in the neighbouring town of Antigua were included for comparison. Trained surveyors used a checklist to characterise each pharmacy with respect to availability and advertising of cessation medications and cigarettes. Results: A total of 505 pharmacies were evaluated. Cessation medications were available in 115 (22.8%), while cigarettes were available in 29 (5.7%) pharmacies. When available, medications were advertised in 1.7% (2) and cigarettes in 72.4% (21) of pharmacies. Chain pharmacies were significantly more likely to sell cessation medications and cigarettes, and to advertise cigarettes than were non-profit and independent pharmacies. Conclusion: Most pharmacies in Guatemala do not stock cessation medications or cigarettes. Cigarette advertising was more prevalent than advertising for cessation medications. FCTC provisions have not been implemented in Guatemala pharmacies.


Document Type: Article
Source: Scopus

 

Vitiello, B.a , Riddle, M.A.b , Yenokyan, G.b , Axelson, D.A.c , Wagner, K.D.d , Joshi, P.e , Walkup, J.T.f , Luby, J.g , Birmaher, B.c , Ryan, N.D.c , Emslie, G.h , Robb, A.e , Tillman, R.g
Treatment moderators and predictors of outcome in the Treatment of Early Age Mania (TEAM) study
(2012) Journal of the American Academy of Child and Adolescent Psychiatry, 51 (9), pp. 867-878.
a National Institute of Mental Health (NIMH), 6001 Executive Blvd., Bethesda, MD 20892-9633, United States
b Johns Hopkins University, United States
c University of Pittsburgh, United States
d University of Texas at Galveston, United States
e Children National Medical Center, George Washington University, United States
f Cornell University, United States
g Washington University in St. Louis, United States
h University of Texas, Southwestern Medical Center, United States

Abstract
Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome. TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-nave patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome. Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS. Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration informationTreatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681. © 2012 American Academy of Child and Adolescent Psychiatry.


Author Keywords
bipolar;  moderators;  predictors;  treatment


Document Type: Article
Source: Scopus

 

Patel, J.R.a , Williams, J.L.a , Muccigrosso, M.M.a , Liu, L.a , Sun, T.d , Rubin, J.B.d , Klein, R.S.a b c e
Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS
(2012) Acta Neuropathologica, pp. 1-14. Article in Press. 

a Department of Internal Medicine, Washington University School of Medicine, St Louis, 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, 63110, United States
d Department of Pediatrics, Washington University School of Medicine, St Louis, 63110, United States
e Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, 63110-1093, United States

Abstract
Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination with progressive failure of remyelination. Prior studies using murine models of MS indicate that remyelination within the adult central nervous system (CNS) requires the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes. Here, we extend these studies by examining the role of TNFR2 in the expression of the CXCR4 ligand, CXCL12, within the corpus callosum (CC) during cuprizone (CPZ) intoxication and by demonstrating that lentiviral-mediated gene delivery of CXCL12 to the demyelinated CC improves OPC proliferation and myelin expression during remyelination. Activated astrocytes and microglia express both TNFR1 and TNFR2 within the demyelinated CC. However, CPZ intoxicated TNFR2-/- mice exhibit loss of up-regulation of CXCL12 in astrocytes with concomitant decreases in numbers of CXCR4+ NG2+ OPCs within the CC. While CXCR4 antagonism does not affect OPC migration from subventricular zones into the CC, it decreases their proliferation and differentiation within the CC. Stereotactic delivery of lentivirus expressing CXCL12 protein into the CC of acutely demyelinated TNFR2-/- mice increases OPC proliferation and expression of myelin. In contrast, chronically demyelinated wild-type mice, which exhibit significant loss of astrocytes and OPCs, are unable to be rescued via CXCL12 lentivirus alone but instead required engraftment of CXCL12-expressing astrocytes for increased myelin expression. Our results show that TNFR2 activation induces CXCL12 expression in the demyelinated CC via autocrine signaling specifically within astrocytes, which promotes OPC proliferation and differentiation. In addition, gene delivery of critical pro-myelinating proteins might be a feasible approach for the treatment of remyelination failure in MS. © 2012 The Author(s).


Document Type: Article in Press
Source: Scopus

 

Kaufmann, W.A.a , Matsui, K.b , Jeromin, A.c , Nerbonne, J.M.d , Ferraguti, F.a
Kv4.2 potassium channels segregate to extrasynaptic domains and influence intrasynaptic NMDA receptor NR2B subunit expression
(2012) Brain Structure and Function, pp. 1-18. Article in Press. 
a Department of Pharmacology, Innsbruck Medical University, Peter-Mayr Strasse 1a, Innsbruck, 6020, Austria
b Division of Cerebral Structure, National Institute for Physiological Sciences, 444-8787, Myodaiji, Okazaki, Japan
c NextGen Sciences DX, 02110, Boston, United States
d Department of Developmental Biology, Washington University Medical School, St. Louis, MO, United States

 

Abstract
Neurons of the intercalated cell clusters (ITCs) represent an important relay site for information flow within amygdala nuclei. These neurons receive mainly glutamatergic inputs from the basolateral amygdala at their dendritic domains and provide feed-forward inhibition to the central nucleus. Voltage-gated potassium channels type-4.2 (Kv4.2) are main players in dendritic signal processing and integration providing a key component of the A currents. In this study, the subcellular localization and distribution of the Kv4.2 was studied in ITC neurons by means of light- and electron microscopy, and compared to other types of central principal neurons. Several ultrastructural immunolocalization techniques were applied including pre-embedding techniques and, most importantly, SDS-digested freeze-fracture replica labeling. We found Kv4.2 densely expressed in somato-dendritic domains of ITC neurons where they show a differential distribution pattern as revealed by nearest neighbor analysis. Comparing ITC neurons with hippocampal pyramidal and cerebellar granule cells, a cell type- and domain-dependent organization in Kv4.2 distribution was observed. Kv4.2 subunits were localized to extrasynaptic sites where they were found to influence intrasynaptic NMDA receptor subunit expression. In samples of Kv4.2 knockout mice, the frequency of NR1-positive synapses containing the NR2B subunit was significantly increased. This indicates a strong, yet indirect effect of Kv4.2 on the synaptic content of NMDA receptor subtypes, and a likely role in synaptic plasticity at ITC neurons. © 2012 The Author(s).


Author Keywords
Freeze-fracture replica;  Glutamatergic synapse;  Immuno-electron microscopy;  Nearest neighbor analysis;  Voltage-gated potassium channel


Document Type: Article in Press
Source: Scopus

 

DeJong, S.L.a , Birkenmeier, R.L.b , Lang, C.E.a b c
Person-specific changes in motor performance accompany upper extremity functional gains after stroke
(2012) Journal of Applied Biomechanics, 28 (3), pp. 304-316. 

a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
In animal models, hundreds of repetitions of upper extremity (UE) task practice promote neural adaptation and functional gain. Recently, we demonstrated improved UE function following a similar intervention for people after stroke. In this secondary analysis, computerized measures of UE task performance were used to identify movement parameters that changed as function improved. Ten people with chronic poststroke hemiparesis participated in high-repetition UE task-specific training 3 times per week for 6 weeks. Before and after training, we assessed UE function with the Action Research Arm Test (ARAT), and evaluated motor performance using computerized motion capture during a reach-grasp-transport-release task. Movement parameters included the duration of each movement phase, trunk excursion, peak aperture, aperture path ratio, and peak grip force. Group results showed an improvement in ARAT scores (p = .003). Although each individual changed significantly on at least one movement parameter, across the group there were no changes in any movement parameter that reached or approached significance. Changes on the ARAT were not closely related to changes in movement parameters. Since aspects of motor performance that contribute to functional change vary across individuals, an individualized approach to upper extremity motion analysis appears warranted. © 2012 Human Kinetics, Inc.


Author Keywords
Force;  Grasp;  Kinematic;  Reach


Document Type: Article
Source: Scopus

 

Azmeh, R.a , Lueder, G.T.a b
Delayed visual maturation in otherwise normal infants
(2012) Graefe's Archive for Clinical and Experimental Ophthalmology, pp. 1-4. Article in Press. 

a Departments of Ophthalmology and Visual Sciences and Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, United States
b St. Louis Children's Hospital, Washington University School of Medicine, One Children's Place (Rm 2s89), St. Louis, 63110, United States

Abstract
Background: Children may present in early infancy for evaluation of decreased visual responsiveness. Most such infants have systemic or ocular abnormalities that explain their poor fixation and tracking. Some infants, however, have no other medical or ocular problems. This study evaluated prognostic factors in this latter group of otherwise normal infants with decreased visual responsiveness. Methods: This was a retrospective cohort study in which medical records of infants evaluated for decreased visual responsiveness were reviewed to identify children who had no history of premature birth or systemic problems associated with developmental delay. Examination findings that were predicted to indicate a good prognosis included: the presence of some reaction to light, normal pupil responses, no nystagmus, and no structural ocular abnormalities. Follow-up information was obtained from office visits and telephone interviews. Main outcome measures were visual acuity and developmental status. Results: Thirty-two children met the criteria noted above. Six were excluded due to lack of follow-up. Four were normal by the time of their initial examination. Follow-up for the remaining patients ranged from 3 months to 11 years (mean 2.94 years). One patient developed strabismus and required surgery. The remaining patients all had normal vision and development. Conclusions: Otherwise normal infants who present for evaluation of decreased visual responsiveness have a good prognosis if they have some reaction to light, normal pupil responses, absence of nystagmus, and no structural ocular abnormalities. The developmental prognosis for these infants appears to be good. Additional testing at the time of initial evaluation is not indicated. © 2012 Springer-Verlag.


Author Keywords
Cortical inattention;  Delayed visual maturation


Document Type: Article in Press
Source: Scopus

 

Delamater, A.M.a , Patiño-Fernández, A.M.a , Smith, K.E.b , Bubb, J.c
Measurement of diabetes stress in older children and adolescents with type 1 diabetes mellitus
(2012) Pediatric Diabetes, . Article in Press. 

a Department of Pediatrics University of Miami School of Medicine Miami, FL USA
b Department of Pediatrics University of Texas Medical Branch at Galveston Galveston, TX USA
c Department of Pediatrics Washington University School of Medicine St. Louis, Missouri USA

Abstract
Objective: Studies indicate general psychological stress plays a role in the glycemic control of individuals with type 1 diabetes mellitus (T1DM). Disease-specific rather than general measures may be more closely related to measures of health outcomes. Therefore, measurement of diabetes-related stress is needed to advance knowledge of significant relationships between stress and glycemic control. The objective of this study was to evaluate the psychometric properties of a measure of diabetes-related stress for youth with T1DM. Research design and methods: A 65-item diabetes stress questionnaire for youths (DSQY) was previously developed for use with older children and adolescents. The DSQY was completed by 417 youths with T1DM and the results were analyzed to determine the factor structure and psychometric properties of the questionnaire, as well as relationships of diabetes stress with demographic and clinical variables. Results: A factor analysis of the DSQY yielded an eight-factor solution with acceptable internal consistencies. Significant relationships were observed between glycemic control and stress related to parents and dietary issues. While age and socioeconomic status were unrelated with DSQY scores, higher stress was associated with longer diabetes duration, female gender, and racial/ethnic minority status. Conclusions: The DSQY is a reliable and valid measure for assessment of diabetes-specific stress in youths with T1DM. © 2012 John Wiley & Sons A/S.


Author Keywords
Stress;  T1DM;  Youth


Document Type: Article in Press
Source: Scopus

 

de Pisapia, N.a b , Sandrini, M.a c d , Braver, T.S.e , Cattaneo, L.a
Integration in working memory: A magnetic stimulation study on the role of left anterior prefrontal cortex
(2012) PLoS ONE, 7 (8), art. no. e43731, . 

a CIMeC - Center for Mind/Brain Sciences, University of Trento, Rovereto (TN), Italy
b DiSCoF - Department of Cognitive Science and Education, University of Trento, Rovereto (TN), Italy
c Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Henry M. Jackson Foundation, Bethesda, MD, United States
d Human Cortical Physiology and Stroke Neuro-Rehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
e Cognitive Control and Psychopathology (CCP) Laboratory, Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Integration is a fundamental working memory operation, requiring the insertion of information from one task into the execution of another concurrent task. Previous neuroimaging studies have suggested the involvement of left anterior prefrontal cortex (L-aPFC) in relation to working memory integration demands, increasing during presentation of information to be integrated (loading), throughout its maintenance during a secondary task, up to the integration step, and then decreasing afterward (unloading). Here we used short bursts of 5 Hz repetitive Transcranic Magnetic Stimulation (rTMS) to modulate L-aPFC activity and to assess its causal role in integration. During experimental blocks, rTMS was applied (N = 10) over L-aPFC or vertex (control site) at different time-points of a task involving integration of a preloaded digit into a sequence of arithmetical steps, and contrasted with a closely matched task without integration demand (segregation). When rTMS was applied during the loading phase, reaction times during secondary task were faster, without significant changes in error rates. RTMS instead worsened performance when applied during information unloading. In contrast, no effects were observed when rTMS was applied during the other phases of integration, or during the segregation condition. These results confirm the hypothesis that L-aPFC is causally and selectively involved in the integration of information in working memory. They additionally suggest that pre-integration loading and post-integration unloading of information involving this area may be active and resource-consuming processes. © 2012 De Pisapia et al.


Document Type: Article
Source: Scopus

 

Kim, S.a , Cai, X.b , Hwang, J.c d , Lee, D.a
Prefrontal and striatal activity related to values of objects and locations
(2012) Frontiers in Neuroscience, (JULY), pp. 1-13. 
a Department of Neurobiology, Yale University School of Medicine, New Haven, CT, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY, United States
d Zanvyl Krieger Mind/Brain Institute, John Hopkins University, Baltimore, MD, United States

 

Abstract
The value of an object acquired by a particular action often determines the motivation to produce that action. Previous studies found neural signals related to the values of different objects or goods in the orbitofrontal cortex, while the values of outcomes expected from different actions are broadly represented in multiple brain areas implicated in movement planning. However, how the brain combines the values associated with various objects and the information about their locations is not known. In this study, we tested whether the neurons in the dorsolateral prefrontal cortex (DLPFC) and striatum in rhesus monkeys might contribute to translating the value signals between multiple frames of reference. Monkeys were trained to perform an oculomotor intertemporal choice in which the color of a saccade target and the number of its surrounding dots signaled the magnitude of reward and its delay, respectively. In both DLPFC and striatum, temporally discounted values (DVs) associated with specific target colors and locations were encoded by partially overlapping populations of neurons. In the DLPFC, the information about reward delays and DVs of rewards available from specific target locations emerged earlier than the corresponding signals for target colors. Similar results were reproduced by a simple network model built to compute DVs of rewards in different locations.Therefore, DLPFC might play an important role in estimating the values of different actions by combining the previously learned values of objects and their present locations.© 2012 Kim, Cai, Hwang and Lee.


Author Keywords
Intertemporal choice;  Prefrontal cortex;  Reward;  Temporal discounting;  Utility


Document Type: Article
Source: Scopus

 

Pearce, T.M., Moran, D.W.
Strategy-dependent encoding of planned arm movements in the dorsal premotor cortex
(2012) Science, 337 (6097), pp. 984-988.

Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
The kinematic strategy encoded in motor cortical areas for classic straight-line reaching is remarkably simple and consistent across subjects, despite the complicated musculoskeletal dynamics that are involved. As tasks become more challenging, however, different conscious strategies may be used to improve perceived behavioral performance. We identified additional spatial information that appeared both in single neurons and in the population code of monkey dorsal premotor cortex when obstacles impeded direct reach paths. The neural correlate of movement planning varied between subjects in a manner consistent with the use of different strategies to optimize task completion. These distinct planning strategies were manifested in the timing and strength of the information contained in the neural population code.


Document Type: Article
Source: Scopus

 

Sivagurunathan, S.a c , Schnittker, R.R.a , Razafsky, D.S.a d , Nandini, S.b , Plamann, M.D.a , King, S.J.a b
Analyses of dynein heavy chain mutations reveal complex interactions between dynein motor domains and cellular dynein functions
(2012) Genetics, 191 (4), pp. 1157-1179. 

a School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, United States
b Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States
c Department of Biology, Indiana University, Bloomington, IN 47405, United States
d Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Cytoplasmic dynein transports cargoes for a variety of crucial cellular functions. However, since dynein is essential in most eukaryotic organisms, the in-depth study of the cellular function of dynein via genetic analysis of dynein mutations has not been practical. Here, we identify and characterize 34 different dynein heavy chain mutations using a genetic screen of the ascomycete fungus Neurospora crassa, in which dynein is nonessential. Interestingly, our studies show that these mutations segregate into five different classes based on the in vivo localization of the mutated dynein motors. Furthermore, we have determined that the different classes of dynein mutations alter vesicle trafficking, microtubule organization, and nuclear distribution in distinct ways and require dynactin to different extents. In addition, biochemical analyses of dynein from one mutant strain show a strong correlation between its in vitro biochemical properties and the aberrant intracellular function of that altered dynein. When the mutations were mapped to the published dynein crystal structure, we found that the three-dimensional structural locations of the heavy chain mutations were linked to particular classes of altered dynein functions observed in cells. Together, our data indicate that the five classes of dynein mutations represent the entrapment of dynein at five separate points in the dynein mechanochemical and transport cycles. We have developed N. crassa as a model system where we can dissect the complexities of dynein structure, function, and interaction with other proteins with genetic, biochemical, and cell biological studies. © 2012 by the Genetics Society of America.


Document Type: Article
Source: Scopus

 

Shurtleff, T., Engsberg, J.
Long-term effects of hippotherapy on one child with cerebral palsy: A research case study
(2012) British Journal of Occupational Therapy, 75 (8), pp. 359-366. 

Program in Occupational Therapy, School of Medicine, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, MO 63108, United States

Abstract
Introduction: This case study followed a 6-year-old child with cerebral palsy for an additional 24 weeks after a 12-week pilot study of hippotherapy (HPOT). Method: Pre-post measures were performed using a video motion capture system before and after 12 weeks, showing head/trunk control improvements. Results: The third measure after 24 more weekly treatments showed no further improvement on the original variables. However, an unanticipated improvement in postural sway was found at the end of 9 months. Conclusion: This suggests that additional investigations are needed with more children with cerebral palsy over longer periods to identify outcomes from extended interventions beyond the 6-12 weeks of most published HPOT studies. Such further work could support better treatment planning and inform discharge criteria considering diminishing returns. The information would provide better evidence-based criteria for referrals and funding. This may make HPOT more accessible for those with disabilities who can benefit in specific and predictable ways. © The College of Occupational Therapists Ltd.


Author Keywords
Cerebral palsy;  Hippotherapy;  Intervention


Document Type: Article
Source: Scopus

 

Cluzeau, C.V.a , Watkins-Chow, D.E.b , Fu, R.a d , Borate, B.c , Yanjanin, N.a , Dail, M.K.a , Davidson, C.D.e , Walkley, S.U.e , Ory, D.S.f , Wassif, C.A.a , Pavan, W.J.b , Porter, F.D.a
Microarray expression analysis and identification of serum biomarkers for niemann-pick disease, type c1
(2012) Human Molecular Genetics, 21 (16), art. no. dds193, pp. 3632-3646. 

a Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda 3, MD 20892, United States
b Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892, United States
c Molecular Genetics Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, United States
d Health Science Center, Peking University, Beijing, 100191, China
e Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States
f Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1 -/- survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials. Published by Oxford University Press 2012.


Document Type: Article
Source: Scopus

 

Erickson, B.J.a , Pan, T.b , Marcus, D.S.c
Whitepapers on imaging infrastructure for research: Part 1: General workflow considerations
(2012) Journal of Digital Imaging, 25 (4), pp. 449-453. 

a Department of Radiology, 200 First Street SW, Rochester, MN 55905, United States
b Center for Comprehensive Informatics, Emory University, 201 Dowman Drive, Atlanta, GA 30322, United States
c Radiology Washington University School of Medicine, Campus Box 8225, 4525 Scott Ave, St. Louis, MO 63110, United States

Document Type: Article
Source: Scopus

 

Nolle, A.P., Gulbas, L., Kuhlberg, J.A., Zayas, L.H.
Sacrifice for the Sake of the Family: Expressions of Familism by Latina Teens in the Context of Suicide
(2012) American Journal of Orthopsychiatry, 82 (3), pp. 319-327. 

Washington University in St. Louis, United States

Abstract
Familism is a core value promoted by many individuals of Hispanic or Latino descent that emphasizes the primacy of the family over the individual. This study illuminates some aspects of the relationship between familism and adolescent suicidal behavior. Qualitative data from 24 female Hispanic teens with and without a history of suicidal behaviors and their parents were analyzed to understand the ways in which familism is expressed in their lives. Both suicide attempters and nonattempters demonstrate familism by making material or emotional (or both) sacrifices for the sake of their families. However, for those attempters who expressed a clear intent to die, a third type of sacrifice emerged: Girls expressed a desire to kill themselves in order to make things better for their families, literally sacrificing themselves for the sake of family. Findings point to the complexity of familism in understanding the risks of suicide attempts among teen Latinas and to the value of mixed methods in studying deeply the cultural factors that influence problem behaviors. © 2012 American Orthopsychiatric Association.


Author Keywords
Emotional sacrifice;  Familism;  Latina adolescents;  Material sacrifice;  Parents of Latina adolescents;  Suicidal behavior


Document Type: Article
Source: Scopus

 

Meyer, H.B.a , Katsman, A.b , Sones, A.C.c , Auerbach, D.E.d , Ames, D.e f , Rubin, R.T.e g
Yoga as an ancillary treatment for neurological and psychiatric disorders:A review
(2012) Journal of Neuropsychiatry and Clinical Neurosciences, 24 (2), pp. 152-164. 

a Dept. of Psychiatry, West Los Angeles VA Medical Center, United States
b The David Geffen School of Medicine, University of California at Los Angeles, United States
c Washington University in St. Louis, United States
d University of California at Berkeley, United States
e Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, United States
f Psychosocial Rehabilitation and Recovery Center, United States
g West Los Angeles VA Medical Center, United States

Abstract
Yoga is gaining acceptance as an ancillary medical treatment, but there have been few studies evaluating its therapeutic benefits in neurological and major psychiatric conditions. The authors reviewed the literature in English on the efficacy of yoga for these disorders. Only randomized, controlled trials were included, with the exception of the only study of yoga for bipolar disorder, which was observational. Trials were excluded if yoga was not the central component of the intervention. Of seven randomized, controlled trials of yoga in patients with neurological disorders, six found significant, positive effects. Of 13 randomized, controlled trials of yoga in patients with psychiatric disorders, 10 found significant, positive effects. These results, although encouraging, indicate that additional randomized, controlled studies are needed to critically define the benefits of yoga for both neurological and psychiatric disorders. © 2012 American Psychiatric Association.


Document Type: Review
Source: Scopus